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The immunosuppressive effect of methylmercury does not preclude development of autoimmunity in genetically susceptible mice
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Analytical Chemistry, Department of Chemistry, Umeå University, Umeå, Sweden.
Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
2005 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 208, no 1, 149-164 p.Article in journal (Refereed) Published
Abstract [en]

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

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

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

Place, publisher, year, edition, pages
2005. Vol. 208, no 1, 149-164 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-30139DOI: 10.1016/j.tox.2004.11.020Local ID: 15619OAI: oai:DiVA.org:liu-30139DiVA: diva2:250960
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-22Bibliographically approved
In thesis
1. Studies on cytokines in experimental metal-induced systemic autoimmunity
Open this publication in new window or tab >>Studies on cytokines in experimental metal-induced systemic autoimmunity
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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

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

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

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

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

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 64 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 863
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22315 (URN)1510 (Local ID)91-7373-837-9 (ISBN)1510 (Archive number)1510 (OAI)
Public defence
2004-10-22, Eken, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-22Bibliographically approved

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Häggqvist, BoHavarinasab, SaidHultman, Per

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