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  • 1.
    Ekstrand, Jimmy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nielsen, Jesper B
    University South Denmark.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Zalups, Rudolfs K
    Mercer University.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. 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 Clinical Genetics.
    Mercury toxicokinetics-dependency on strain and gender2010In: TOXICOLOGY AND APPLIED PHARMACOLOGY, ISSN 0041-008X, Vol. 243, no 3, p. 283-291Article in journal (Refereed)
    Abstract [en]

    Mercury (Hg) exposure from dental amalgam fillings and thimerosal in vaccines is not a major health hazard, but adverse health effects cannot be ruled out in a small and more susceptible part of the exposed population. Individual differences in toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.SW and B10.S mice and their F1- and F2-hybrids were given HgCl2 with 2.0 mg Hg/L drinking water and traces of Hg-203. Whole-body retention (WBR) was monitored until steady state after 5 weeks, when the organ Hg content was assessed. Despite similar Hg intake, A.SW males attained a 20-30% significantly higher WBR and 2- to 5-fold higher total renal Hg retention/concentration than A.SW females and B10.S mice. A selective renal Hg accumulation but of lower magnitude was seen also in B10.S males compared with females. Differences in WBR and organ Hg accumulation are therefore regulated by non-H-2 genes and gender. Lymph nodes lacked the strain- and gender-dependent Hg accumulation profile of kidney, liver and spleen. After 15 days without Hg A.SW mice showed a 4-fold higher WBR and liver Hg concentration, but 11-fold higher renal Hg concentration, showing the key role for the kidneys in explaining the slower Hg elimination in A.SW mice. The trait causing higher mercury accumulation was not dominantly inherited in the F1 hybrids. F2 mice showed a large inter-individual variation in Hg accumulation, showing that multiple genetic factors influence the Hg toxicokinetics in the mouse. The genetically heterogeneous human population may therefore show a large variation in mercury toxicokinetics.

  • 2.
    Fryland, Linda
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Tobias
    Department of Molecular Biology, Umeå University, Umeå, Sweden.
    Bergström, Sven
    Department of Molecular Biology, Umeå University, Umeå, Sweden.
    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 Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
    Mapping of T-cell subsets in relation to disease course in experimental Borrelia burgdorferi infection2012Manuscript (preprint) (Other academic)
    Abstract [en]

    Resolution of Lyme borreliosis has previously been shown to be associated with a strong initial Th1 response, followed by a subsequent Th2 response,  shutting off inflammation. We mapped markers for Th1, Th2, Th17, cytotoxic and T regulatory subsets in a murine model, where the outcome of Borrelia (B.) burgdorferi sensu stricto (s.s.) infection was altered by immune-deviation towards Th2 by exposure to a subtoxic dose of mercury. Twenty-one B. burgdorferi s.s.-infected (Bb), 21 immune-deviated B. burgdorferi s.s.-infected (BbId), and seven control C3H/HeN mice were sacrificed on days 15, 28 and 43 post-infection (p.i.) with B. burgdorferi s.s. BbId mice had increased joint swelling compared with Bb at the height of the disease (28 p.i.), and also showed a trend for increased spirochaetal load that became significant on day 43 p.i. BbId had an increased histopathology score on day 28 p.i. compared with both earlier and later time points. mRNA expression of IL-4 (p=0.018), IL-10 (p=0.018) and EBI-3 (p=0.009) decreased in Bb mice, but not in BbId, over the course of infection. A trend for higher expression of IL-12p40 mRNA in Bb mice compared with BbId was seen late in the disease course, while BbId showed trends for higher levels of Foxp3 and GM-CSF. At the protein level, BbId showed decreased levels of CXCL9 compared to the Bb group on day 15 p.i (p=0.007). Bb mice showed increases of CXCL9 and CXCL10 at all time points compared with day 0 p.i. (p≤0.014), whereas BbId mice showed an initial decrease in both chemokines at day 15 p.i. compared with day 0 (p≤0.008). In conclusion, both the clinical signs of infection and the trends for increased expression of pro-inflammatory GM-CSF and T-regulatory marker Foxp3 in BbId mice suggested ongoing inflammation. Although our findings support the need for a strong Th1 response followed by anti-inflammatory response for optimal resolution, the anti-inflammatory response seems to be more complex than only dampening the inflammation by a Th1-antagonistic Th2 response.

  • 3.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Effect of thimerosal on the murine immune system: especially induction of systemic autoimmunity2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The organic mercury compound ethylmercurithiosalicylate (thimerosal), an antiseptic and a preservative, has recently raised public health concern due to its presence in vaccines globally. Thimerosal dissociates in the body to thiosalicylate and ethyl mercury (EtHg), which is partly converted to inorganic mercuric mercury (Hg2+). The immunosuppressive, immunostimulatory, and de novo autoimmunogen effect of thimerosal in mice, as well as the accelerating/aggravating effect on spontaneous systemic autoimmunity including dose-response aspects were the subject of this thesis.

    Thimerosal perorally (590 μg Hg/kg body weight (bw)/day) to genetically susceptible (H-2s) mice caused immunosuppression during the first week with reduction of the total number of splenocytes, T- and B-cells. The suppression lasted 2 weeks for CD4+ cells, but was superseded by a strong immunostimulation/proliferation including T- as well as B-cells, and polyclonal B-cell activation (PBA). Antinuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin (AFA) appeared after 10 days, followed by renal mesangial and systemic vessel wall immune-complex (IC) deposits. The Lowest Observed Adverse Effect Level (LOAEL) was in the order AFA = glomerular and splenic vessel wall deposits < hyperimmunoglobulinemia < PBA. The LOAEL for AFA was 118 μg Hg/kg bw/day. The LOAEL for the different parameters of this thimerosal-induced systemic autoimmune condition (HgIA) was 3-11-fold higher compared with HgIA induced by HgCl2. The thimerosal-induced HgIA shared with HgCl2 a significant dose-response relationship, and requirement for: T-cells, the costimulatory factor CD28, the IFN-γ/IFN-γ-receptor pathway,but not IL-4. The mRNA expression in lymph nodes of IL-2, IFN-γ, IL-4, and IL-15 was significantly increased but not delayed compared with HgCl2.

    Treatment with the ubiquitous organic Hg compound methyl Hg using equimolar doses of Hg (533 μg Hg/kg bw/day) caused a transient immunosuppression, followed by a weak immunostimulation and AFA. The IgG AFA isotypes induced by the organic Hg compounds MeHg and EtHg were stable and dominated by a Th1-like pattern over a broad time- and dose range. Treatment with inorganic HgCl2 caused a dose- and time-dependent pattern of IgG AFA isotypes. Low doses favored a Th1-like pattern, a high dose a balanced or Th2-like pattern. Middle-range doses showed initially a Th1-like pattern which gradually evolved into a balanced or Th2-like pattern. The qualitative difference in IgG AFA isotypes between organic and inorganic Hg may be due to differences in activation and/or suppression of T-helper cell subsets or factors influencing the Th1/Th2-function. Speciation of the renal Hg2+ concentration and comparison with the threshold dose for induction of AFA by HgCl2 showed that even with the lowest doses of thimerosal and MeHg used in this thesis, the AFA response might from a dose threshold point of view have been caused by conversion of the organic Hg species to Hg2+.

    Primary treatment with inorganic Hg (HgCl2) accelerates/aggravates murine systemic autoimmunity, both spontaneous (genetic) and induced by other means. This capacity was assessed for thimerosal over a broad dose range using the (NZB X NZW)F1 hybrid mouse model. Significantly increased antinuclear antibodies (ANA) was seen after 4-7 weeks treatment (LOAEL 147 μg Hg/kg bw/day), and the response was dose-dependent up to 13 weeks. Renal mesangial and systemic vessel walls deposits similar to those in de novo HgIA were present after 7 weeks treatment. Twenty-two to 25 weeks treatment with thimerosal caused, in a dose-dependent fashion (LOAEL 295 μg Hg/kg bw/day), relocalization of the spontaneously developing glomerular IC deposits from the capillary vessel walls to the mesangium, which attenuated histological kidney damage and proteinuria, and increased survival. Thimerosal caused systemic vessel wall IC-deposits over a broad dose range: the Low Observed Adverse Effect Level (LOAEL) for renal and splenic vessel wall IC deposits was 18 and 9 μg Hg/kg bw/day, respectively. The No Observed Adverse Effect Level (NOAEL) could not be determined for the latter, since deposits were present even with the lowest dose used.

    Thimerosal causes in genetically susceptible mice an initial, transient immunosuppression which is superseded by a strong immunostimulation and systemic autoimmunity, sharing many characteristics with the HgIA induced by inorganic HgCl2. The IgG AFA isotype pattern is however qualitatively different, and the threshold dose substantially higher. In contrast, long-term treatment with thimerosal induces systemic vessel wall IC-deposits also using doses below those needed to induce HgIA de novo in H-2s mice.

    List of papers
    1. Dose-response study of thimerosal-induced murine systemic autoimmunity
    Open this publication in new window or tab >>Dose-response study of thimerosal-induced murine systemic autoimmunity
    2004 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 194, no 2, p. 169-179Article in journal (Refereed) Published
    Abstract [en]

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury.

    A.SW mice were exposed to 1.25–40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose–response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.

    Keywords
    Thimerosal, Ethylmercury, Mice, Autoimmunity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13815 (URN)10.1016/j.taap.2003.09.006 (DOI)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2009-08-18
    2. Immunosuppressive and autoimmune effects of thimerosal in mice
    Open this publication in new window or tab >>Immunosuppressive and autoimmune effects of thimerosal in mice
    Show others...
    2005 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 204, no 2, p. 109-121Article in journal (Refereed) Published
    Abstract [en]

    The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2s) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 μg Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-γ mRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment with increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-1-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2s strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (t1), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2s mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell co-stimulatory molecule CD28 (B10.S–CD28−/−), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2s strains with targeted mutations, we found that IFN-γ and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 81 μg Hg/g. EtHg made up 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.

    Keywords
    Thimerosal; Ethylmercury; Mice; Immunosuppression; Autoimmunity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13816 (URN)10.1016/j.taap.2004.08.019 (DOI)
    Available from: 2006-04-21 Created: 2006-04-21
    3. The autoimmunogen effect of the organic mercury species methyl mercury and ethyl mercury
    Open this publication in new window or tab >>The autoimmunogen effect of the organic mercury species methyl mercury and ethyl mercury
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13817 (URN)
    Available from: 2006-04-21 Created: 2006-04-21 Last updated: 2010-01-13
    4. Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury)
    Open this publication in new window or tab >>Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury)
    2006 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 214, no 1, p. 43-54Article in journal (Refereed) Published
    Abstract [en]

    Inorganic mercury may aggravate murine systemic autoimmune diseases which are either spontaneous (genetically determined) or induced by non-genetic mechanisms. Organic mercury species, the dominating form of mercury exposure in the human population, have not been examined in this respect. Therefore, ethyl mercury in the form of thimerosal, a preservative recently debated as a possible health hazard when present in vaccines, was administered in a dose of 0.156–5 mg/L drinking water to female (NZB × NZW)F1 (ZBWF1) mice. These mice develop an age-dependent spontaneous systemic autoimmune disease with high mortality primarily due to immune-complex (IC) glomerulonephritis. Five mg thimerosal/L drinking water (295 μg Hg/kg body weight (bw)/day) for 7 weeks induced glomerular, mesangial and systemic vessel wall IC deposits and antinuclear antibodies (ANA) which were not present in the untreated controls. After 22–25 weeks, the higher doses of thimerosal had shifted the localization of the spontaneously developing renal glomerular IC deposits from the capillary wall position seen in controls to the mesangium. The altered localization was associated with less severe histological kidney damage, less proteinuria, and reduced mortality. The effect was dose-dependent, lower doses having no effect compared with the untreated controls. A different effect of thimerosal treatment was induction of renal and splenic vessel walls IC deposits. Renal vessel wall deposits occurred at a dose of 0.313–5 mg thimerosal/L (18–295 μg Hg/kg bw/day), while splenic vessel wall deposits developed also in mice given the lowest dose of thimerosal, 0.156 mg/L (9 μg Hg/kg bw/day). The latter dose is 3- and 15-fold lower than the dose of Hg required to induce vessel wall IC deposits in genetically susceptible H-2s mice by HgCl2 and thimerosal, respectively. Further studies on the exact conditions needed for induction of systemic IC deposits by low-dose organic mercurials in autoimmune-prone individuals, as well as the potential effect of these deposits on the vessel walls, are warranted.

    Keywords
    Thimerosal; Mice; Autoimmunity; Immune-complex; (NZB × NZW)F1 mice
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13818 (URN)10.1016/j.taap.2005.12.004 (DOI)
    Available from: 2006-04-21 Created: 2006-04-21
  • 4.
    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.

  • 5.
    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.

  • 6.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental 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.
    Alteration of the spontaneous systemic autoimmune disease in (NZB x NZW)F1 mice by treatment with thimerosal (ethyl mercury)2006In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 214, no 1, p. 43-54Article in journal (Refereed)
    Abstract [en]

    Inorganic mercury may aggravate murine systemic autoimmune diseases which are either spontaneous (genetically determined) or induced by non-genetic mechanisms. Organic mercury species, the dominating form of mercury exposure in the human population, have not been examined in this respect. Therefore, ethyl mercury in the form of thimerosal, a preservative recently debated as a possible health hazard when present in vaccines, was administered in a dose of 0.156–5 mg/L drinking water to female (NZB × NZW)F1 (ZBWF1) mice. These mice develop an age-dependent spontaneous systemic autoimmune disease with high mortality primarily due to immune-complex (IC) glomerulonephritis. Five mg thimerosal/L drinking water (295 μg Hg/kg body weight (bw)/day) for 7 weeks induced glomerular, mesangial and systemic vessel wall IC deposits and antinuclear antibodies (ANA) which were not present in the untreated controls. After 22–25 weeks, the higher doses of thimerosal had shifted the localization of the spontaneously developing renal glomerular IC deposits from the capillary wall position seen in controls to the mesangium. The altered localization was associated with less severe histological kidney damage, less proteinuria, and reduced mortality. The effect was dose-dependent, lower doses having no effect compared with the untreated controls. A different effect of thimerosal treatment was induction of renal and splenic vessel walls IC deposits. Renal vessel wall deposits occurred at a dose of 0.313–5 mg thimerosal/L (18–295 μg Hg/kg bw/day), while splenic vessel wall deposits developed also in mice given the lowest dose of thimerosal, 0.156 mg/L (9 μg Hg/kg bw/day). The latter dose is 3- and 15-fold lower than the dose of Hg required to induce vessel wall IC deposits in genetically susceptible H-2s mice by HgCl2 and thimerosal, respectively. Further studies on the exact conditions needed for induction of systemic IC deposits by low-dose organic mercurials in autoimmune-prone individuals, as well as the potential effect of these deposits on the vessel walls, are warranted.

  • 7.
    Havarinasab, Said
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology .
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Organic mercury compounds and autoimmunity2005In: Autoimmunity Reviews, ISSN 1568-9972, E-ISSN 1873-0183, Vol. 4, no 5, p. 270-275Article, review/survey (Refereed)
    Abstract [en]

    Based on in vitro studies and short-term in vivo studies, all mercurials were for a long time considered as prototypic immunosuppressive substances. Recent studies have confirmed that organic mercurials such as methyl mercury (MeHg) and ethyl mercury (EtHg) are much more potent immunosuppressors than inorganic mercury (Hg). However, Hg interacts with the immune system in the presence of a susceptible genotype to cause immunostimulation, antinucleolar antibodies targeting fibrillarin, and systemic immune-complex (IC) deposits, a syndrome called Hg-induced autoimmunity (HgIA). Recent studies in mice with a susceptible genotype has revealed that the immunosuppressive effect of MeHg and EtHg will within 1-3 weeks be superseded by immunostimulation causing an HgIA-like syndrome. At equimolar doses of Hg, MeHg has the weakest immunostimulating, autoimmunogen, and IC-inducing effect, while the effect of thimerosal is similar to that of inorganic mercury. The immunosuppression is caused by the organic mercurials per se. Since they undergo rapid transformation to inorganic Hg, studies are being undertaken to delineate the importance of the organic substances per se and the newly formed inorganic Hg for induction of autoimmunity. © 2004 Elsevier B.V. All rights reserved.

  • 8.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Björn, Erik
    Department of Chemistry, Analytical Chemistry, Umeå University, Umeå, Sweden.
    Pollard, K.M.
    Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Immunosuppressive and autoimmune effects of thimerosal in mice2005In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 204, no 2, p. 109-121Article in journal (Refereed)
    Abstract [en]

    The possible health effects of the organic mercury compound thimerosal (ethylmercurithiosalicylate), which is rapidly metabolized to ethylmercury (EtHg), have recently been much debated and the effect of this compound on the immune system is largely unknown. We therefore studied the effect of thimerosal by treating A.SW (H-2s) mice, susceptible to induction of autoimmunity by heavy metals, with 10 mg thimerosal/L drinking water (internal dose ca 590 μg Hg/kg body weight/day) for up to 30 days. The lymph node expression of IL-2 and IL-15 mRNA was increased after 2 days, and of IL-4 and IFN-γ mRNA after 6 and 14 days. During the first 14 days treatment, the number of splenocytes, including T and B cells as well as Ig-secreting cells decreased. A strong immunostimulation superseded after 30 days treatment with increase in splenic weight, number of splenocytes including T and B cells and Ig-secreting cells, and Th2- as well as Th-1-dependent serum immunoglobulins. Antinucleolar antibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin, and systemic immune-complex deposits developed. The H-2s strains SJL and B10.S also responded to thimerosal treatment with ANoA. The A.TL and B10.TL strain, sharing background genes with the A.SW and B10.S strain, respectively, but with a different H-2 haplotype (t1), did not develop ANoA, linking the susceptibility to H-2. Thimerosal-treated H-2s mice homozygous for the nu mutation (SJL-nu/nu), or lacking the T-cell co-stimulatory molecule CD28 (B10.S–CD28−/−), did not develop ANoA, which showed that the autoimmune response is T-cell dependent. Using H-2s strains with targeted mutations, we found that IFN-γ and IL-6, but not IL-4, is important for induction of ANoA by thimerosal. The maximum added renal concentration of thimerosal (EtHg) and inorganic mercury occurred after 14 days treatment and was 81 μg Hg/g. EtHg made up 59% and inorganic mercury 41% of the renal mercury. In conclusion, the organic mercury compound thimerosal (EtHg) has initial immunosuppressive effects similar to those of MeHg. However, in contrast to MeHg, thimerosal treatment leads in genetically susceptible mice to a second phase with strong immunostimulation and autoimmunity, which is T-cell dependent, H-2 linked and may at least partly be due to the inorganic mercury derived from the metabolism of ethyl mercury.

  • 9.
    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.

  • 10.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Lambertsson, Lars
    Department of Chemistry, Analytical Chemistry, Umeå University, Umeå, Sweden.
    Qvarnström, Johanna
    Department of Chemistry, Analytical Chemistry, Umeå University, Umeå, Sweden.
    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 Clinical Genetics.
    Dose-response study of thimerosal-induced murine systemic autoimmunity2004In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 194, no 2, p. 169-179Article in journal (Refereed)
    Abstract [en]

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury.

    A.SW mice were exposed to 1.25–40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose–response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.

  • 11.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Pollard, K M
    Scripps Research Institute.
    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 Clinical Genetics.
    Gold- and silver-induced murine autoimmunity - requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 3, p. 567-576Article in journal (Refereed)
    Abstract [en]

    Treatment with gold in the form of aurothiomaleate, silver or mercury (Hg) in genetically susceptible mouse strains (H-2(s) ) induces a systemic autoimmune condition characterized by anti-nuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin, as well as lymphoproliferation and systemic immune-complex (IC) deposits. In this study we have examined the effect of single-gene deletions for interferon (IFN)-gamma, interleukin (IL)-4, IL-6 or CD28 in B10.S (H-2(s) ) mice on heavy metal-induced autoimmunity. Targeting of the genes for IFN-gamma, IL-6 or CD28 abrogated the development of both anti-fibrillarin antibodies (AFA) and IC deposits using a modest dose of Hg (130 mu g Hg/kg body weight/day). Deletion of IL-4 severely reduced the IgG1 AFA induced by all three metals, left the total IgG AFA response intact, but abrogated the Hg-induced systemic IC deposits. In conclusion, intact IFN-gamma and CD28 genes are necessary for induction of AFA with all three metals and systemic IC deposits using Hg, while lack of IL-4 distinctly skews the metal-induced AFA response towards T helper type 1. In a previous study using a higher dose of Hg (415 mu g Hg/kg body weight/day), IC deposits were preserved in IL-4(-/-) and IL-6(-/-) mice, and also AFA in the latter mice. Therefore, the attenuated autoimmunity following loss of IL-4 and IL-6 is dose-dependent, as higher doses of Hg are able to override the attenuation observed using lower doses.

  • 12.
    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.

  • 13. 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.

  • 14. Qvarnström, Johanna
    et al.
    Lambertsson, Lars
    Havarinasab, Said
    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.
    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.
    Frech, Wolfgang
    Determination of methylmercury, ethylmercury, and inorganic mercury in mouse tissues, following administration of thimerosal, by species-specific isotope dilution GC-inductively coupled plasma-MS2003In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 75, no 16, p. 4120-4124Article in journal (Refereed)
    Abstract [en]

    Isotopically enriched HgO standards were used to synthesize CH 3200Hg+ and C2H5199Hg+ using Grignard re-agents. These species were employed for isotope dilution GC-ICPMS to study uptake and biotransformation of ethylmercury in mice treated with thimerosal, (sodium ethylmercurithiosalicylate) 10 mg L-1 in drinking water ad libitum for 1, 2.5, 6, or 14 days. Prior to analysis, samples were spiked with aqueous solutions of CH3200Hg+, C2H 5199Hg+, and 201Hg2+ and then digested in 20% tetramethylammonium hydroxide and extracted at pH 9 with DDTC/toluene. Extracted mercury species were reacted with butylmagnesium chloride to form butylated derivatives. Absolute detection limits for CH 3Hg+, C2H5Hg+, and Hg2+ were 0.4, 0.2, and 0.6 pg on the basis of 3s of five separate blanks. Up to 9% of the C2H5Hg+ was decomposed to Hg2+ during sample preparation, and it is therefore crucial to use a species-specific internal standard when determining ethylmercury. No demethylation, methylation, or ethylation during sample preparation was detected. The ethylmercury component of thimerosal was rapidly taken up in the organs of the mice (kidney, liver, and mesenterial lymph nodes), and concentrations of C2H5Hg+ as well as Hg2+ increased over the 14 days of thimerosal treatment. This shows that C2H5Hg+ in mice to a large degree is degraded to Hg2+. Increased concentrations of CH3Hg + were also observed, which was found to be due to impurities in the thimerosal.

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