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Fcγ-receptors in systemic autoimmune conditions: lessons from murine mercury-induced autoimmunity
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-19161ISBN: 978-91-7393-619-4 (print)OAI: oai:DiVA.org:liu-19161DiVA: diva2:223466
Public defence
2009-06-05, Elsa Brännströms sal, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2009-08-21Bibliographically approved
List of papers
1. The role of Fc-receptors in murine mercury-induced systemic autoimmunity
Open this publication in new window or tab >>The role of Fc-receptors in murine mercury-induced systemic autoimmunity
2006 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 144, no 2, 309-318 p.Article in journal (Refereed) Published
Abstract [en]

Inorganic mercury (Hg) in genetically susceptible mouse strains induces a T cell-dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, anti-nuclear antibodies (ANA) and systemic immune-complex (IC) deposits. The exact phenotypic expression of HgIA in different strains depends on H-2 and non-H-2 genes. Fc receptors (FcRs) are important in the development of many autoimmune diseases. In this study, the effect of targeted mutations for activating and inhibiting FcRs in the BALB/c model of HgIA was examined. Hg-treated BALB/c mice without mutation (wild-type, wt) showed heavy IC deposits in the renal glomerular mesangium, as well as in renal and splenic vessel walls. The renal mesangial IC deposits were severely reduced in Hg-treated BALB/c mice without the gamma-chain (lack of the activating receptors FcgammaRI, FcgammaRIII and FcinRI), but unchanged in mice lacking the inhibitory FcgammaRIIB. The Hg-induced vessel wall IC deposits present in wt mice were abolished and reduced in the FcRgamma and FcgammaRIIB strains, respectively. Hg-treated BALB/c wt mice and mice without the gamma-chain showed an increase in serum IgE, while the increase in IgG1 was attenuated in the latter strain. In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE. In conclusion, FcRs are important mainly for the induction of systmeic IC deposits in the HgIA model, but also affects serum IgG1 and IgE levels.

Keyword
Autoimmunity, Fc ! R, Fc ! RIIB, mercury, mice
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19156 (URN)10.1111/j.1365-2249.2006.03057.x (DOI)16634805 (PubMedID)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
2. The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity
Open this publication in new window or tab >>The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity
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.

Keyword
Mercury, FcgR, Autoimmunity, Mice, ANoA
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19157 (URN)10.1016/j.jaut.2008.01.002 (DOI)18314309 (PubMedID)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
3. Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex deposits
Open this publication in new window or tab >>Lack of Fcγ-receptors increases circulating immune complexes but delays development of tissue immune complex deposits
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Inorganic mercury (Hg) induces in susceptible mouse strains a T-cell dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, antinuclear antibodies, and immune-complex (IC) deposits in glomeruli and vessel walls. Activating Fcγ-receptors (FcγRs) are important for induction of HgIA. We have examined if activating FcγRs affect circulating immune complexes (CIC), the initial development of tissue IC deposits and their composition in HgIA. BALB/c mice with a targeted mutation for activating FcγRs and BALB/c mice without any mutation (wild type - wt - mice) were treated up to 35 days with Hg. Wild type mice showed a significant but modest increase of CIC from day 12 until day 18 and day 35 for IgG2a- and IgG1-containing CIC, respectively. Mercury-treated FcγR−/− mice showed significantly higher CIC levels than Hg-treated wt mice during the entire treatment time for IgG1-CIC, and after 26 and 35 days for IgG2a-CIC. Tissue IC deposits developed later in the FcγR−/− mice especially in the renal mesangium. After 35 days of Hg treatment the fraction of mice with and/or the amount of IgG1 and C3c deposits were significantly reduced in vessel walls and for IgG1 also in the renal mesangium compared with wt mice. We conclude that susceptible mice lacking activating FcγRs respond to an autoimmune stimulus with increased levels and altered quality of CIC compared with wt mice. It is likely that lack of FcγRs reduced elimination of CIC as indicated by delayed and significantly reduced IC deposits in the tissues of mice without activating receptors.

Keyword
Mercury, FcγR, CIC, autoimmunity, mice
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19158 (URN)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2010-01-14Bibliographically approved
4. Cytokines in induction of ANoA and hypergammaglobulinemia in mercury-induced autoimmunity: a lesson from Fc!RIII deficient mice
Open this publication in new window or tab >>Cytokines in induction of ANoA and hypergammaglobulinemia in mercury-induced autoimmunity: a lesson from Fc!RIII deficient mice
(English)Manuscript (Other academic)
Abstract [en]

Xenobiotic agents such as metals, drugs, toxic oils and pristane can induce autoimmune diseases. Heavy metal induction of autoimmunity has been observed for mercury (Hg), silver and gold in mice. Mercury-induced autoimmunity (HgIA) in mice is characterised by lymphoproliferation, hypergammaglobulinemia, antinucleolar autoantibodies (ANoA) and immune complex deposits in the renal glomerular mesangium and systemically in vessel walls. HgIA is T-cell dependent, IFNγ is necessary for all manifestations of HgIA, and the activating Fc!RIII enhance development of ANoA. This study focused firstly on exploring the cytokine profile in the genetically susceptible DBA/1 (H-2q) wild type (wt) and DBA/1 FcγRIII-/- mice treated with 15 mg/l Hg, and secondly on the hypothesis that IFN-! producing NK cells are vital for induction of ANoA in the HgIA model. DBA/1 wt mice showed a significantly more marked Th1 profile compared to DBA/1 FcγRIII-/- mice following Hg treatment, whereas the total Th2 and Th17 profile increased in both DBA/1 wt and DBA/1 FcγRIII-/- mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in DBA/1 FcγRIII-/- mice compared with DBA/1 wt mice. However, we were unable to show that the increased Th1 profile in the DBA/1 wt mice was due to IFN-γsecretion from NK cells. Our findings suggest that the delayed ANoA induction in DBA/1 FcγRIII-/- mice is due to the attenuated Th1 profile. In addition the reduced expression of IL-21 in DBA/1 FcγRIII-/- mice might be responsible for the lack of serum IgG1 response in these mice.

Keyword
Fc!RIII, NK-cells, autoimmunity, cytokines, mercury
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19159 (URN)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2010-01-14Bibliographically approved

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