Fcγ-receptors in systemic autoimmune conditions : lessons from murine mercury-induced autoimmunity

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