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  • 1.
    Almroth, Gabriel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Lindell, Å
    Åselius, H
    Sörén, Lars
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Svensson, L
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Eribe, ERK
    Olsen, I
    Acute glomerulonephritis associated with streptococcus pyogenes with concomitant spread of streptococcus constellatus in four rural families2005In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 110, no 3, p. 217-231Article in journal (Refereed)
    Abstract [en]

    We studied history, renal histopathology and microbiology of an epidemic of acute glomerulonephritis associated with throat infections and uncommon culture results in four neighbour families. A 40-year-old man (index patient) was referred to a university hospital for dialysis and kidney biopsy due to a suspected acute glomerulonephritis. An acute tonsillitis had preceded the condition. Penicillin treatment had been started four days before the discovery of renal failure. Throat swabs were positive for β-hemolytic streptococci, group C (GCS). GCS were also found in throat cultures from his wife and two of their children. The bacteria were typed as Streptococcus constellatus. A third child had S. constellatus expressing Lancefield antigen group G. A neighbour and two of his children fell ill the following week with renal involvement. Throat swabs from both these children were positive for S. constellatus. His third child had erythema multiforme and S. constellatus in the throat while a fourth child had β-hemolytic streptococci group A, Streptococcus pyogenes. Kidney biopsies on the index patient and his neighbour showed an acute diffuse prolipherative glomerulonephritis compatible with acute post-streptococcal nephritis and microbiological analysis of renal tissue revealed in both cases S. pyogenes and S. constellatus. The families had had much contact and had consumed unpasteurized milk from our index patient's farm. In four of seven persons in two additional neighbouring families S. constellatus was found in throat swabs during the same month while two persons carried Streptococcus anginosus expressing the Lancefield C antigen. In conclusion spread of S. constellatus coincided with the occurrence of four cases of acute glomerulonephritis. The two biopsied patients had both S. pyogenes and S. constellatus present in renal tissue. The epidemic either suggested that the outbreak of glomerulonephritis was due to S. pyogenes but coincided with the transmission and colonization of S. constellatus or that the S. constellatus strains were highly pathogenic or nephritogenic and that this organism can be transmitted in such cases.

  • 2.
    Amarzguioui, Mohammed
    et al.
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Mucchiano, Gerd
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Häggqvist, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Kavlie, Anita
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Sletten, Knut
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Prydz, Hans
    The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, Oslo, Norway.
    Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation1998In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 242, no 3, p. 534-539Article in journal (Refereed)
    Abstract [en]

    In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.

  • 3.
    Bergdahl, Björn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Eintrei, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre, Department of Intensive Care UHL.
    Fyrenius, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Läkarutbildningen i Linköpings förnyas. Problembaserat lärande, basvetenskap och folkhälsa förstärks2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 102, no 38, p. 2654-2658Article in journal (Other academic)
  • 4.
    Cederbrant, K
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Gunnarsson, L G
    Marcusson, J
    Mercury intolerance and lymphocyte transformation test with nickel sulfate, palladium chloride, mercuric chloride, and gold sodium thiosulfate.2000In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 84, p. 140-144Article in journal (Refereed)
  • 5.
    Cederbrant, Karin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Anderson, C
    Andersson, T
    Marcusson-Ståhl, M
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Cytokine production, lymphocyte proliferation and T-cell receptor Vbeta expression in primary peripheral blood mononuclear cell cultures from nickel-allergic individuals2003In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 132, no 4, p. 373-379Article in journal (Refereed)
    Abstract [en]

    Background: Clinical history and patch test constitute the two cornerstones in the diagnosis of nickel (Ni) allergy. Due to technical and interpretative limits of the patch test, the in vitro lymphocyte transformation test (LTT) has been developed for confirming contact allergy, however, most studies show an overlap in lymphocyte proliferation between Ni-allergic and nonallergic subjects using the LTT. The aim of this study was to see if the secretion of cytokines, especially interleukin (IL)-10 and IL-17, or the use of T-cell receptor (TCR) V▀ families in Ni-stimulated primary peripheral blood mononuclear cell (PBMC) cultures might be more useful for discriminating between allergic and nonallergic subjects. Methods: Ni2+-stimulated primary PBMC cultures derived from female subjects diagnosed as Ni-allergic (n = 5) or nonallergic (n = 5) on the basis of a positive or negative patch test were assessed for cell proliferation by tritiated thymidine incorporation and for production of interferon-?, IL-4, IL-10 and IL-17 in the culture supernatant by ELISA. The immunophenotype and TCR-V▀ family affiliation of the Ni2+-induced lymphoblasts were determined by flow cytometry. Results: Lymphocytes from Ni-allergic individuals challenged with a high and a low concentration of Ni showed significantly higher cell proliferation than lymphocytes from nonallergic individuals, but all subjects showed a positive LTT result (stimulation index>2). We found a significantly higher release of IL-10 in Ni2+-treated cultures from Ni-allergic compared with nonallergic subjects that provided better separation between individuals in the two groups than did lymphocyte proliferation. The proliferating lymphoblasts were predominantly CD4+, and in 2 of the 5 Ni-allergic subjects, but in none of the 5 nonallergic subjects, the CD4+ lymphoblasts showed a dominance of TCR-V▀17. Conclusions: Determination of IL-10 production in primary PBMC cultures is a potentially promising in vitro method for discrimination of Ni allergy in females, as compared with cell proliferation. Copyright ⌐ 2003 S. Karger AG, Basel.

  • 6.
    Cederbrant, Karin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, L-G
    Department of Neurology and Neurophysiology and Centre for Environmental Sensitivity, Örebro Medical Centre Hospital, Örebro, Sweden.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Norda, R.
    Department of Transfusion Medicine and Immunohaemotherapy, Örebro Medical Centre Hospital, Örebro, Sweden.
    Tibbling-Grahn, L.
    Linköping University, Department of Neuroscience and Locomotion, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    In vitro Lymphoproliferative Assays with HgCl2 Cannot Identify Patients with Systemic Symptoms Attributed to Dental Amalgam1999In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 78, no 8, p. 1450-1458Article in journal (Refereed)
    Abstract [en]

    Dental amalgam is suspected, by some exposed individuals, to cause various systemic psychological, sensory, and neurological symptoms. Since not all amalgam-bearers experience such reactions, an individual characteristic—for example, a susceptible immune system—might explain these conditions. In vitro lymphocyte proliferation is a valuable tool in the diagnosis of allergy. With HgCl2 as the antigen, however, the test is hampered, because Hg2+ can cause unspecific lymphocyte proliferation, optimal at 1.4 to 9.5 μg HgCl2/mL. Recently, the use of suboptimal HgCl2 concentrations (≤ 0.5 μg/mL) has been suggested to circumvent these problems. The main aim of this study was to investigate whether patients with systemic symptoms alleged to result from the presence of dental amalgam differ from healthy controls, with reference to in vitro lymphoproliferative responses to HgCl2 ≤ 0.5 μg/mL. Three different test protocols—lymphocyte transformation test (LTT) in micro- and macro-cultures, and the memory lymphocyte immunostimulation assay (MELISA®)—were used. Other immune parameters—such as a standard patch test for dental materials, the number of T- and B-lymphocytes, monocytes, granulocytes, and NK cells in peripheral blood, allergic symptoms, and predisposition-were also investigated. Twenty-three amalgam patients, 30 healthy blood donors with amalgam, ten healthy subjects without amalgam, and nine patients with oral lichen planus (OLP) adjacent to dental amalgam and a positive patch test to Hg0 were tested. None of the investigated immune parameters revealed any significant differences between amalgam patients and controls. The sensitivity of in vitro lymphocyte proliferation ranged from 33 to 67%, with the OLP patients as a positive control group, and the specificity from 0 to 70% for healthy controls with a negative patch test to Hg°. Thus, despite the use of HgCl2 ≤ 0.5 μg/mL, a high frequency of positive results was obtained among healthy subjects with or without dental amalgam. Consequently, in vitro lymphocyte proliferation with HgCl2 cannot be used as an objective marker for mercury allergy in dental amalgam-bearers.

  • 7.
    Cederbrant, Karin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Characterization of mercuric mercury (Hg2+)-induced lymphoblasts from patients with mercury allergy and from healthy subjects2000In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 121, no 1, p. 23-30Article in journal (Refereed)
    Abstract [en]

    Hg2+ induces lymphocyte proliferation when added to cell cultures from both healthy and mercury-allergic subjects. Consequently, when measuring DNA synthesis a possible Hg2+-specific response, resulting from proliferating memory cells, cannot be discriminated from a non-allergic response. The mechanism behind this non-allergic response is unknown but a superantigenic effect of Hg2+ has been suggested. In this study, five mercury-allergic patients, with oral lichen planus (OLP) lesions adjacent to dental amalgam and a positive patch test to Hg0, and five healthy subjects without amalgam were examined. The immunophenotype and the T cell receptor Vβ (TCR Vβ) repertoire of Hg2+-induced lymphoblasts as well as the expression of the lymphocyte activation markers CD23 and CD134 were analysed for possible differences between healthy and allergic subjects. The mechanism of Hg2+-induced proliferation was examined by comparing the TCR Vβ expression of Hg- and staphylococcal enterotoxin B (SEB)-activated lymphoblasts, the latter used as a positive superantigen control. It was not possible to discriminate between mercury-allergic and healthy subjects using the immunophenotype or the TCR Vβ profile of the Hg2+-induced lymphoblasts or the expression of CD23 and CD134. However, Hg2+-induced CD4+ lymphoblasts showed a skewing towards Vβ2. This relative increase in Vβ2 was only detected in the CD4+ but not in the CD8+ lymphoblast population. In conclusion, Hg2+ induced a proliferation-dependent skewing towards CD4+ but not CD8+ lymphocytes expressing Vβ2. In this respect Hg2+ differs from the classical bacterial superantigen SEB, which also stimulates unique TCR Vβ families among CD8+ cells.

  • 8.
    Cederbrant, Karin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson-Ståhl, M.
    AstraZeneca R & D Södertälje, Safety Assessment, Department of Molecular Toxicology and Immunotoxicology, Södertälje, Sweden.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Characterization of primary recall in vitro lymphocyte responses to bacampicillin in allergic subjects2000In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 30, no 10, p. 1450-1459Article in journal (Refereed)
    Abstract [en]

    Background

    Antigen-specific cell lines or clones are often used as models of drug-specific allergy. However, cloning procedures are time consuming, and the repeated antigen stimulation cycles as well as the addition of various growth enhancers may affect the in vivo relevance of these systems.

    Objective

    Using bacampicillin-allergic subjects, we wanted to investigate the applicability of primary recall in vitro lymphocyte responses to characterize type I and type IV allergy. The sensitivity and specificity of LTT (Lymphocyte transformation test), when used as an in vitro diagnostic tool, were also assessed.

    Methods

    A total of 39 patients with symptoms of type I (rhinitis) or type IV (allergic contact dermatitis, ACD) allergy following occupational exposure to bacampicillin, were included. Ten individuals without penicillin allergy or occupational exposure to bacampicillin served as controls. All subjects were LTT tested. Four patients with rhinitis and two patients with ACD were available for studying the immunophenotype and the TCR-Vβ repertoire of bacampicillin induced lymphoblasts as well as the cytokine profiles and expression of the activation markers CD23 and CD134 in primary PBMC cultures.

    Results

    LTT was positive in 87% and at least one of the skin tests was positive in 85% of the patients with allergic symptoms. 69% of the patients with type I allergies were patch test-positive. Results from LTT and skin test correlated in 87% of the cases. The combined sensitivity of LTT and skin tests was 92%. The specificity of LTT was 90% in healthy controls. Bacampicillin induced lymphoblasts were mainly CD4 + in both ACD and rhinitis patients. The TCR-Vβ profiles of the predominant CD4 + lymphoblasts were heterogeneous with individual skewing towards Vβ2, Vβ3, Vβ5.1 and/or Vβ14. An increased expression of IFNγ was detected in bacampicillin treated PBMC cultures from the ACD but not from rhinitis patients. IL-5 was detected in bacampicillin exposed PBMC cultures from all patients but not from healthy controls. This Th2 environment could also be verified by CD23 and CD134 expression.

    Conclusion

    LTT and skin tests are equally sensitive in identifying bacampicillin allergic subjects. When the two tests are combined, the sensitivity increases. The patch test is useful not only for detection of type IV but also for the identification of type I allergies. When using primary PBMC cultures, IFNγ is the most suitable cytokine to discriminate between type I and type IV allergy. IL-5 can possibly be used as a general marker for bacampicillin induced allergy. Thus, primary cell cultures may be considered as an alternative to T-cell lines or clones for the study of drug induced allergy.

  • 9.
    Christiansen Clifford, Jenny
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Färm, Gunilla
    Department of Dermatology, University Hospital, 701 85 Örebro, Sweden.
    Eid-Forest, Ruth
    Department of Dermatology, University Hospital, 701 85 Örebro, Sweden.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Dermatology and Venerology UHL.
    Cederbrant, Karin
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology.
    Interferon-gamma secreted from peripheral blood mononuclear cells as a possible diagnostic marker for allergic contact dermatitis to gold2006In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 55, no 2, p. 101-112Article in journal (Refereed)
    Abstract [en]

    10% of patch-tested patients have a positive reaction to gold. Most lack clinical symptoms, but allergic contact dermatitis (ACD) to gold is increasing. In this study, 77 dermatological outpatients were divided into 3 groups depending on epicutaneous patch test outcomes: a group positive to gold (EPI+), a group negative to gold (EPI-), and a group with irritant reactions to gold (EPI-IR). Lymphocytes were stimulated in vitro with gold sodium thiosulfate. Proliferation was assessed using the lymphocyte transformation test (LTT), and cytokine secretion was assessed using a multibead array (Luminex; Linco Research Inc., St. Charles, MO, USA), in order to evaluate whether an in vitro method with high diagnostic accuracy could be devised. The EPI+ group showed a significantly increased secretion of interferon (IFN)-gamma, interleukin (IL)-2, and IL-13 and also showed a significantly higher stimulation indexes for LTT, compared to the other 2 subject groups. Sensitivity and specificity were calculated for all methods individually and combined, but IFN-gamma assessment alone was the most accurate method for identifying ACD to gold, with sensitivity and specificity of 81.8% and 82.1%, respectively. This method also identified 87.5% of the EPI-IR subjects as non-allergic. Therefore, assessment of secretion of IFN-gamma should be a valuable complement to patch test for diagnosing gold allergy.

  • 10.
    Eintrei, Christina
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre, Department of Intensive Care UHL.
    Bergdahl, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Fyrenius, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Revising a medical PBL-curriculum - the Linköping strategy2004In: Association for Medical Education in Europe,2004, 2004Conference paper (Other academic)
  • 11. Ellnebo-Svedlund, Katarina
    et al.
    Larsson, Lasse
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Jonasson, Jon
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Magnusson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Rapid genotyping of the osteoporosis-associated polymorphic transcription factor Sp1 binding site in the COL1A1 gene by pyrosequencing2004In: Molecular Biotechnology, ISSN 1073-6085, E-ISSN 1559-0305, Vol. 26, p. 87-90Article in journal (Refereed)
  • 12.
    Eneström, S
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Nilsson, A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Peen, E
    Transportation and storage of cryosections in PBS-Dulbecco.1999In: Biotechnic & Histochemistry, ISSN 1052-0295, E-ISSN 1473-7760, Vol. 74, p. 34-39Article in journal (Refereed)
  • 13. Erga, KS
    et al.
    Peen, E
    Eneström, S
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Reed, RK
    Effects of lactoferrin on rat dermal interstitial fluid pressure (Pif) and in vitro endothelial barrier function2001In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 171, no 4, p. 419-425Article in journal (Refereed)
    Abstract [en]

    We recently demonstrated that intravenous (i.v.) injection of the iron-binding protein lactoferrin (Lf) followed by antilactoferrin (aLf) antibodies or iron-saturated Lf alone increased albumin extravasation in vivo in several tissues including skin. Increased driving pressure for blood-tissue exchange or direct effects of Lf on the endothelial barrier are possible mechanisms. We therefore, firstly, measured interstitial fluid pressure (Pif) in dermis of rats given 1 mg Lf i.v. followed 30 min later by aLf or saline and circulatory arrest 1 or 5 min thereafter and compared with controls. Secondly, transmonolayer passage of Evans blue labelled albumin (EB-albumin) was evaluated in porcine pulmonary artery endothelial cells exposed to iron-free or iron-saturated Lf (both 100 ╡g mL-1) in the absence and presence of 0.5 mM hydrogen peroxide. Pif increased significantly at 11-30 min following Lf to +2.1 ▒ 0.3 and +1.7 ▒ 0.2 mmHg at 11-20 and 21-30 min, respectively, compared with +0.1 ▒ 0.2 mmHg before Lf (P < 0.05, n = 25). Endothelial transmonolayer passage of EB-albumin during 3 h was not affected by iron-free or iron-saturated Lf neither in the absence nor presence of hydrogen peroxide that increased passage 3.5 times compared with controls. In conclusion, Lf-induced increase in albumin extravasation in rat skin is not explained by changes in Pif (because Lf raised Pif significantly) or direct effects of Lf on the endothelial barrier.

  • 14.
    Gunnarsson, Tove
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Östergötlands Läns Landsting, Reconstruction Centre, Department of Neurosurgery UHL.
    Leszniewski, W
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Östergötlands Läns Landsting, Reconstruction Centre, Department of Neurosurgery UHL.
    Bak, Julia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Davidsson, L
    An intradural cervical chordoma mimicking a neurinoma. Case illustration.2001In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 95, p. 144-144Article in journal (Refereed)
  • 15.
    Hammar, Mats
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Tagesson, Christer
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Strålning, cancer och forskarutbildning2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104Article in journal (Other academic)
  • 16.
    Havarinasab, Said
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Björn, Erik
    Umeå Universitet.
    Ekstrand, Jimmy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Dose and Hg species determine the T-helper cell activation in murine autoimmunity2007In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 229, no 1-2, p. 23-32Article in journal (Refereed)
    Abstract [en]

    Inorganic mercury (mercuric chloride-HgCl2) induces in mice an autoimmune syndrome (HgIA) with T cell-dependent polyclonal B cell activation and hypergammaglobulinemia, dose- and H-2-dependent production of autoantibodies targeting the 34 kDa nucleolar protein fibrillarin (AFA), and systemic immune-complex deposits. The organic mercury species methylmercury (MeHg) and ethylmercury (EtHg-in the form of thimerosal) induce AFA, while the other manifestations of HgIA seen after treatment with HgCl2 are present to varying extent. Since these organic Hg species are converted to the autoimmunogen Hg2+ in the body, their primary autoimmunogen potential is uncertain and the subject of this study. A moderate dose of HgCl2 (8 mg/L drinking water - internal dose 148 μg Hg/kg body weight [bw]/day) caused the fastest AFA response, while the induction was delayed after higher (25 mg/L) and lower (1.5 and 3 mg/L) doses. The lowest dose of HgCl2 inducing AFA was 1.5 mg/L drinking water which corresponded to a renal Hg2+ concentration of 0.53 μg/g. Using a dose of 8 mg HgCl2/L this threshold concentration was reached within 24 h, and a consistent AFA response developed after 8-10 days. The time lag for the immunological part of the reaction leading to a consistent AFA response was therefore 7-9 days. A dose of thimerosal close to the threshold dose for induction of AFA (2 mg/L drinking water-internal dose 118 μg Hg/kg bw per day), caused a renal Hg2+ concentration of 1.8 μg/g. The autoimmunogen effect of EtHg might therefore be entirely due to Hg2+ formed from EtHg in the body. The effect of organic and inorganic Hg species on T-helper type 1 and type 2 cells during induction of AFA was assessed as the presence and titre of AFA of the IgG1 and IgG2a isotype, respectively. EtHg induced a persistent Th1-skewed response irrespectively of the dose and time used. A low daily dose of HgCl2 (1.5-3 mg/L) caused a Th1-skewed AFA response, while a moderate dose (8 mg/L) after 2 weeks resulted in a balanced or even Th2-skewed response. Higher daily doses of HgCl2 (25 mg/L) caused a balanced Th2-Th1 response already from onset. In conclusion, while metabolically formed Hg2+ might be the main AFA-inducing factor also after treatment with EtHg, the quality of the Hg-induced AFA response is modified by the species of Hg as well as the dose. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 17.
    Havarinasab, Said
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Björn, Erik
    Umeå Universitet.
    Nielsen, Jesper B.
    Danmark.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mercury species in lymphoid and non-lymphoid tissues after exposure to methyl mercury: Correlation with autoimmune parameters during and after treatment in susceptible mice2007In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 221, no 1, p. 21-28Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is present in the environment as a result of the global cycling of mercury, although anthropogenic sources may dramatically increase the availability in confined geographical areas. Accumulation of MeHg in the aquatic food chain is the dominating way of exposure in mammals, which accumulate MeHg in all organs, including the brain. Demethylation has been described in the organs, especially in phagocytic cells, but mainly in the flora of the intestinal tract. While most of the inorganic mercury (Hg2+) formed in the intestine is excreted, a fraction is reabsorbed which together with the local demethylation increases the organ Hg2+ concentration. MeHg is a well-known immunosuppressive agent, while Hg2+ is associated with immunostimulation and autoimmunity especially in genetically susceptible rodents, creating a syndrome, i.e. mercury-induced autoimmunity (HgIA). This study aimed at exploring the effect of MeHg with regard to HgIA, and especially the immunological events after stopping treatment, correlated with the presence of MeHg and Hg2+ in the organs. Treatment of A.SW mice for 30 days with 4.2 mg MeHg/L drinking water (corresponding to approximately 420 μg Hg/kg body weight/day) caused all the HgIA features observed after primary treatment with inorganic Hg, except systemic immune complex deposits. The total Hg concentration was 5-fold higher in the kidneys as compared with lymph nodes, but the fraction of Hg2+ was similar (17-20%). After stopping treatment, the renal and lymph node MeHg concentration declined according to first order kinetics during the initial 4-6 weeks, but then slower. A similar decline in the organ Hg2+ concentration occurred during the initial 2 weeks after stopping treatment but then ceased, causing the Hg2+ concentration to exceed that of MeHg in the lymph nodes and kidneys after 3 and 8 weeks, respectively. The selective increase in lymph node Hg2+ fraction is likely to be due to demethylation of MeHg in the macrophage-rich lymphoid tissue. The major autoantibody in HgIA, anti-fibrillarin antibodies, tended to increase during the initial 6 weeks after stopping treatment, while all other HgIA features including antichromatin antibodies declined to control levels after 2-4 weeks. This indicates differences in either dose requirement or induction mechanisms for the different HgIA parameters. The selective accumulation of Hg2+ in lymph nodes following MeHg treatment should be taken into account when the effect of MeHg on the immune system is evaluated. © 2007 Elsevier Inc. All rights reserved.

  • 18.
    Havarinasab, Said
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Johansson, Uno
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Pollard, KM
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Gold causes genetically determined autoimmune and immunostimulatory responses in mice2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 150, no 1, p. 179-188Article in journal (Refereed)
    Abstract [en]

    Natrium aurothiomaleate (GSTM) is a useful disease-modifying anti-rheumatic drug, but causes a variety of immune-mediated adverse effects in many patients. A murine model was used to study further the interaction of GSTM with the immune system, including induction of systemic autoimmunity. Mice were given weekly intramuscular injections of GSTM and controls equimolar amounts of sodium thiomaleate. The effects of gold on lymphocyte subpopulations were determined by flow cytometry. Humoral autoimmunity was measured by indirect immunofluorescence and immunoblotting, and deposition of immunoglobulin and C3 used to assess immunopathology. Gold, in the form of GSTM, stimulated the murine immune system causing strain-dependent lymphoproliferation and autoimmunity, including a major histocompatibility complex (MHC)-restricted autoantibody response against the nucleolar protein fibrillarin. GSTM did not cause glomerular or vessel wall IgG deposits. However, it did elicit a strong B cell-stimulating effect, including both T helper 1 (Th1)- and Th2-dependent isotypes. All these effects on the immune system were dependent on the MHC genotype, emphasizing the clinical observations of a strong genetic linkage for the major adverse immune reactions seen with GSTM treatment. © 2007 British Society for Immunology.

  • 19.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Environmental factors that contribute to autoimmunity.2006In: Autoantibodies and autoimmunity.: molecular mechanisms in health and disease / [ed] Michael Pollard, 2006, 1, p. 519-541Chapter in book (Other academic)
    Abstract [en]

    This is the first book to address all aspects of the biology of autoantibodies in a single volume, including a discussion of immunology, experimental models, clinical aspects, and the use of autoantibodies as probes in molecular and cellular biology. The editor, currently professor at the W.M. Keck Autoimmune Disease Center of The Scripps Research Institute, has assembled an all-star team of authors to report on the latest research, technologies, and applications. Following an introductory chapter, the book goes on to cover such topics as cellular mechanisms of autoantibody production, clinical and diagnostic usefulness in human disease, and animal models used to study the elicitation of autoantibodies. The whole is rounded off with a look at future perspectives. With its comprehensive coverage, this volume will appeal not only to immunologists and clinicians but also to cell and molecular biologists.

  • 20.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Environmental factors that contribute to autoimmunity.2005In: Autoantibodies and autoimmunity: molecular mechanisms in health and disease / [ed] Michael Pollard., WileyVCH , 2005, 1, p. 519-541Chapter in book (Other academic)
    Abstract [en]

    This is the first book to address all aspects of the biology of autoantibodies in a single volume, including a discussion of immunology, experimental models, clinical aspects, and the use of autoantibodies as probes in molecular and cellular biology. The editor, currently professor at the W.M. Keck Autoimmune Disease Center of The Scripps Research Institute, has assembled an all-star team of authors to report on the latest research, technologies, and applications. Following an introductory chapter, the book goes on to cover such topics as cellular mechanisms of autoantibody production, clinical and diagnostic usefulness in human disease, and animal models used to study the elicitation of autoantibodies. The whole is rounded off with a look at future perspectives.With its comprehensive coverage, this volume will appeal not only to immunologists and clinicians but also to cell and molecular biologists.

  • 21.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Immunotoxicology of metals2007In: Handbook on the toxicology of metals / [ed] Gunnar F. Nordberg, Elsevier , 2007, 3, p. 197-211Chapter in book (Other academic)
    Abstract [en]

    Handbook of the Toxicology of Metals is the standard reference work for physicians, toxicologists and engineers in the field of environmental and occupational health. This new edition is a comprehensive review of the effects on biological systems from metallic elements and their compounds. An entirely new structure and illustrations represent the vast array of advancements made since the last edition. Special emphasis has been placed on the toxic effects in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-to-date reference provides easy access to a broad range of basic toxicological data and also gives a general introduction to the toxicology of metallic compounds. * Covers up-to-date toxicological information on 31 metallic elements and their compounds, each in a separate chapter * New chapters on general chemistry, biological monitoring and biomarkers, essential metals, principles for prevention of the toxic effects of metals, and more

  • 22.
    Hultman, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Hansson-Georgiadis, H
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Methyl mercury-induced autoimmunity in mice. 1999In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 154, p. 203-211Article in journal (Refereed)
  • 23.
    Hultman, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Nielsen, J
    The effect of dose, gender, and non-H-2 genes in murine mercury-induced autoimmunity2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 17, no 1, p. 27-37Article in journal (Refereed)
    Abstract [en]

    We have studied the effect of dose, treatment time, gender and non-H-2 genes on immune parameters and toxicokinetics in murine mercury-induced autoimmunity (HgAI). The partly-proven mechanism for HgAI is the modification of the autoantigen fibrillarin by mercury, followed by a T cell-dependent immune response driven by the modified fibrillarin. In the H-2 congenic (H-2S) mouse strains A.SW and B10.S given 203HgCl2 in a dose of 0.25-8 mg Hg/l drinking water for up to 10 weeks, the internal dose measured as the whole-body retention of mercury reached steady state within 5 weeks. Fifty percent of the steady state level was reached already after 2 days. Conditions therefore exist for a rapid modification of fibrillarin, followed by a T cell-dependent immune response, which is consistent with the presence of anti-fibrillarin antibodies (AFA) in serum after 2 weeks. AFA developed in a dose-dependent pattern. Serum IgE showed a dose-dependent increase with a maximum after 1-2.5 weeks followed by a distinct decline towards the baseline level. Substantial polyclonal B-cell activation (PBA) developed in the highest dose groups only. Since AFA developed using lower doses too, PBA can be excluded as a general mechanism for induction of AFA. Tissue immune-complex (IC) deposits were present in the highest dose groups only, indicating a possible causality between PBA and IC deposits. The substantially lower whole body and organ mercury level needed to induce AFA in the A.SW strain as compared with the H-2 congenic B10.S strain, demonstrates that genetic factors outside the H-2 region, and not related to toxicokinetics, modifies the autoimmune response. In contrast, the difference in mercury thresholds for induction of IgE was only slight between A.SW and B10.S mice, indicating basically different mechanisms for induction of AFA and serum IgE.

  • 24.
    Häggqvist, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Studies on cytokines in experimental metal-induced systemic autoimmunity2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The effect on the imnnme system of inorganic mercury (Hg), organic mercury (methyl mercury-MeHg), and silver was examined in mouse strains genetically susceptible or resistant to metal-induced systemic autoimmunity (MIA). The major aim was to study the cytokine mRNA expression in the immune system of metal-treated mice, and relate these findings to the different parameters of MIA.

    Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay (RPA) and phosphorimaging. The baseline expression of IL-2 and IFN-γ mRNA was higher in a strain (A.SW) susceptible to induction of MIA, compared with a resistant strain (A.TL). In A.SW mice Hg treatment caused early upregulation of IL-2 and IFN-γ mRNA expression, followed by substantial expression of IL-4 mRNA, and induction of antifibrillarin antibodies (AFA), lymphoproliferation and systemic immune-complex (IC) deposits. Hg treatment caused in MIA-resistant A.TL mice unchanged expression of IFN-γ mRNA, but reduced IL-2 expression. A major difference between A.SW and A.TL mice was the greatly increased IL-10 mRNA expression in the latter strain. Silver treatment of A.SW mice, which leads to a modified MIA with AFA, minimal lymphoproliferation, but no IC deposits, caused an early increase of IL-2 and IFN-γ mRNA, but only a slight increase of IL-4 mRNA.

    The observation of a preferential expression of IL-10 mRNA in Hg-treated genetically MIA-resistant mice was further examined by using a strain with a targeted mutation for the IL-10 gene, as well as treatruent of genetically susceptible mice with recombinaot IL-10 (rIL-10). The IL-10 deficient strain did not develop AFA during Hg treatment, but showed a significant increase in antinuclear antibodies with a homogeneous pattern and a higher serum lgE concentration compared with Hg-treated resistant mice lacking the IL-10 mutation. The susceptible A.SW strain showed during intense treabnent with riL-10 and Hg a reduced induction of AFA, antichromalin antibodies (ACA), and serum IgE, as compared with A.SW mice only receiving Hg.

    The paradigm of T helper cells type 1 (Th1) aod 2 (Th2) is often discussed in the pathogenesis of autoimmnne diseases. MIA has many characteristics of a Th2 type of reaction, but the disease induction is critically depeodent on the Th1 cytokine IFN-γ. In order to study the relevance of the Th1/Th2 concept for MIA, and to see if the disease could be aggravated by a strong deviation towards Th1, rIL-12 was given in combination with anti-IL-4 monoclonal aotibody (Mab) during treatmeut with Hg to the susceptible A.SW strain. The combined treatment reduced the Th2-dependent serum Ig isotypes, but increased the Th1-dependent IgG2a isotype. The IgG-AFA developed earlier and attained a higher titre. The renal IC deposits were severely reduced after combined treatment during the induction phase. Treatment with rIL-12 + Hg increased the Th1-dependent AFA of the IgG2a isotype, the polyclonal B-cell activation (PBA), and the IC deposits in renal and splenic vessel wall. Using only anti-IL-4 Mab during induction of MIA, the Th2-dependent serum IgG isotypes were reduced, while the development of AFA was not affected. The renal vessel wall IC deposits were reduced while the splenic vessel wall deposits were unaffected.

    A previous study showed that the organic mercury compound MeHg causes a different MIA pattern than Hg. In order to examine the relation between cytokine expression and different MIA parameters, susceptible A.SW mice were treated with MeHg, which caused an initial immunosuppression especially with regard to B-cells. The immunosuppression was superseded by a modest induction of AFA and IL-4 mRNA, but a lack of increase in IL-2 and IFN-γ mRNA, PBA, and systemic IC deposits. While increasing the dose ofMeHg accelerated and increased AFA development, the immuno-stimulation or IC deposits could not be aggravated. Speciation of mercury showed that the organ content of MeHg and Hg gradually increased.

    List of papers
    1. Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains
    Open this publication in new window or tab >>Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains
    2001 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 126, no 1, p. 157-164Article in journal (Refereed) Published
    Abstract [en]

    Cytokines play an important and complex role in the pathogenesis of systemic autoimmune diseases. In susceptible H-2s mice, inorganic mercury (Hg) induces lymphoproliferation, antinucleolar antibodies against the 34-kDa-protein fibrillarin, and systemic immune-complex (IC) deposits. Here, we report extensive analysis of cytokine mRNA levels in susceptible A.SW (H-2s) and resistant A.TL (H-2tl) mice under unstimulated conditions and during oral treatment with Hg and/or silver nitrate (Ag). Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay and phosphorimaging. Baseline expression of IL-2 and IFN-γ mRNA was higher in A.SW than in A.TL mice. In A.SW mice, Hg treatment caused early up-regulation of IL-2 and IFN-γ levels, followed by substantial expression of IL-4 mRNA, which was significant compared to control A.SW and Hg-treated A.TL mice. Hg-exposed A.TL mice exhibited unchanged IFN-γ, reduced IL-2 and greatly increased IL-10 mRNA expression. Ag-treated A.SW mice, which develop antifibrillarin antibodies (AFA) but exhibit minimal immune activation and no IC deposits, showed an early increase in IL-2 and IFN-γ mRNA, but only a small and delayed rise in IL-4 mRNA. In conclusion, H-2-linked resistance to Hg-induced AFA is characterized by low constitutive expression of IL-2 and IFN-γ mRNA, which is not increased by Hg, and a marked increase in IL-10 expression. Conversely, the key features of H-2-linked susceptibility to Hg- and Ag-induced AFA are up-regulation of IL-2, IFN-γ and IL-4 mRNA expression, and down-regulation of IL-10 expression.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25960 (URN)10.1046/j.1365-2249.2001.01636.x (DOI)10408 (Local ID)10408 (Archive number)10408 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    2. IL-10 is not a major determinant for resistance to murine mercury-induced systemic autoimmunity
    Open this publication in new window or tab >>IL-10 is not a major determinant for resistance to murine mercury-induced systemic autoimmunity
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.

    The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.

    The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84778 (URN)
    Available from: 2012-10-22 Created: 2012-10-22 Last updated: 2012-10-22Bibliographically approved
    3. Effects of deviating the Th2-response in murine mercury-induced autoimmunity towards a Th1-response
    Open this publication in new window or tab >>Effects of deviating the Th2-response in murine mercury-induced autoimmunity towards a Th1-response
    2003 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 134, no 2, p. 202-209Article in journal (Refereed) Published
    Abstract [en]

    T-helper cells type 1 (Th1) and type 2 (Th2) play an important role in the pathogenesis of autoimmune diseases. In many Th1-dependent autoimmune models, treatment with recombinant interleukin-12 (rIL-12) accelerates the autoimmune response. Mercury-induced autoimmunity (HgIA) in mice is an H-2 regulated condition with antinucleolar antibodies targeting fibrillarin (ANoA), systemic immune-complex (IC) deposits and transient polyclonal B-cell activation (PBA). HgIA has many characteristics of a Th2 type of reaction, including a strong increase of IgE, but disease induction is critically dependent on the Th1 cytokine IFN-γ. The aim of this study was to investigate if a strong deviation of the immune response in HgIA towards Th1 would aggravate HgIA. Injections of both rIL-12 and anti-IL-4 monoclonal antibody (α-IL-4) reduced the HgCl2-(Hg-)induced concentration of the Th2-dependent serum IgE and IgG1, but increased the Th1-dependent serum IgG2a. The IgG-ANoA developed earlier and attained a higher titre after combined treatment, and the ANoA titre of the IgG1 isotype decreased while the ANoA titre of the Th1-associated IgG2a, IgG2b and IgG3-ANoA isotypes increased. Treatment with rIL-12 alone increased the Hg-induced IgG2a and IgG3 ANoA titres, the PBA, and the IC deposits in renal and splenic vessel walls, while treatment with α-IL-4 + Hg inhibited renal but not splenic vessel wall IC deposits. We conclude that manipulating the cytokine status, by altering the Th1/Th2 balance, will influence autoimmune disease manifestations. This might be an important way of modulating human autoimmune diseases.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26489 (URN)10.1046/j.1365-2249.2003.02303.x (DOI)11045 (Local ID)11045 (Archive number)11045 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    4. The immunosuppressive effect of methylmercury does not preclude development of autoimmunity in genetically susceptible mice
    Open this publication in new window or tab >>The immunosuppressive effect of methylmercury does not preclude development of autoimmunity in genetically susceptible mice
    2005 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 208, no 1, p. 149-164Article in journal (Refereed) Published
    Abstract [en]

    Methylmercury (MeHg) is a common environmental pollutant due to both natural and anthropogenic sources. Although the central nervous system (CNS) is considered the critical organ for the toxic effect of MeHg, it has recently been suggested that the immune system might be at least as sensitive as the CNS.

    We have examined the effects of MeHg on the immune system in genetically metal-susceptible mice. Subcutaneous (sc) injections of 2 mg MeHg/kg body weight (bw) every third day (internal dose ca. 540 μg Hg/kg bw/day) to A.SW mice of the H-2s haplotype, caused during the first week a 47 and 9% reduction of B- and T-cells, respectively, which indicates immunosuppression. Subsequently, an autoimmune syndrome developed which shared certain features with the syndrome induced by inorganic mercury in H-2s mice, including antibodies targeting the 34 kDa nucleolar protein fibrillarin, increased expression of IL-4 mRNA, increase of Th2-type of immunoglobulins (IgE and IgG1), and increased MHC class II expression on B-cells. However, the response using MeHg was attenuated compared with even lower doses of Hg in the form of inorganic mercury, and specifically lacked the increased expression of IL-2 and IFN-γ mRNA, the polyclonal B-cell activation (PBA), and the systemic immune-complex (IC) deposits which are induced by inorganic mercury. Increasing the dose of MeHg increased the titre of anti-nucleolar antibodies and shortened the induction time, but did not lead to stronger immunostimulation or systemic IC-deposits. The kidney and liver selectively accumulated MeHg, while the blood, spleen and lymph nodes showed lower levels of MeHg. The accumulation of MeHg and Hg2+ increased throughout the 30-day period. The fraction of Hg2+ in the kidney varied between 4 and 22%, and the lymph nodes showed a maximum of 30% Hg2+.

    We conclude first that MeHg has quantitatively different effect on the immune system compared with inorganic mercury, and secondly that an initial immunosuppression induced by a xenobiotic does not preclude subsequent immunostimulation and autoimmunity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-30139 (URN)10.1016/j.tox.2004.11.020 (DOI)15619 (Local ID)15619 (Archive number)15619 (OAI)
    Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
  • 25.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Havarinasab, Said
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Björn, Erik
    Analytical Chemistry, Department of Chemistry, Umeå University, Umeå, Sweden.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    The immunosuppressive effect of methylmercury does not preclude development of autoimmunity in genetically susceptible mice2005In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 208, no 1, p. 149-164Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is a common environmental pollutant due to both natural and anthropogenic sources. Although the central nervous system (CNS) is considered the critical organ for the toxic effect of MeHg, it has recently been suggested that the immune system might be at least as sensitive as the CNS.

    We have examined the effects of MeHg on the immune system in genetically metal-susceptible mice. Subcutaneous (sc) injections of 2 mg MeHg/kg body weight (bw) every third day (internal dose ca. 540 μg Hg/kg bw/day) to A.SW mice of the H-2s haplotype, caused during the first week a 47 and 9% reduction of B- and T-cells, respectively, which indicates immunosuppression. Subsequently, an autoimmune syndrome developed which shared certain features with the syndrome induced by inorganic mercury in H-2s mice, including antibodies targeting the 34 kDa nucleolar protein fibrillarin, increased expression of IL-4 mRNA, increase of Th2-type of immunoglobulins (IgE and IgG1), and increased MHC class II expression on B-cells. However, the response using MeHg was attenuated compared with even lower doses of Hg in the form of inorganic mercury, and specifically lacked the increased expression of IL-2 and IFN-γ mRNA, the polyclonal B-cell activation (PBA), and the systemic immune-complex (IC) deposits which are induced by inorganic mercury. Increasing the dose of MeHg increased the titre of anti-nucleolar antibodies and shortened the induction time, but did not lead to stronger immunostimulation or systemic IC-deposits. The kidney and liver selectively accumulated MeHg, while the blood, spleen and lymph nodes showed lower levels of MeHg. The accumulation of MeHg and Hg2+ increased throughout the 30-day period. The fraction of Hg2+ in the kidney varied between 4 and 22%, and the lymph nodes showed a maximum of 30% Hg2+.

    We conclude first that MeHg has quantitatively different effect on the immune system compared with inorganic mercury, and secondly that an initial immunosuppression induced by a xenobiotic does not preclude subsequent immunostimulation and autoimmunity.

  • 26.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Effects of deviating the Th2-response in murine mercury-induced autoimmunity towards a Th1-response2003In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 134, no 2, p. 202-209Article in journal (Refereed)
    Abstract [en]

    T-helper cells type 1 (Th1) and type 2 (Th2) play an important role in the pathogenesis of autoimmune diseases. In many Th1-dependent autoimmune models, treatment with recombinant interleukin-12 (rIL-12) accelerates the autoimmune response. Mercury-induced autoimmunity (HgIA) in mice is an H-2 regulated condition with antinucleolar antibodies targeting fibrillarin (ANoA), systemic immune-complex (IC) deposits and transient polyclonal B-cell activation (PBA). HgIA has many characteristics of a Th2 type of reaction, including a strong increase of IgE, but disease induction is critically dependent on the Th1 cytokine IFN-γ. The aim of this study was to investigate if a strong deviation of the immune response in HgIA towards Th1 would aggravate HgIA. Injections of both rIL-12 and anti-IL-4 monoclonal antibody (α-IL-4) reduced the HgCl2-(Hg-)induced concentration of the Th2-dependent serum IgE and IgG1, but increased the Th1-dependent serum IgG2a. The IgG-ANoA developed earlier and attained a higher titre after combined treatment, and the ANoA titre of the IgG1 isotype decreased while the ANoA titre of the Th1-associated IgG2a, IgG2b and IgG3-ANoA isotypes increased. Treatment with rIL-12 alone increased the Hg-induced IgG2a and IgG3 ANoA titres, the PBA, and the IC deposits in renal and splenic vessel walls, while treatment with α-IL-4 + Hg inhibited renal but not splenic vessel wall IC deposits. We conclude that manipulating the cytokine status, by altering the Th1/Th2 balance, will influence autoimmune disease manifestations. This might be an important way of modulating human autoimmune diseases.

  • 27.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    IL-10 is not a major determinant for resistance to murine mercury-induced systemic autoimmunityManuscript (preprint) (Other academic)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.

    The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.

    The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.

  • 28.
    Häggqvist, Bo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Interleukin-10 in murine metal-induced systemic autoimmunity2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 3, p. 422-431Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown aetiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive functions in the immune system have lately received much interest. One of the cytokines in focus in this respect is interleukin (IL)-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on the induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation of the IL-10 gene in a strain resistant to heavy metal-induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A.SW strain during the induction of autoimmunity by metals. The wild-type C57BL/6 J (B6-WT) strain did not react with lymphoproliferation, polyclonal B cell activation, anti-nucleoar autoantibodies (ANoA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, serum IgG1 and IgE showed a modest increase during Hg treatment, while Ag caused a weak increase in IgE and IgG2a. The B6-129P2-Il10tm1Cgn/J strain (IL-10-deficient mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but showed a higher median titre of homogeneous ANA compared with Hg-treated B6-WT mice. Both control and Hg-treated (but not Ag-treated) IL-10-deficient mice showed an increase in splenic weight and serum IgG1 compared with B6-WT control and Hg-treated mice. An early, significant increase in serum IgE was seen in Hg-treated IL-10-deficient and WT mice compared with the controls, the increase was 42- and sixfold, respectively. During ongoing intense treatment with rIL-10 in combination with Hg the susceptible A.SW mice showed a reduced development of ANoA and antichromatin antibodies, as well as serum IgE, compared with mice receiving Hg but not rIL-10. In conclusion, IL-10 suppresses several aspects of HgIA, but is not crucial for resistance to heavy metal-induced autoimmunity. Peroral silver treatment suppresses the spontaneous immune activation seen in IL-10-deficient mice. © 2005 British Society for Immunology.

  • 29.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains2001In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 126, no 1, p. 157-164Article in journal (Refereed)
    Abstract [en]

    Cytokines play an important and complex role in the pathogenesis of systemic autoimmune diseases. In susceptible H-2s mice, inorganic mercury (Hg) induces lymphoproliferation, antinucleolar antibodies against the 34-kDa-protein fibrillarin, and systemic immune-complex (IC) deposits. Here, we report extensive analysis of cytokine mRNA levels in susceptible A.SW (H-2s) and resistant A.TL (H-2tl) mice under unstimulated conditions and during oral treatment with Hg and/or silver nitrate (Ag). Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay and phosphorimaging. Baseline expression of IL-2 and IFN-γ mRNA was higher in A.SW than in A.TL mice. In A.SW mice, Hg treatment caused early up-regulation of IL-2 and IFN-γ levels, followed by substantial expression of IL-4 mRNA, which was significant compared to control A.SW and Hg-treated A.TL mice. Hg-exposed A.TL mice exhibited unchanged IFN-γ, reduced IL-2 and greatly increased IL-10 mRNA expression. Ag-treated A.SW mice, which develop antifibrillarin antibodies (AFA) but exhibit minimal immune activation and no IC deposits, showed an early increase in IL-2 and IFN-γ mRNA, but only a small and delayed rise in IL-4 mRNA. In conclusion, H-2-linked resistance to Hg-induced AFA is characterized by low constitutive expression of IL-2 and IFN-γ mRNA, which is not increased by Hg, and a marked increase in IL-10 expression. Conversely, the key features of H-2-linked susceptibility to Hg- and Ag-induced AFA are up-regulation of IL-2, IFN-γ and IL-4 mRNA expression, and down-regulation of IL-10 expression.

  • 30.
    Häggqvist, Bo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Näslund, J
    Sletten, K
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Mucchiano, G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Tjernberg, LO
    Nordstedt, C
    Engström, U
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common form of human amyloid. 1999In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, p. 8669-8674Article in journal (Refereed)
  • 31.
    Johan, Katarzyna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Engström, Ulla
    Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Gustavsson, Åsa
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, p. 2558-2563Article in journal (Refereed)
    Abstract [en]

    Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms β-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after ≈25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA–amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

  • 32. Kono, DH
    et al.
    Park, MS
    Szydlik, A
    Haraldsson, KM
    Kuan, JD
    Pearson, DL
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Pollard, KM
    Resistance to xenobiotic-induced autoimmunity maps to chromosome 11.2001In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 167, p. 2396-2403Article in journal (Refereed)
  • 33.
    Leckström, A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Lundquist, I
    Ma, Z
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (oblob) mouse. 1999In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 18, p. 266-273Article in journal (Refereed)
  • 34.
    Leckström, Arnold
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Islet amyloid polypeptide: Perspectives on the storage and plasma concentration of islet amyloid polypeptide (IAPP) in rodent models of obesity and non-insulin-dependent diabetes mellitus and aspects of amyloidogenesis andelimination of IAPP1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present study was aimed to investigate plasma concentrations and pancreatic storage of IAPP in relation to that of insulin in four different animal models with hyperglycemia, hyperinsulinemia, obesity and/or NIDDM. The NMRI mice fed a high-fat diet for six months, the Psammomys on high-energy (HE) diet and the genetically obese (ob/ob) mice studied for one year all revealed significantly elevated plasma IAPP concentrations, while the IAPP levels were unchanged in the spontaneously diabetic GK rats during a glucose tolerance test.

    In the NMRI mice the fasting plasma glucose and insulin concentrations had also increased, suggesting a possible development of insulin resistance. The increase in plasma IAPP concentrations was even greater than that of insulin, which was reflected in an increased plasma IAPP/insulin molar ratio.

    The Psammomys developed obesity, hyperinsulinemia and hyperglycemia in response to the HE diet. The plasma IAPP concentration was also elevated, but changed in parallel with that of insulin. After vanadyl sulphate treatment the glucose and insulin concentrations were normalized, while IAPP remained elevated.

    The OK rats showed significantly decreased plasma concentrations of IAPP and insulin during the glucose tolerance test. The insulin response to the glucose load was even lower than that of IAPP, resulting in a modest elevation of the plasma IAPP/insulin ratio. The elevated IAPP/insulin ratios in these three animal models might reflect a negative feedback effect of IAPP on insulin release.

    In the ob/ob mice the plasma glucose concentration was initially greatly elevated, but had by the end of study returned to almost normal, presumbly due to the tremendous increase in hyperinsulinemia. The plasma IAPP concentration reached extremely high levels, which however was relatively low to that of insulin, resulting in a sudden significant decrease in the plasma IAPP/insulin ratio at 21 weeks of age, possibly indicating a deficiency in the negative feedback effect of IAPP on insulin secretion.

    IAPP-immunoreactivity was detected in the morning urine of healthy human volunteers and was by reverse phase HPLC-analysis confirmed to be identical to full-length IAPP. This finding gives strong support to the previous suggestions that IAPP is eliminated by the kidneys, why slight disturbances in plasma TAPP/insulin ratios in dynamic situations (as e.g. in the GK rat) should be carefully interpreted.

  • 35.
    Lundmark, Katarzyna
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Studies on Pathogenesis of Experimental AA Amyloidosis: Effects of Amyloid Enhancing Factor and Amyloid-Like Fibrils in Rapid Amyloid Induction2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyloidosis is a group of diseases, caused by an extracellular deposition of a characteristic proteinaceous material, amyloid, in various organs. Fibril formation occurs in all of amyloid related diseases, making it a crucial mechanism to understand.

    Experimental inflammatozy-induced amyloidosis (AA amyloidosis) is proposed to be a nucleation dependent process developing after a lag phase of weeks. The lag phase may be shortened to days by administration of a material extracted from amyloid-loaded tissues. This material is referred to as amyloid enhancing factor (AEF), and is supposed to contain a nucleus that starts fibril formation. However, the nature of this nucleus has not been definitely established.

    We have established a murine model of accelerated AA amyloidosis. In this model we have studied amyloid enhancing effects of preparations containing fibrillazy structures extracted from murine amyloid and from amyloid-like fibrils produced in vitro.

    Our results show that the murine AEF preparation contains no components other than AA amyloid fibrils and is active infemtomolar doses. This AEF preparation is active when administered orally and retains its activity in animals for months after administration. Amyloid fibrils prepared in vitro from amyloidogenic peptides and certain non amyloidogenic proteins have AEF effect as well. Denaturation of the AA protein in AEF abolishes itsamyloidogenic effect. Nonfibrillazy preparation of amyloidogenic peptide has no AEF effect. Radioiodinated amyloid-like fibrils can be detected in newly formed splenic amyloid, and co-localization of such fibrils with AN/SAA is demonstrated.

    Therefore we propose that the active component in AEF is the amyloid fibril itself. The mechanism of nucleation is considered to be similar to the seeded nucleation proposed forprion propagation, in which fibrils, small fibril fragments, or oligomers of scrapie prion protein (PrP) induce profound conformational change in cellular PrP. We propose that experimental AA amyloidosis belongs to the transmissible amyloidoses. The finding that amyloidlike fibrils from naturally occurring nonamyloidogenic proteins act as AEF is of great interest. Ingestion or inhalation of such fibrils may introduce seeds that can start the nucleation process in individuals with elevated SAA levels. Hypothetically, this may explain why only a fraction of patients with longstanding inflammatozy conditions develop amyloid deposits and may implicate environmental factors as important risk factors for AA amyloidosis.

    List of papers
    1. Fibrils from Synthetic Amyloid-Related Peptides Enhance Development of Experimental AA-Amyloidosis in Mice
    Open this publication in new window or tab >>Fibrils from Synthetic Amyloid-Related Peptides Enhance Development of Experimental AA-Amyloidosis in Mice
    Show others...
    1994 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 199, no 1, p. 306-312Article in journal (Refereed) Published
    Abstract [en]

    Amyloid enhancing factor is an incompletely characterized activity of extracts from many amyloid-containing tissues and which greatly shortens the preamyloidotic phase during experimental induction of AA-amyloidosis. In this communication we show that amyloid-like fibrils made in vitro from synthetic peptides, corresponding to segments of amyloid fibril proteins, have amyloid enhancing factor-like activity. Thus, there is a possibility that amyloid enhancing factor activity depends on small fibrils serving as nucleation centers for fibril elongation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80889 (URN)10.1006/bbrc.1994.1229 (DOI)
    Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
    2. Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils
    Open this publication in new window or tab >>Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils
    Show others...
    1998 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, p. 2558-2563Article in journal (Refereed) Published
    Abstract [en]

    Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms β-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after ≈25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA–amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80890 (URN)
    Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
    3. Transmissibility of systemic amyloidosis by a prion-like mechanism
    Open this publication in new window or tab >>Transmissibility of systemic amyloidosis by a prion-like mechanism
    Show others...
    2002 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 10, p. 6979-6984Article in journal (Refereed) Published
    Abstract [en]

    The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20805 (URN)10.1073/pnas.092205999 (DOI)12011456 (PubMedID)
    Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
    4. Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
    Open this publication in new window or tab >>Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Experimental AA amyloidosis, where the acute phase protein serum AA (SAA) forms amyloid fibrils, can be induced in mice provoked with inflannnatmy challenge. The time for development of amyloid is dramatically shortened when the animals concomitantly receive extract of a tissue from another mouse with amyloid 1-3. The active elusive principle has been named Amyloid Enhancing Factor (AEF) and experimental secondary amyloidosis was supposed to be a nucleation dependent process. The nature of the nucleus, however, was unknown for a long time. Our studies with synthetic amyloid-like fibrils made frmn short amyloidogenic pep tides instead of AEF 4, 5, indicate that the amyloid fibrils theruselves may act as nuclei for fibril formation (Fig. 1a). Here we present the enhanced development of AA -amyloidosis by naturally occurring amyloid-like protein fibrils.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80892 (URN)
    Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2012-09-03Bibliographically approved
  • 36.
    Lundmark, Katarzyna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindquist, Susan
    Howard Hughes Medical Institute, University of Chicago, Il, USA.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, Sweden.
    Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanismManuscript (preprint) (Other academic)
    Abstract [en]

    Experimental AA amyloidosis, where the acute phase protein serum AA (SAA) forms amyloid fibrils, can be induced in mice provoked with inflannnatmy challenge. The time for development of amyloid is dramatically shortened when the animals concomitantly receive extract of a tissue from another mouse with amyloid 1-3. The active elusive principle has been named Amyloid Enhancing Factor (AEF) and experimental secondary amyloidosis was supposed to be a nucleation dependent process. The nature of the nucleus, however, was unknown for a long time. Our studies with synthetic amyloid-like fibrils made frmn short amyloidogenic pep tides instead of AEF 4, 5, indicate that the amyloid fibrils theruselves may act as nuclei for fibril formation (Fig. 1a). Here we present the enhanced development of AA -amyloidosis by naturally occurring amyloid-like protein fibrils.

  • 37.
    Ma, Zhi
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Islet amyloid polypeptide (IAPP): Mechanisms of Amyloidogenesis in the Pancreatic Islets and Potential Roles in Diabetes Mellitus2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Islet amyloid is the most common characteristic feature of the islets in type 2 diabetes, being found in up to 90% of diabetic patients at post-mortem. lt has as its unique component the islet beta-cell peptide islet amyloid polypeptide (IAPP), which is eo-secreted with insulin. Because all human subjects produce and secrete the amyloidogenic form of IAPP, yet not all develop islet amyloid, some other factors must be involved in islet amyloid formation. The aim of the research presented in this thesis was to study factors of importance for the IAPP amyloidogenesis in type 2 diabetes. We developed a mouse monoclonal antibody to raVmouse IAPP (MAb4A5). MAb4A5 shows reactivity with IAPP in different species without detecting its close relative CGRP. In the pancreatic islets from patients with type 2 diabetes and diabetic cat, MAb4A5 labels immunohistochemically cellular IAPP but not IAPP in islet amyloid deposits. In contrast to MAb4A5 polyclonal rabbitiAPP antisera label beta cells close to amyloid only weakly, but label strongly IAPP in its amyloid form. The varying findings of IAPP immunoreactivity in pancreatic islets indicate that IAPP undergoes structural changes (impaired cleavage of proiAPP, conformational change, or post-transitional modifications) during the amyloidogenesis. A potentially important finding was the increased IAPP immunoreactivity in beta cells in islets of impaired glucose tolerant cats, irrespective of presence of amyloid in these islets. The finding may indicate that the formation of first islet amyloid occurs before Type 2 diabetes is manifest. Given the immunohistochemical results with MAb 4A5, we investigated whether the altered immunoreactivity of IAPP in association with the amyloidogenesis is due to a modification of IAPP (e.g. non-enzymatic glycation). We used synthetic IAPP fibrils glycated in vitro to study if non-enzymatic glycation may result in loss of an antigenic epitope. The results showed that a possible explanation of the lack of immunoreactivity of islet amyloid with MAb 4A5 actually is an nonenzymatic glycation. Association of an IAPP gene mutation with Type 2 diabetes has been found in the Japanese and Chinese population. We studied the possible enhanced fibril formation capacity of the mutant IAPP in vitro. Full-length and truncated IAPPS20G can form more amyloid-like fibrils and do this faster compared to wild type IAPP in vitro. We concluded that mutant (S20G) IAPP is a more amyloidogenic IAPP molecule and may be associated with an increased islet amyloid formation in vivo.

    Based on the reports on the occurrence of islet amyloid in transgenic mice fed high fat diet, we investigated effects of free fatty acids on IAPP amyloid formation in isolated islets from transgenic mice expressing the gene for human IAPP but deficient of endogenous murine IAPP, and effects of FFAs on polymerization of IAPP in vitro. We found free fatty acids accelerate and increase polymerization of IAPP in vitro and promote amyloid like aggregation occurring in cultivated transgenic mouse isolated islets. All these results indicate that the pathogenesis of the islet amyloid may be a complex process involving many different mechanisms.

    List of papers
    1. Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis
    Open this publication in new window or tab >>Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis
    Show others...
    1997 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 40, no 7, p. 793-801Article in journal (Refereed) Published
    Abstract [en]

    We have developed a mouse monoclonal antibody against rat/mouse islet amyloid polypeptide (IAPP). The antibody recognises an epitope in the N-terminal part of the molecule, which is conserved between different species. The antibody immunohistochemically labelled beta cells in normal islets of most different mammalian species including man and in one avian species. Previous immunohistochemical studies of human pancreatic tissue from individuals with non-insulin-dependent diabetes mellitus (NIDDM) have revealed a paradoxical and unexplained lack of IAPP immunoreactivity in beta cells close to amyloid in spite of the presence of IAPP mRNA. In contrast to these findings we show that the newly developed monoclonal IAPP antibody strongly labels such beta cells while islet amyloid deposits which are labelled by polyclonal antisera do not bind the monoclonal antibody. These findings with the polyclonal antisera and the monoclonal antibody indicate that IAPP undergoes one or several structural changes during the amyloidogenesis. Knowledge of these structural changes that may include abnormal folding or chemical modification of IAPP is probably important for the understanding of the amyloidogenesis and the pathogenesis of the islet lesion in NIDDM.

    Keywords
    islet amyloid polypeptide, monoclonal antibody, non-insulin-dependent diabetes mellitus, immunohistochemistry, deposits.
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80001 (URN)10.1007/s001250050751 (DOI)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
    2. Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats
    Open this publication in new window or tab >>Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats
    Show others...
    1998 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 5, no 4, p. 255-261Article in journal (Refereed) Published
    Abstract [en]

    Islet amyloid polypeptide (IAPP, “amylin”) has been proposed as having important roles in the pathogenesis of type 2 diabetes mellitus via its biological activity and by forming islet amyloid. The domestic cat develops a type of diabetes that closely resembles type 2 diabetes in humans, including the frequent formation of islet amyloid deposits in the impaired glucose tolerant (IGT) and diabetic state. With the aid of computerized image analysis and immuno-histochemistry, we examined the IAPP and insulin content inpancreatic islets of normal, IGT and diabetic cats. IAPP immunoreactivity in beta cells from IGT cats was significantly stronger (p < 0.01) as compared with cells from normal cats, while the insulin labelling strength was unchanged. Overtly diabetic cats were usually almost devoid of beta cells. As in humans, cellular IAPP but not IAPP in islet amyloid deposits was labelled by the newly developed monoclonal antibody to IAPP 4A5, thus providing further evidence that IAPP is modified by a yet unknown mechanism during the amyloidogenic process. The study provides evidence that an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes.

    Keywords
    islet amyloid polypeptide, impaired glucose tolerance, non-insulin-dependent diabetes mellitus, immunohistochemistry, cat, amyloidosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80002 (URN)10.3109/13506129809007298 (DOI)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
    3. Amyloid in Human Islets of Langerhans: Immunologic Evidence That Islet Amyloid Polypeptide Is Modified in Amyloidogenesis
    Open this publication in new window or tab >>Amyloid in Human Islets of Langerhans: Immunologic Evidence That Islet Amyloid Polypeptide Is Modified in Amyloidogenesis
    2000 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 21, no 2, p. 212-218Article in journal (Refereed) Published
    Abstract [en]

    Amyloid derived from the beta-cell product islet amyloid polypeptide (IAPP) has been implicated for a beta-cell lesion in Type II diabetes mellitus. The pathogenesis of islet amyloid is poorly understood, and in addition to an amyloidogenic IAPP molecule and possibly increased concentration of IAPP, other unknown factors seem to be included. It was shown previously that polyclonal rabbit IAPP antisera label beta cells close to amyloid only weakly. Whether this lack of immunoreactivity depends on lack of IAPP or on hidden epitopes is in question. In the present study, we show that the IAPP immunoreactivity of these beta cells is possible to retrieve. On the other hand, the monoclonal IAPP antibody 4A5, which labels IAPP in beta cells, does not label IAPP in its native amyloid form. We show evidence that this lack of immunoreactivity is not dependent on conformational change of the IAPP molecules in the amyloidogenesis but is likely owing to glycation of IAPP in human islet amyloid deposits.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25449 (URN)10.1097/00006676-200008000-00015 (DOI)9895 (Local ID)9895 (Archive number)9895 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide
    Open this publication in new window or tab >>Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide
    Show others...
    2001 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 8, no 4, p. 242-249Article in journal (Refereed) Published
    Abstract [en]

    Islet amyloid polypeptide (IAPP, “amylin”) is the amyloid-fibril-forming polypeptide in the islets of Langerhans associated with type 2 diabetes mellitus. A missense mutation in the IAPP gene associated with early-onset type 2 diabetes has been identified in the Japanese population. This mutation results in a glycine for serine substitution at position 20 of the mature IAPP molecule. Whether or not formation of islet amyloid with resulting destruction of islet tissue is the cause of this diabetes is yet not known. The present in vitro study was performed in order to investigate any influence of the amino acid substitution on the fibril formation capacity. Synthetic full-length wild type (lAPPwt) and mutant (IAPPS20G) as well as corresponding truncated peptides (position 18-29) were dissolved in dimethylsulfoxide (DMSO) or in 10% acetic acid at a concentration of 10 mg/mL and their fibril forming capacity was checked by Congo red staining, electron microscopy, a Congo red affinity assay and Thioflavine T fluorometric assay. It was found that full-length and truncated IAPPS20G both formed more amyloid-like fibrils and did this faster compared to IAPPwt. The fibril morphology differed slightly between the preparations. Conclusion: The amino acid substitution (S20G) is situated close to the region of the IAPP molecule implicated in the IAPP fibrillogenesis. The significantly increased formation of amyloid-like fibrils by IAPPS20G is highly interesting and may be associated with an increased islet amyloid formation in vivo and of fundamental importance in the pathogenesis of this specific form of diabetes.

    Keywords
    Islet amyloid polypeptide, fibrillogenesis, mutation, dye fluorescence, type 2 diabetes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25451 (URN)10.3109/13506120108993820 (DOI)9897 (Local ID)9897 (Archive number)9897 (OAI)
    Note
    On the day of the defence day the status of this article was submittedAvailable from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    5. Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice overexpressing human IAPP
    Open this publication in new window or tab >>Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice overexpressing human IAPP
    2002 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, no 12, p. 863-868Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Islet amyloid polypeptide (IAPP) is deposited as amyloid in the islets of Langerhans in type 2 diabetes. The mechanism behind the formation of the cytotoxic fibrils is unknown. Islet amyloid develops in a mouse IAPP null mouse strain that expresses human IAPP (+hIAPP/-mIAPP) after 9 months on a high-fat diet. Herein we investigate the effect that individual free fatty acids (FFAs) exert on formation of amyloid-like fibrils from synthetic IAPP and the effects of FFAs on IAPP polymerization in +hIAPP/-mIAPP islets cultivated in vitro.

    MATERIALS AND METHODS: In the study myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid were used together with albumin. Thioflavin T (Th T) assay was used for quantification of amyloid-like fibrils. Islets were isolated from the +hIAPP/-mIAPP transgenic strain and cultured in the presence of the FFAs for 2 days. Immuno-electron microscopy was used for evaluation.

    RESULTS: The Th T assay showed that all studied FFAs potentiated fibril formation but that myristic acid revealed the highest capacity. In some cells from cultured islets, intragranular aggregates were present. These aggregates had a filamentous appearance and labeled with antibodies against IAPP. In some cells cultured in the presence of linoleic acid, large amounts of intracellular amyloid were present. Earlier, this has not been observed after such a short incubation period.

    CONCLUSIONS: Our studies suggest that FFAs can potentiate amyloid formation in vitro, probably without being integrated in the fibril. Cultivation of +hIAPP/-mIAPP transgenic mouse islets with FFAs results in altered morphology of the secretory granules with appearance of IAPP- immunoreactive fibrillar material. We suggest that such fibrillar material may seed extracellular amyloid formation after exocytosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26538 (URN)11099 (Local ID)11099 (Archive number)11099 (OAI)
    Note
    On the day of the defence day the status of this article was a manuscriptAvailable from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 38.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sakagashira, S.
    First Department of Medicine, Wakayama University of Medical Science, Kagawa Medical University, Japan.
    Sanke, T.
    First Department of Medicine, Wakayama University of Medical Science, Kagawa Medical University, Japan.
    Gustavsson, Å
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Sakamoto, H.
    Department of Pathology, Kagawa Medical University, Japan.
    Engstrom, U.
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala University, Uppsala, Sweden.
    Nanjo, K.
    First Department of Medicine, Wakayama University of Medical Science, Kagawa Medical University, Japan.
    Westermark, P.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide2001In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 8, no 4, p. 242-249Article in journal (Refereed)
    Abstract [en]

    Islet amyloid polypeptide (IAPP, “amylin”) is the amyloid-fibril-forming polypeptide in the islets of Langerhans associated with type 2 diabetes mellitus. A missense mutation in the IAPP gene associated with early-onset type 2 diabetes has been identified in the Japanese population. This mutation results in a glycine for serine substitution at position 20 of the mature IAPP molecule. Whether or not formation of islet amyloid with resulting destruction of islet tissue is the cause of this diabetes is yet not known. The present in vitro study was performed in order to investigate any influence of the amino acid substitution on the fibril formation capacity. Synthetic full-length wild type (lAPPwt) and mutant (IAPPS20G) as well as corresponding truncated peptides (position 18-29) were dissolved in dimethylsulfoxide (DMSO) or in 10% acetic acid at a concentration of 10 mg/mL and their fibril forming capacity was checked by Congo red staining, electron microscopy, a Congo red affinity assay and Thioflavine T fluorometric assay. It was found that full-length and truncated IAPPS20G both formed more amyloid-like fibrils and did this faster compared to IAPPwt. The fibril morphology differed slightly between the preparations. Conclusion: The amino acid substitution (S20G) is situated close to the region of the IAPP molecule implicated in the IAPP fibrillogenesis. The significantly increased formation of amyloid-like fibrils by IAPPS20G is highly interesting and may be associated with an increased islet amyloid formation in vivo and of fundamental importance in the pathogenesis of this specific form of diabetes.

  • 39.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice overexpressing human IAPP2002In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, no 12, p. 863-868Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Islet amyloid polypeptide (IAPP) is deposited as amyloid in the islets of Langerhans in type 2 diabetes. The mechanism behind the formation of the cytotoxic fibrils is unknown. Islet amyloid develops in a mouse IAPP null mouse strain that expresses human IAPP (+hIAPP/-mIAPP) after 9 months on a high-fat diet. Herein we investigate the effect that individual free fatty acids (FFAs) exert on formation of amyloid-like fibrils from synthetic IAPP and the effects of FFAs on IAPP polymerization in +hIAPP/-mIAPP islets cultivated in vitro.

    MATERIALS AND METHODS: In the study myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid were used together with albumin. Thioflavin T (Th T) assay was used for quantification of amyloid-like fibrils. Islets were isolated from the +hIAPP/-mIAPP transgenic strain and cultured in the presence of the FFAs for 2 days. Immuno-electron microscopy was used for evaluation.

    RESULTS: The Th T assay showed that all studied FFAs potentiated fibril formation but that myristic acid revealed the highest capacity. In some cells from cultured islets, intragranular aggregates were present. These aggregates had a filamentous appearance and labeled with antibodies against IAPP. In some cells cultured in the presence of linoleic acid, large amounts of intracellular amyloid were present. Earlier, this has not been observed after such a short incubation period.

    CONCLUSIONS: Our studies suggest that FFAs can potentiate amyloid formation in vitro, probably without being integrated in the fibril. Cultivation of +hIAPP/-mIAPP transgenic mouse islets with FFAs results in altered morphology of the secretory granules with appearance of IAPP- immunoreactive fibrillar material. We suggest that such fibrillar material may seed extracellular amyloid formation after exocytosis.

  • 40.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Johnsson, Kenneth H.
    Department of Veterinary Patho Biology, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, 55108, USA.
    O'Brien, Timothy D.
    Department of Veterinary Diagnostic Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, 55108, USA .
    Westermark, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats1998In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 5, no 4, p. 255-261Article in journal (Refereed)
    Abstract [en]

    Islet amyloid polypeptide (IAPP, “amylin”) has been proposed as having important roles in the pathogenesis of type 2 diabetes mellitus via its biological activity and by forming islet amyloid. The domestic cat develops a type of diabetes that closely resembles type 2 diabetes in humans, including the frequent formation of islet amyloid deposits in the impaired glucose tolerant (IGT) and diabetic state. With the aid of computerized image analysis and immuno-histochemistry, we examined the IAPP and insulin content inpancreatic islets of normal, IGT and diabetic cats. IAPP immunoreactivity in beta cells from IGT cats was significantly stronger (p < 0.01) as compared with cells from normal cats, while the insulin labelling strength was unchanged. Overtly diabetic cats were usually almost devoid of beta cells. As in humans, cellular IAPP but not IAPP in islet amyloid deposits was labelled by the newly developed monoclonal antibody to IAPP 4A5, thus providing further evidence that IAPP is modified by a yet unknown mechanism during the amyloidogenic process. The study provides evidence that an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes.

  • 41.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, P.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Amyloid in Human Islets of Langerhans: Immunologic Evidence That Islet Amyloid Polypeptide Is Modified in Amyloidogenesis2000In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 21, no 2, p. 212-218Article in journal (Refereed)
    Abstract [en]

    Amyloid derived from the beta-cell product islet amyloid polypeptide (IAPP) has been implicated for a beta-cell lesion in Type II diabetes mellitus. The pathogenesis of islet amyloid is poorly understood, and in addition to an amyloidogenic IAPP molecule and possibly increased concentration of IAPP, other unknown factors seem to be included. It was shown previously that polyclonal rabbit IAPP antisera label beta cells close to amyloid only weakly. Whether this lack of immunoreactivity depends on lack of IAPP or on hidden epitopes is in question. In the present study, we show that the IAPP immunoreactivity of these beta cells is possible to retrieve. On the other hand, the monoclonal IAPP antibody 4A5, which labels IAPP in beta cells, does not label IAPP in its native amyloid form. We show evidence that this lack of immunoreactivity is not dependent on conformational change of the IAPP molecules in the amyloidogenesis but is likely owing to glycation of IAPP in human islet amyloid deposits.

  • 42. Marcusson, JA
    et al.
    Cederbrant, K
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Gunnarsson, L-G
    Serotonin production in lymphocytes and mercury intolerance.2000In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 14, p. 133-137Article in journal (Refereed)
  • 43. Marcusson-Ståhl, Maritha
    et al.
    Cederbrant, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    A flow-cytometric NK-cytotoxicity assay adapted for use in rat repeated dose toxicity studies.2003In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 193, p. 269-279Article in journal (Refereed)
  • 44. McAdam, KPWJ
    et al.
    Raynes, JG
    Alpers, MP
    Westermark, Gunilla
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Amyloidosis: a global problem common in Papua New Guinea. 1999In: Papau New Guinea Medical Journal, ISSN 0031-1480, Vol. 39, p. 284-296Article in journal (Refereed)
  • 45. Mellergård, Johan
    et al.
    Havarinasab, Said
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Short- and long-term effects of T-cell modulating agents in experimental autoimmunity2004In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 196, no 3, p. 197-209Article in journal (Refereed)
    Abstract [en]

    Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2 s) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2s) mice were given 6mg HgCl2/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.

  • 46.
    Mucchiano, Gerd
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Apolipoprotein A-1 derived amyloid in the atherosclerotic intima of the human aorta2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyloid is insoluble fibrillar protein deposited in the extracellular space. The resulting heterogeneous group of disorders, amyloidosis, can be sporadic or hereditary, and the amyloid is systemically distributed or localized in single organs. Systemic hereditary amyloidoses are disorders caused by mutant forms of plasma proteins such as transthyretin (TTR) or less frequently, apolipoprotein A-1 (apo A-1), the major protein in high-density lipoprotein (HDL). Local deposition of amyloid associated with aging may be pathogenically important in Alzheimer's disease and type II diabetes. Localized amyloid in the medial and intimal layer of the aorta, commonly found in elderly humans, is of unknown sigoificance. The aim of this work was to investigate the nature of amyloid in the atherosclerotic intima of the human aorta, its fibrillogenesis and potential pathogenic importance. Two biochemically different forms of localized amyloid deposits in the aorta were identified; one affecting the atherosclerotic plaques of the intima and the other the media. Amyloid fibrils from the media has subse quently been found to consist of a protein fragment derived from lactadherin. Purified amyloid protein from atherosclerotic plaques of aortas in utopsy cases was shown by amino acid sequence analysis to be derived from apo A-1. Apo A-1 derived amyloid was immunohistochemically confirmed in 14% of 72 autopsy cases. A mutation was found in the apo A-1 gene (Δ Lys 1 07) in one of the 9 cases with intimal amyloid. Thus wild type, as well as mutant apo A-1, is amyloidogenic in humans. There was a tendency towards higher plasma levels of apo A-1 in patients with apo A-1 derived amyloid who underwent arterial reconstruction, compared to those without amyloid (p= 0.055). Levels of LDL- and total cholesterol were higher in the group with amyloid. Atherosclerosis induces high concentration of the acute phase reactant SAA in atherosclerotic lesions. SAA may displace apo A-1 from HDL, which, in addition to high levels of plasma apo A-1, could lead to an increased concentration oflipid free apo A-1 in the intima. Conformational changes in apo A-1 are then induced, making it more prone to fibril formation. Since some forms of amyloid fibrils are known to be cytotoxic, apo A-1 derived amyloid may contribute to the injury caused by other factors in atherosclerotic lesions.

    List of papers
    1. Senile aortic amyloid: Evidence for two distinct forms of localized deposits
    Open this publication in new window or tab >>Senile aortic amyloid: Evidence for two distinct forms of localized deposits
    1992 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 140, no 4, p. 871-877Article in journal (Refereed) Published
    Abstract [en]

    Aortic tissues obtained at autopsy were examined from 84 patients (age, 18-96 years). Amyloid deposits were present in the media in 61 of 63 (97%) of the patients above the age of 50. In addition, intimal amyloid deposits were present in 35% of this group. Intimal amyloid differed from medial amyloid both in its morphologic characteristics and its association with atherosclerosis. An antiserum raised to a low molecular weight protein extracted from amyloid fibrils of the aortic media reacted specifically with medial amyloid but did not react with intimal deposits. Neither type of amyloid reacted with anti-ATTR (Senile systemic amyloid), anti-AANF (isolated atrial amyloid), or antisera to other known forms of amyloid. These findings are consistent with the presence of two separate forms of localized amyloid in the aging aorta.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79732 (URN)1562050 (PubMedID)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2017-12-07Bibliographically approved
    2. Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques
    Open this publication in new window or tab >>Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques
    Show others...
    1995 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 147, no 5, p. 1186-1192Article in journal (Refereed) Published
    Abstract [en]

    Amyloid deposits in the aortic intima are very common in association with atherosclerosis and aging. In the present study, a major fibril protein purified from amyloid present in human atherosclerotic plaques was shown to be a 69-amino acid N-terminal fragment of apolipoprotein AI. Although senile form of localized apolipoprotein AI-derived amyloidosis has recently been documented in pulmonary vessels of dogs, this is the first example of a localized human amyloid derived from this apolipoprotein.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79733 (URN)7485381 (PubMedID)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2017-12-07Bibliographically approved
    3. Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation
    Open this publication in new window or tab >>Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation
    Show others...
    1998 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 242, no 3, p. 534-539Article in journal (Refereed) Published
    Abstract [en]

    In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79734 (URN)10.1006/bbrc.1997.8005 (DOI)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2017-12-07Bibliographically approved
    4. Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta
    Open this publication in new window or tab >>Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta
    2001 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 193, no 2, p. 270-275Article in journal (Refereed) Published
    Abstract [en]

    Previous studies have shown that the amyloid localized to the aortic intima may be a biochemical entity different from other forms of localized amyloid. The amyloid fibril protein in one patient studied consisted of an N-terminal fragment of apolipoprotein A-1 (apo A-1). Since this patient was later shown to carry a missense mutation in the apo A-1 gene, leading to a deletion at position 107 of the mature protein, the question remained whether wild-type apo A-1 is amyloidogenic. In autopsy specimens from the thoracic aorta from 69 individuals, intimal atherosclerotic plaque-related amyloid was present in 11 cases (16%) and amyloid outside plaques in 37 cases (54%). The immunoreactivity of amyloid localized to the aortic intima was evaluated with the aid of antisera against N-terminal segments of apo A-1. The amyloid in association with atherosclerotic plaques was positively labelled by immunohistochemistry. The amyloid fibril protein from one patient, previously shown not to carry any mutation in the apo A-1 gene, was purified and shown by amino acid sequence analysis to be of apo A-1 nature. The result shows that wild-type apo A-1 is amyloidogenic and gives rise to a common localized form of amyloid associated with atherosclerosis.

    Keywords
    amyloid, aorta, intima, apolipoprotein A-1, atherosclerosis, immunocytochemistry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25966 (URN)10.1002/1096-9896(2000)9999:9999<::AID-PATH753>3.0.CO;2-S (DOI)10414 (Local ID)10414 (Archive number)10414 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    5. Apolipoprotein A-I–Derived Amyloid in Atherosclerosis: Its Association With Plasma Levels of Apolipoprotein A-I and Cholesterol
    Open this publication in new window or tab >>Apolipoprotein A-I–Derived Amyloid in Atherosclerosis: Its Association With Plasma Levels of Apolipoprotein A-I and Cholesterol
    Show others...
    2001 (English)In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722, Vol. 115, p. 298-303Article in journal (Refereed) Published
    Abstract [en]

    Wild-type apolipoprotein A-I (apo A-I)–derived amyloid commonly occurs in atherosclerotic plaques. To clarify apo A-I amyloid formation, plasma levels of apo A-I and cholesterol were related to the presence of amyloid in atherosclerotic plaques in 15 patients with peripheral atherosclerosis, subjected to arterial reconstruction. Plasma levels of apo A-I and high-density lipoprotein (HDL) cholesterol were slightly higher in patients with apo A-I–derived amyloid than in those without, but the difference was not significant. Levels of low-density lipoprotein cholesterol and total cholesterol were significantly higher in the group with amyloid. High concentrations of apo A-I in the arterial intima are probably of greater importance to amyloid formation than high plasma levels of the protein. During atherosclerosis, the acute phase reactant serum amyloid A may displace apo A-I from HDL, leading to increased concentration of lipid-free apo A-I in the intima and conformational changes of apo A-I, which make it more fibrillogenic. Some forms of amyloid fibrils have been shown to be cytotoxic. Apo AI–derived amyloid is possibly a pathogenically important factor in atherosclerosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25965 (URN)10413 (Local ID)10413 (Archive number)10413 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 47.
    Mucchiano, Gerd
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Häggqvist, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Sletten, Knut
    Department of Biochemistry and Biotechnology Center of Oslo, University of Oslo, Norway.
    Westermark, Per
    Department of Genetics and Pathology, Uppsala University, Sweden.
    Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta2001In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 193, no 2, p. 270-275Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that the amyloid localized to the aortic intima may be a biochemical entity different from other forms of localized amyloid. The amyloid fibril protein in one patient studied consisted of an N-terminal fragment of apolipoprotein A-1 (apo A-1). Since this patient was later shown to carry a missense mutation in the apo A-1 gene, leading to a deletion at position 107 of the mature protein, the question remained whether wild-type apo A-1 is amyloidogenic. In autopsy specimens from the thoracic aorta from 69 individuals, intimal atherosclerotic plaque-related amyloid was present in 11 cases (16%) and amyloid outside plaques in 37 cases (54%). The immunoreactivity of amyloid localized to the aortic intima was evaluated with the aid of antisera against N-terminal segments of apo A-1. The amyloid in association with atherosclerotic plaques was positively labelled by immunohistochemistry. The amyloid fibril protein from one patient, previously shown not to carry any mutation in the apo A-1 gene, was purified and shown by amino acid sequence analysis to be of apo A-1 nature. The result shows that wild-type apo A-1 is amyloidogenic and gives rise to a common localized form of amyloid associated with atherosclerosis.

  • 48.
    Mucchiano, Gerd I.
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Department of Medicine, Högland Hospital, Eksjö.
    Häggqvist, Bo
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Einarsson, Eibert
    Department of Surgery, Högland Hospital, Eksjö.
    Westermark, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Apolipoprotein A-I–Derived Amyloid in Atherosclerosis: Its Association With Plasma Levels of Apolipoprotein A-I and Cholesterol2001In: American Journal of Clinical Pathology, ISSN 0002-9173, E-ISSN 1943-7722, Vol. 115, p. 298-303Article in journal (Refereed)
    Abstract [en]

    Wild-type apolipoprotein A-I (apo A-I)–derived amyloid commonly occurs in atherosclerotic plaques. To clarify apo A-I amyloid formation, plasma levels of apo A-I and cholesterol were related to the presence of amyloid in atherosclerotic plaques in 15 patients with peripheral atherosclerosis, subjected to arterial reconstruction. Plasma levels of apo A-I and high-density lipoprotein (HDL) cholesterol were slightly higher in patients with apo A-I–derived amyloid than in those without, but the difference was not significant. Levels of low-density lipoprotein cholesterol and total cholesterol were significantly higher in the group with amyloid. High concentrations of apo A-I in the arterial intima are probably of greater importance to amyloid formation than high plasma levels of the protein. During atherosclerosis, the acute phase reactant serum amyloid A may displace apo A-I from HDL, leading to increased concentration of lipid-free apo A-I in the intima and conformational changes of apo A-I, which make it more fibrillogenic. Some forms of amyloid fibrils have been shown to be cytotoxic. Apo AI–derived amyloid is possibly a pathogenically important factor in atherosclerosis.

  • 49. Nielsen, J.B
    et al.
    Ekstrand, Jimmy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Zalups, R.K
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Inheritance of susceptibility: mercury kinetics in two mouse strains (A.SW and B10.S) and their F1 generation.2006In: Metal ions in biological systems, ISSN 0161-5149, E-ISSN 2154-9214, Vol. 9, p. 351-355Article in journal (Refereed)
    Abstract [en]

       

  • 50. Nielsen, JB
    et al.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Experimental studies on genetically determined susceptibility to mercury-induced autoimmune response. 1999In: Renal failure, ISSN 0886-022X, E-ISSN 1525-6049, Vol. 21, p. 343-348Article in journal (Refereed)
12 1 - 50 of 70
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