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  • 1.
    Andersson, Manne
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. County Hospital Ryhov, Jönköping, Sweden .
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Björnsson, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    University of Copenhagen, Denmark.
    Andersson, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. County Hospital Ryhov, Jönköping, Sweden.
    Can New Inflammatory Markers Improve the Diagnosis of Acute Appendicitis?2014In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 38, no 11, p. 2777-2783Article in journal (Refereed)
    Abstract [en]

    The diagnosis of appendicitis is difficult and resource consuming. New inflammatory markers have been proposed for the diagnosis of appendicitis, but their utility in combination with traditional diagnostic variables has not been tested. Our objective is to explore the potential of new inflammatory markers for improving the diagnosis of appendicitis. The diagnostic properties of the six most promising out of 21 new inflammatory markers (interleukin [IL]-6, chemokine ligand [CXCL]-8, chemokine C-C motif ligand [CCL]-2, serum amyloid A [SAA], matrix metalloproteinase [MMP]-9, and myeloperoxidase [MPO]) were compared with traditional diagnostic variables included in the Appendicitis Inflammatory Response (AIR) score (right iliac fossa pain, vomiting, rebound tenderness, guarding, white blood cell [WBC] count, proportion neutrophils, C-reactive protein and body temperature) in 432 patients with suspected appendicitis by uni- and multivariable regression models. Of the new inflammatory variables, SAA, MPO, and MMP9 were the strongest discriminators for all appendicitis (receiver operating characteristics [ROC] 0.71) and SAA was the strongest discriminator for advanced appendicitis (ROC 0.80) compared with defence or rebound tenderness, which were the strongest traditional discriminators for all appendicitis (ROC 0.84) and the WBC count for advanced appendicitis (ROC 0.89). CCL2 was the strongest independent discriminator beside the AIR score variables in a multivariable model. The AIR score had an ROC area of 0.91 and could correctly classify 58.3 % of the patients, with an accuracy of 92.9 %. This was not improved by inclusion of the new inflammatory markers. The conventional diagnostic variables for appendicitis, as combined in the AIR score, is an efficient screening instrument for classifying patients as low-, indeterminate-, or high-risk for appendicitis. The addition of the new inflammatory variables did not improve diagnostic performance further.

  • 2.
    Atikuzzaman, Mohammad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Sanz, Libia
    Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
    Pla, Davinia
    Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
    Alvarez-Rodriguez, Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Calvete, Juan J.
    Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Selection for higher fertility reflects in the seminal fluid proteome of modern domestic chicken2017In: Comparative Biochemistry and Physiology - Part D: Genomics and Proteomics, ISSN 1744-117X, E-ISSN 1878-0407, Vol. 21, p. 27-40Article in journal (Refereed)
    Abstract [en]

    The high egg-laying capacity of the modern domestic chicken (i.e. White Leghorn, WL) has arisen from the low egg-laying ancestor Red Junglefowl (RJF) via continuous trait selection and breeding. To investigate whether this long-term selection impacted the seminal fluid (SF)-proteome, 2DE electrophoresis-based proteomic analyses and immunoassays were conducted to map SF-proteins/cytokines in RJF, WL and a 9th generation Advanced Intercross Line (AIL) of RJF/WL-L13, including individual SF (n = 4, from each RJF, WL and AIL groups) and pools of the SF from 15 males of each group, analyzed by 2DE to determine their degree of intra-group (AIL, WL, and RJF) variability using Principal Component Analysis (PCA); respectively an inter-breed comparative analysis of intergroup fold change of specific SF protein spots intensity between breeds. The PCA clearly highlighted a clear intra-group similarity among individual roosters as well as a clear inter-group variability (e.g. between RJF, WL and AIL) validating the use of pools to minimize confounding individual variation. Protein expression varied considerably for processes related to sperm motility, nutrition, transport and survival in the female, including signaling towards immunomodulation. The major conserved SF-proteins were serum albumin and ovotransferrin. Aspartate aminotransferase, annexin A5, arginosuccinate synthase, glutathione S-transferase 2 and l-lactate dehydrogenase-A were RJF-specific. Glyceraldehyde-3-phosphate dehydrogenase appeared specific to the WL-SF while angiotensin-converting enzyme, γ-enolase, coagulation factor IX, fibrinogen α-chain, hemoglobin subunit α-D, lysozyme C, phosphoglycerate kinase, Src-substrate protein p85, tubulins and thioredoxin were AIL-specific. The RJF-SF contained fewer immune system process proteins and lower amounts of the anti-inflammatory/immunomodulatory TGF-β2 compared to WL and AIL, which had low levels- or lacked pro-inflammatory CXCL10 compared to RJF. The seminal fluid proteome differs between ancestor and modern chicken, with a clear enrichment of proteins and peptides related to immune-modulation for sperm survival in the female and fertility.

  • 3.
    Barranco, Isabel
    et al.
    University of Murcia, Spain.
    Roca, Jordi
    University of Murcia, Spain.
    Tvarijonaviciute, Asta
    University of Murcia, Spain.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vicente Carrillo, Alejandro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ceron, Jose J.
    University of Murcia, Spain.
    Martinez, Emilio A.
    University of Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Measurement of Activity and Concentration of Paraoxonase 1 (PON-1) in Seminal Plasma and Identification of PON-2 in the Sperm of Boar Ejaculates2015In: Molecular Reproduction and Development, ISSN 1040-452X, E-ISSN 1098-2795, Vol. 82, no 1, p. 58-65Article in journal (Refereed)
    Abstract [en]

    This study revealed and characterised the presence of the antioxidant enzymes paraoxonase (PON) type 1 (PON-1, extracellular) and type 2 (PON-2, intracellular) in boar semen. To evaluate PON-1, an entire ejaculate from each of ten boars was collected and the seminal plasma was harvested after double centrifugation (1,500g for 10min). Seminal plasma was analysed for concentration as well as enzymatic activity of PON-1 and total cholesterol levels. Seminal-plasma PON-1 concentration ranged from 0.961 to 1.670ng/ml while its enzymatic activity ranged from 0.056 to 0.400 IU/ml, which represent individual variance. Seminal-plasma PON-1 concentration and enzymatic activity were negatively correlated (r=-0.763; Pless than0.01). The activity of seminal-plasma PON-1 negatively correlated with ejaculate volume (r=-0.726, Pless than0.05), but positively correlated with sperm concentration (r=0.654, Pless than0.05). Total seminal-plasma cholesterol concentration positively correlated with PON-1 activity (r=0.773; Pless than0.01), but negatively correlated with PON-1 concentration (r=-0.709; Pless than0.05). The presence of intracellular PON-2 was determined via immunocytochemistry in spermatozoa derived from artificial insemination. PON-2 localised to the post-acrosomal area of the sperm head and principal piece of the tail in membrane-intact spermatozoa. In summary, PON is present in boar semen, with PON-1 at low levels in seminal plasma and PON-2 within the spermatozoa. Further studies are needed to characterise the relationship between antioxidant PONs with sperm and other seminal-plasma parameters. Mol. Reprod. Dev. 82: 58-65, 2015. (c) 2014 Wiley Periodicals, Inc.

  • 4.
    Barranco, Isabel
    et al.
    University of Murcia, Spain.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Perez-Patino, Cristina
    University of Murcia, Spain.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Martinez, Emilio A.
    University of Murcia, Spain.
    Roca, Jordi
    University of Murcia, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    The Seminal Plasma of the Boar is Rich in Cytokines, with Significant Individual and Intra-Ejaculate Variation2015In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 6, p. 523-532Article in journal (Refereed)
    Abstract [en]

    Problem The boar, as human, sequentially ejaculates sperm-rich and sperm-poor fractions. Seminal plasma (SP) spermadhesins (PSP-I/PSP-II) induce a primary endometrial inflammatory response in female sows, similar to that elicited by semen deposition in other species, including human. However, the SP is also known to mitigate such response, making it transient to allow for embryo entry to a cleansed endometrium. Although cytokine involvement has been claimed, the exploration of cytokines in different SP fractions is scarce. This study determines Th1, Th2, Th17 and Th3 cytokine profiles in specific ejaculate SP fractions from boars of proven fertility. Methods SP samples from the sperm-rich fraction (SRF) and the sperm-poor post-SRF fraction (post-SRF) of manually collected ejaculates from eight boars (four ejaculates per boar) were analysed by commercial multiplex bead assay kits (Milliplex MAP, Millipore, USA) for interferon-gamma, interferon gamma-induced protein 10, macrophage-derived chemokine, growth-regulated oncogene, granulocyte-macrophage colony-stimulating factor, monocyte chemo-attractant protein-1, interleukins (IL)-6, IL-8, IL-10, IL-15, IL-17 and transforming growth factor (TGF)-beta 1-beta 3. Results Cytokine concentrations differed between the ejaculate fractions among boars, being highest in the post-SRF. Conclusion Boar SP is rich in Th1, Th2, Th17 and Th3 cytokines, with lowest concentrations in the sperm-peak-containing fraction, indicating its main immune influence might reside in the larger, protein-rich sperm-poor post-SRF.

  • 5.
    Jonsson, Yvonne
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences.
    Nieminen, Katri
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences.
    Sharma, Surendra
    Departments of Pediatrics and Pathology, Brown University and Women and Infants’ Hospital of Rhode Island, Providence, RI, USA.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Cytokine mapping of sera from women with preeclampsia and from women with normal pregnancies2006In: Journal of Reproductive Immunology, ISSN 0165-0378, Vol. 70, no 1-2, p. 83-91Article in journal (Refereed)
    Abstract [en]

    Introduction

    Preeclampsia is a pregnancy-specific syndrome. The immune system in preeclampsia is changed with an increased innate activity and there is a hypothesis of a shift towards Th1-type immunity. The aim of this study was to determine a spectrum of soluble immunological factors denoting different aspects of immune activation in third trimester sera from women with preeclampsia (N = 15) and compare with levels in sera from normal pregnant women (N = 15).

    Material and methods

    IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p40, IL-13, IL-15, IL-17, IFN-α, IFN-γ, TNF-α, GM-CSF, MIP-lα, MIP-1β, MCP-1, eotaxin and RANTES were measured in serum using multiplex bead arrays. The levels of soluble CD14 and soluble IL-4 receptor were measured by enzyme-linked immunoassay (ELISA).

    Results

    Preeclamptic women had significantly increased levels of circulating IL-6 (p = 0.002), IL-8 (p = 0.003) and soluble IL-4R (p = 0.037), compared to women with normal pregnancies.

    Conclusion

    This study supports the hypothesis of increased inflammatory responses in preeclampsia, illustrated by the increased levels of IL-6 and IL-8. The finding of increased levels of soluble IL-4 receptor is an intriguing finding with several interpretations, which may partly support the hypothesis of a Th1 shift in preeclampsia.

  • 6.
    Rodriguez-Martinez, Heriberto
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Tienthai, P.
    Chulalongkorn University, Thailand.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vicente Carrillo, Alejandro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Alvarez-Rodriguez, Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    The ubiquitous hyaluronan: Functionally implicated in the oviduct?2016In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 86, no 1, p. 182-186Article, review/survey (Refereed)
    Abstract [en]

    Hyaluronan (hyaluronic acid) is a simple, nonantigenic, nonsulfated glycosaminoglycan present everywhere in the extracellular compartments of the body. Noteworthy, it is highly conserved phylogenetically, from sauropsida to mammals; and plays a plethora of roles from embryonic/fetal development to adult physiological and pathological events, including tumor development. In reproduction, hyaluronan has proven related to initial events as sperm survival, buildup of the sperm reservoir in the oviduct, regulation of sperm capacitation, and prefertilization to later participate in embryo, fetal, and placental development. Synthesis, binding (via the CD44 membrane receptor), and degradation of hyaluronan occur in male and female genital organs, the oviduct being no exception. This review discusses our current knowledge on roles of this ubiquitous glycosaminoglycan on the survival of immunologically foreign spermatozoa in the pig oviduct, a relevant event for fertility. During preovulatory storage in the functional tubal sperm reservoir, spermatozoa are entrapped in a mucus-like tubal fluid. This fluid contains fluctuating levels of hyaluronan, which is synthesized by the lining epithelium by hyaluronan synthase 3. Both hyaluronan and its CD44 receptor are particularly evident in the deep mucosal furrows of the sperm reservoir, in which most spermatozoa are embedded in; kept alive, uncapacitated but also undetected by the immune system of the female. Hyaluronan is also present in the seminal plasma, and evidence points toward an involvement of hyaluronan and its receptor in the local (tubal and possibly uterine) production of antiinflammatory cytokines, such as interleulcin-10, pertaining maternal immune tolerance of these foreign cells. (C) 2015 Elsevier Inc. All rights reserved.

  • 7.
    Rubér, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Immunopathogenic aspects of resolving and progressing appendicitis2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Appendicitis is one of the most common diseases requiringemergency surgical intervention. There are several indications that the diagnosisappendicitis harbours two different entities, one progressing to gangrene and perforation(advanced) and one that resolves spontaneously (phlegmonous). An immunologically drivenpathogenesis in appendicitis has been suggested on the basis of an inverse relationshipbetween appendicitis and ulcerative colitis, a positive association with Crohn’s disease, anda decreased incidence during pregnancy, generating the hypothesis that theimmunopathogenesis in advanced appendicitis is characterized by a Th1 inflammatoryresponse. The aim of this thesis was to test this hypothesis and investigate the immuneresponse in advanced and phlegmonous appendicitis.

    Material and Methods: The immunologic response was investigated in appendicitis tissue and compared to the immunological response in peripheral blood, analysed by enzyme-linked immunospot assay (ELISPOT). The response pattern was also investigated in patients with an actual appendicitis in the peripheral plasma and peripheral serum before surgery, analysed with Luminex. The immunological response pattern was investigated in peripheral blood several months to years after an appendectomy using ELISPOT and enzyme-linked immunosorbent assay (ELISA).

    Results: The local immune response in the appendiceal tissue in appendicitis was similar to the response in peripheral blood. Patients with actual advanced appendicitis had increased levels of IL-6, CCL20, CCL2, TGF-β, IL-17, IFN-γ, IL-12p70, IL-10, IL-1ra, IL-4, MMP-8, MMP-9 and MPO compared with those with phlegmonous appendicitis. Sex, age or duration of symptoms could not explain the differences between the groups. Individuals with a history of advanced appendicitis had increased secretion of IFN-γ months to years after the appendectomy compared with individuals with a history of phlegmonous appendicitis.

    Conclusions: The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of peripheral blood in studies on appendicitis. The immunological response pattern in peripheral blood suggests Th1/Th17- induced inflammation in advanced appendicitis that is present at an early stage. Individuals with a history of advanced appendicitis have stronger Th1 responses than individuals with a history of phlegmonous appendicitis. This may reflect constitutional differences between patients with different outcomes of appendicitis. The increased inflammatory response observed early in advanced appendicitis suggests a more violent inflammation and supports the hypothesis of different immune pathogeneses, where excessive induction of Th1/Th17 immunity and/or deficiencies in down-regulatory feedback mechanisms may explain the excessive inflammation in advanced appendicitis, where the inflammation eventuates in gangrene and perforation.

    List of papers
    1. Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis
    Open this publication in new window or tab >>Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis
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    2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 1, p. 117-124Article in journal (Refereed) Published
    Abstract [en]

    Appendicitis is one of the most common and costly acute abdominal states of illnesses. Previous studies suggest two types of appendicitis which may be different entities, one which may resolve spontaneously and another that progresses to gangrene and perforation. Gangrenous appendicitis has a positive association to states of Th1 mediated immunity whereas Th2 associated immune states are associated with lower risk of appendicitis. This study investigated the inflammatory response pattern in patients previously appendicectomized for gangrenous (n = 7), or phlegmonous appendicitis (n = 8) and those with a non-inflamed appendix (n = 5). Peripheral blood mononuclear cells were analysed with ELISPOT analysis for number of spontaneous or antigen/mitogen stimulated IFN-γ, IL-4, IL-10 and IL-12 secreting cells or with ELISA for concentration of spontaneous or antigen/mitogen stimulated IFN-γ, IL-5 and IL-10. Spontaneously IL-10 secreting cells/100 000 lymphocytes were increased in the gangrenous group compared to the phlegmonous group (P = 0.015). The median concentration of IL-10 secreted after Tetanus toxoid (TT)-stimulation were higher in the gangrenous group and the control group, than the phlegmonous group (P = 0.048 and P = 0.027, respectively). The median concentration of TT induced IFN-γ secretion was higher for the gangrenous group compared to both the phlegmonous group and the control group (P = 0.037 and P = 0.003). Individuals with a history of gangrenous appendicitis demonstrated ability to increased IL-10 and IFN-γ production. The increased IFN-γ may support the notion of gangrenous appendicitis as an uncontrolled Th1 mediated inflammatory response and increased IL-10 may speculatively indicate the involvement of cytotoxic cells in the progression to perforation. © 2005 British Society for Immunology.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-37618 (URN)10.1111/j.1365-2249.2005.02957.x (DOI)36747 (Local ID)36747 (Archive number)36747 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    2. Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis
    Open this publication in new window or tab >>Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis
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    2010 (English)In: SURGERY, ISSN 0039-6060, Vol. 147, no 3, p. 366-372Article in journal (Refereed) Published
    Abstract [en]

    Background. Increasing circumstantial evidence suggests that not all patients with appendicitis will progress to perforation and that appendicitis that resolves may be a common event. Based on this theory and on indications of aberrant regulation of inflammation in gangrenous appendicitis, we hypothesized that. phlegmonous and gangrenous appendicitis are different entities with divergent immunoregulation. Methods. Blood samples were collected from patients with gangrenous appendicitis (n = 16), phlegmonous appendicitis (n = 21), and nonspecific abdominal pain (n = 42). Using multiplex bead arrays, we analyzed a range of inflammatory markers, such as interleukin (IL)-1ra, IL-1r beta, IL-2 IL-6, IL-10, IL-12p70, IL-15, and IL-17; interferon-gamma; tumor necrosis factor; CXCL8; CCL2; CCL3; and matrix metalloproteinase (MMP)-1 MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13 in blood. Results. Compared with patients with phlegmonous appendicitis and nonspecific abdominal pain, the patients With gangrenous appendicitis had increased levels of the proinflammatory markers IL-6, CCL2, IL-17, MMP-8, and MMP-9 (P andlt;= .04 each) accompanied by increased levels of the anti-inflammatory cytokines IL-1ra and IL-10 (P andlt;= .02). Patients with phlegmonous appendicitis had increased levels of IL-10 only. Conclusion. The finding of a pattern inflammatory markers compatible with the highly inflammatory A 17 subset in sera from, patients with gangrenous appendicitis, but not in phlegmonous appendicitis, supports the hypothesis that gangrenous and phlegmonous appendicitis are different entities with diver gent immune regulation. Additional studies of the differential immunopathogenesis of phlegmonous and gangrenous appendicitis are warranted, as this may have important implications in the diagnosis and management of patients with suspicion of appendicitis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54601 (URN)10.1016/j.surg.2009.09.039 (DOI)000275350700007 ()
    Available from: 2010-03-26 Created: 2010-03-26 Last updated: 2013-08-29
    3. Dysregulated Th1/Th17 response in advanced appendicitis
    Open this publication in new window or tab >>Dysregulated Th1/Th17 response in advanced appendicitis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The pathogenesis of appendicitis, the most common abdominal emergency for surgical intervention, is still unknown. Epidemiological differences between perforated and nonperforated appendicitis, polymorphism in the interleukin (IL)-6 gene associated with severity of appendicitis and a more pronounced Th1/Th17-like deviation in advanced compared to phlegmonous appendicitis has been reported. Altogether these findings may indicate that appendicitis harbours two different entities with different immuno-pathogenesis, one progressing to gangrene and perforation and one resolving. In this study we aimed to further investigate systemic cytokine profiles in a large sample of patients, with advanced and phlegmonous appendicitis from a Th1, Th2, Th17 and innate perspective, and also clarify if time as duration of symptoms could explain the differences.

    Methods: Blood samples were preoperatively collected from patients with advanced (n=61) and phlegmonous appendicitis (n=108). The Th1-associated (IFN-γ, IL-12p70), Th2-associated (IL-4, IL-5), Th17-associated (IL-17, IL-6, CCL20, CCL2) and innate-associated (IL-1β, IL-6, MPO, CXCL8, GM-CSF), markers were analyzed in plasma using multiplex bead assay.

    Results: Patients with advanced appendicitis had increased levels of IL-6 (P=0.0001), CCL2 (P=0.001), MPO (P=0.039), IL-12p70 (P=0.010) and CCL20 (P=0.002) as compared to phlegmonous appendicitis and age, sex or duration of symptoms at sampling could not explain the differences.

    Conclusion: The findings suggest a dysregulated Th1/Th17 type inflammation in advanced appendicitis, already early in the disease course, that eventuates in gangrene and perforation and gives further support to the notion of appendicitis as two entities.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80373 (URN)
    Available from: 2012-08-24 Created: 2012-08-24 Last updated: 2012-08-24Bibliographically approved
    4. Local and systemic cytokine secretion in advanced and phlegmonous appendicitis
    Open this publication in new window or tab >>Local and systemic cytokine secretion in advanced and phlegmonous appendicitis
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Appendicitis is the most common abdominal emergency for surgery, but its underlying pathogenesis is still unknown. Appendicitis most likely harbors two different entities with different pathogenesis, one progressing to gangrene and perforation and one resolving. Previous studies on cytokines in peripheral blood points to different immunopathogenesis in advanced and resolving appendicitis. The relation of the peripheral blood analyzes to the local immune response in appendix is unclear. This study investigated local immune response in the appendix compared to blood, utilizing enzyme linked immunospot essay (ELISpot) which allows detection of low grade cytokine secretion from single cells.

    Methods: Appendiceal tissue and blood samples were collected from patients with advanced (gangrenous or perforated) (n=11) and phlegmonous appendicitis (n=7). Mononuclear cells were analyzed with ELISpot for number of spontaneous and PHA stimulated IFN-γ-, IL-12p70-(both Th1), IL-4-(Th2), IL-17-(Th17), TGF-β-(anti-inflammatory/Th17) and IL-10-(anti-inflammatory/Th1) secreting cells.

    Results: In appendix, the number of IL-4-(P=0.042) and IL-10-(P=0.042) secreting cells was increased in advanced appendicitis as compared to phlegmonous and a trend for increase was observed for IL-12p70 (P=0.055) and TGF-β (P=0.067). In blood the number of IL-4-(P=0.045), TGF-β-(P=0.007) and IFN-γ-(P=0.019), secreting cells were increased in patients with advanced appendicitis and a trend for increase was observed for IL-12p70 (P=0.068)

    Conclusion: Present findings are in line with previous studies demonstrating an increased inflammatory response in advanced as compared to phlegmonous appendicitis. The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of analyzes on peripheral blood when investigating immune response in appendicitis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80374 (URN)
    Available from: 2012-08-24 Created: 2012-08-24 Last updated: 2012-08-24Bibliographically approved
  • 8.
    Rubér, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Andersson, Manne
    Unit for Autoimmunity and Immune regulation, County hospital Ryhov, Jönköping, Sweden.
    Olaison, Gunnar
    Copenhagen University, Faculty of Health Sciences, Department of Surgery, Hospital Nord, Holbæk, Denmark.
    Andersson, Roland E
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Unit for Autoimmunity and Immune regulation, County hospital Ryhov, Jönköping, Sweden.
    Dysregulated Th1/Th17 response in advanced appendicitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background: The pathogenesis of appendicitis, the most common abdominal emergency for surgical intervention, is still unknown. Epidemiological differences between perforated and nonperforated appendicitis, polymorphism in the interleukin (IL)-6 gene associated with severity of appendicitis and a more pronounced Th1/Th17-like deviation in advanced compared to phlegmonous appendicitis has been reported. Altogether these findings may indicate that appendicitis harbours two different entities with different immuno-pathogenesis, one progressing to gangrene and perforation and one resolving. In this study we aimed to further investigate systemic cytokine profiles in a large sample of patients, with advanced and phlegmonous appendicitis from a Th1, Th2, Th17 and innate perspective, and also clarify if time as duration of symptoms could explain the differences.

    Methods: Blood samples were preoperatively collected from patients with advanced (n=61) and phlegmonous appendicitis (n=108). The Th1-associated (IFN-γ, IL-12p70), Th2-associated (IL-4, IL-5), Th17-associated (IL-17, IL-6, CCL20, CCL2) and innate-associated (IL-1β, IL-6, MPO, CXCL8, GM-CSF), markers were analyzed in plasma using multiplex bead assay.

    Results: Patients with advanced appendicitis had increased levels of IL-6 (P=0.0001), CCL2 (P=0.001), MPO (P=0.039), IL-12p70 (P=0.010) and CCL20 (P=0.002) as compared to phlegmonous appendicitis and age, sex or duration of symptoms at sampling could not explain the differences.

    Conclusion: The findings suggest a dysregulated Th1/Th17 type inflammation in advanced appendicitis, already early in the disease course, that eventuates in gangrene and perforation and gives further support to the notion of appendicitis as two entities.

  • 9.
    Rubér, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Andersson, Manne
    County Hospital Ryhov.
    Petersson, B Fredrik
    Karolinska University Hospital.
    Olaison, Gunnar
    University of Copenhagen.
    Andersson, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Systemic Th17-like cytokine pattern in gangrenous appendicitis but not in phlegmonous appendicitis2010In: SURGERY, ISSN 0039-6060, Vol. 147, no 3, p. 366-372Article in journal (Refereed)
    Abstract [en]

    Background. Increasing circumstantial evidence suggests that not all patients with appendicitis will progress to perforation and that appendicitis that resolves may be a common event. Based on this theory and on indications of aberrant regulation of inflammation in gangrenous appendicitis, we hypothesized that. phlegmonous and gangrenous appendicitis are different entities with divergent immunoregulation. Methods. Blood samples were collected from patients with gangrenous appendicitis (n = 16), phlegmonous appendicitis (n = 21), and nonspecific abdominal pain (n = 42). Using multiplex bead arrays, we analyzed a range of inflammatory markers, such as interleukin (IL)-1ra, IL-1r beta, IL-2 IL-6, IL-10, IL-12p70, IL-15, and IL-17; interferon-gamma; tumor necrosis factor; CXCL8; CCL2; CCL3; and matrix metalloproteinase (MMP)-1 MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13 in blood. Results. Compared with patients with phlegmonous appendicitis and nonspecific abdominal pain, the patients With gangrenous appendicitis had increased levels of the proinflammatory markers IL-6, CCL2, IL-17, MMP-8, and MMP-9 (P andlt;= .04 each) accompanied by increased levels of the anti-inflammatory cytokines IL-1ra and IL-10 (P andlt;= .02). Patients with phlegmonous appendicitis had increased levels of IL-10 only. Conclusion. The finding of a pattern inflammatory markers compatible with the highly inflammatory A 17 subset in sera from, patients with gangrenous appendicitis, but not in phlegmonous appendicitis, supports the hypothesis that gangrenous and phlegmonous appendicitis are different entities with diver gent immune regulation. Additional studies of the differential immunopathogenesis of phlegmonous and gangrenous appendicitis are warranted, as this may have important implications in the diagnosis and management of patients with suspicion of appendicitis.

  • 10.
    Rubér, Marie
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Berg, A
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Andersson, Roland
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 1, p. 117-124Article in journal (Refereed)
    Abstract [en]

    Appendicitis is one of the most common and costly acute abdominal states of illnesses. Previous studies suggest two types of appendicitis which may be different entities, one which may resolve spontaneously and another that progresses to gangrene and perforation. Gangrenous appendicitis has a positive association to states of Th1 mediated immunity whereas Th2 associated immune states are associated with lower risk of appendicitis. This study investigated the inflammatory response pattern in patients previously appendicectomized for gangrenous (n = 7), or phlegmonous appendicitis (n = 8) and those with a non-inflamed appendix (n = 5). Peripheral blood mononuclear cells were analysed with ELISPOT analysis for number of spontaneous or antigen/mitogen stimulated IFN-γ, IL-4, IL-10 and IL-12 secreting cells or with ELISA for concentration of spontaneous or antigen/mitogen stimulated IFN-γ, IL-5 and IL-10. Spontaneously IL-10 secreting cells/100 000 lymphocytes were increased in the gangrenous group compared to the phlegmonous group (P = 0.015). The median concentration of IL-10 secreted after Tetanus toxoid (TT)-stimulation were higher in the gangrenous group and the control group, than the phlegmonous group (P = 0.048 and P = 0.027, respectively). The median concentration of TT induced IFN-γ secretion was higher for the gangrenous group compared to both the phlegmonous group and the control group (P = 0.037 and P = 0.003). Individuals with a history of gangrenous appendicitis demonstrated ability to increased IL-10 and IFN-γ production. The increased IFN-γ may support the notion of gangrenous appendicitis as an uncontrolled Th1 mediated inflammatory response and increased IL-10 may speculatively indicate the involvement of cytotoxic cells in the progression to perforation. © 2005 British Society for Immunology.

  • 11.
    Rubér, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Unit for Autoimmunity and Immune regulation, County hospital Ryhov, Jönköping, Sweden.
    Andersson, Roland E
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    Copenhagen University, Faculty of Health Sciences, Department of Surgery, Hospital Nord, Holbæk, Denmark.
    Local and systemic cytokine secretion in advanced and phlegmonous appendicitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Appendicitis is the most common abdominal emergency for surgery, but its underlying pathogenesis is still unknown. Appendicitis most likely harbors two different entities with different pathogenesis, one progressing to gangrene and perforation and one resolving. Previous studies on cytokines in peripheral blood points to different immunopathogenesis in advanced and resolving appendicitis. The relation of the peripheral blood analyzes to the local immune response in appendix is unclear. This study investigated local immune response in the appendix compared to blood, utilizing enzyme linked immunospot essay (ELISpot) which allows detection of low grade cytokine secretion from single cells.

    Methods: Appendiceal tissue and blood samples were collected from patients with advanced (gangrenous or perforated) (n=11) and phlegmonous appendicitis (n=7). Mononuclear cells were analyzed with ELISpot for number of spontaneous and PHA stimulated IFN-γ-, IL-12p70-(both Th1), IL-4-(Th2), IL-17-(Th17), TGF-β-(anti-inflammatory/Th17) and IL-10-(anti-inflammatory/Th1) secreting cells.

    Results: In appendix, the number of IL-4-(P=0.042) and IL-10-(P=0.042) secreting cells was increased in advanced appendicitis as compared to phlegmonous and a trend for increase was observed for IL-12p70 (P=0.055) and TGF-β (P=0.067). In blood the number of IL-4-(P=0.045), TGF-β-(P=0.007) and IFN-γ-(P=0.019), secreting cells were increased in patients with advanced appendicitis and a trend for increase was observed for IL-12p70 (P=0.068)

    Conclusion: Present findings are in line with previous studies demonstrating an increased inflammatory response in advanced as compared to phlegmonous appendicitis. The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of analyzes on peripheral blood when investigating immune response in appendicitis.

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