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The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
2008 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 31, no 1, 22-29 p.Article in journal (Refereed) Published
Abstract [en]

Fc-receptors for IgG (FcgammaR) link cellular and humoral immune responses, controlling the balance between activating and inhibitory immune responses, and are involved in autoimmune diseases. Mercury (Hg) induces an autoimmune condition in genetically (H-2(s,q,f)) susceptible mice characterized by lymphoproliferation, hypergammaglobulinemia and IgG antinucleolar antibodies (ANoA). Here we investigate the role of activating (FcgammaRI, FcgammaRIII) and inhibitory (FcgammaRIIb) Fc-receptors on mercury-induced autoimmunity (HgIA) using DBA/1 mice (H-2(q)) with targeted FcgammaR mutations and wild type (wt) mice. Mice deficient for the FcRgamma-chain or FcgammaRIII and treated with 15 mg/L HgCl(2) showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice. Female Hg-treated FcgammaRIIB(-/-) mice showed a significant increased of IgG2b ANoA development compared to wt mice. The total serum IgG1 response due to Hg was attenuated in FcRgamma(-/-) and FcgammaRIII(-/-) mice compared to wt mice. Hg-treated FcgammaRIIB(-/-) mice showed an increase of both serum IgG1 and IgE compared to wt mice. We conclude that FcgammaRIII is of importance for the rapidity and final strength of the ANoA response and the increase in serum IgG1 in HgIA, while lack of FcgammaRIIb increases the IgG2b ANoA response and the serum IgG1 and IgE response.

Place, publisher, year, edition, pages
2008. Vol. 31, no 1, 22-29 p.
Keyword [en]
Mercury, FcgR, Autoimmunity, Mice, ANoA
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-19157DOI: 10.1016/j.jaut.2008.01.002PubMedID: 18314309OAI: oai:DiVA.org:liu-19157DiVA: diva2:223456
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2014-03-12Bibliographically approved
In thesis
1. Fcγ-receptors in systemic autoimmune conditions: lessons from murine mercury-induced autoimmunity
Open this publication in new window or tab >>Fcγ-receptors in systemic autoimmune conditions: lessons from murine mercury-induced autoimmunity
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis we investigated the role of activating (FcγRI, FcγRIII) and inhibitory (FcγRIIB) Fcγ-receptors on systemic autoimmunity using two mouse strains, DBA/1 (H-2q) and BALB/c mice (H-2d), susceptible to induction of autoimmunity by mercury (Hg).

Fc-receptors for IgG (FcγR) link cellular and humoral immune responses, control the balance between activating and inhibitory immune responses and are important in the development of several autoimmune diseases. Mercury induces a T cell-dependent autoimmune condition, Hg-induced autoimmunity (HgIA) in genetically (H-2s,q,f,t2) susceptible mice characterized in its fullblown type by lymphoproliferation, hypergammaglobulinemia, systemic immune-complex (IC) deposits and antinucleolar antibodies (ANoA). All manifestations in HgIA are dependent on the presence of IFN-γ.

Hg-treated BALB/c mice lacking activating FcγRs (FcγRI, FcγIII and FcεRI) showed significantly higher levels of both IgG1- and IgG2a-CIC whereas renal mesangial and vessel wall IC deposits were severely delayed and reduced/abolished, compared to mice without mutations (wild type, wt). Wt mice developed modest levels of IgG1- and IgG2a-CIC followed by a distinct formation of IC deposits in the renal glomerular mesangium, as well in renal and splenic vessel walls. Compared to wt mice, the mice lacking the inhibitory FcγRIIB showed similar titres of IC deposits in the renal mesangium, whereas vessel wall IC deposits were reduced.

DBA/1 mice deficient for the FcRγ-chain (lack of the activating receptors FcγRI, FcγIII and FcεRI) or FcγRIII and treated with Hg showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice.

Increasing the Hg dose or prolonging the treatment time could not override the attenuated ANoA response seen in FcγRIII mice. Female Hg-treated FcγRIIB mice showed a significant increase of IgG2b ANoA development compared to wt mice.

The total serum IgG1 response due to treatment with Hg was attenuated in both BALB/c mice lacking the Fcγ-chain, and in DBA/1 mice lacking either the Fcγ- chain or specifically the FcγRIII compared to wt mice. This indicates that FcγRIII is the receptor important for the in HgIA characteristic serum IgG1 response. On the other hand, Hg-treated FcγRIIB deficient BALB/c and DBA/1 mice showed an increase of both serum IgG1 and IgE compared to wt mice.

The cytokine profile in DBA/1 wt mice treated with Hg revealed a more marked Th1 profile compared to FcγRIII deficient mice. In contrast, the total Th2 and Th17 profile increased in both wt and FcγRIII deficient mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in FcγRIII deficient mice compared with wt mice. The increased Th1 profile in the wt mice could not be attributed to an increase of IFN-γ secretion from the major IFN-γ cell source, NK cells.

We conclude that FcγRIII are important for the formation of IC deposits as shown by the delayed and reduced formation of IC deposits and the high levels of CIC in mice lacking FcγRIII. The expression of FcγRIII is also of importance for the rapidity and final strength of the ANoA response probably due to a reduced expression of Th1 cytokines and inflammatory factors. The ANoA response is modestly counter-regulated by FcγRIIB. The increase of serum IgG1 in HgIA is dependent on FcγRIII which is likely to be mediated by the low expression of IL- 21 in mice deficient for FcγRIII. In contrast, lack of FcγRIIB increases both the serum IgG1 and IgE response.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 91 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1132
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19161 (URN)978-91-7393-619-4 (ISBN)
Public defence
2009-06-05, Elsa Brännströms sal, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
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Supervisors
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2009-08-21Bibliographically approved

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Martinsson, KlaraKarlsson, LouiseHultman, Per

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