Fc?-receptors in systemic autoimmune conditions lessons from murine mercury-induced autoimmunity

Sammanfattning: In this thesis we investigated the role of activating (Fc?RI, Fc?RIII) and inhibitory (Fc?RIIB) Fc?-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 (Fc?R) 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-?.Hg-treated BALB/c mice lacking activating Fc?Rs (Fc?RI, Fc?III and Fc?RI) 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 Fc?RIIB showed similar titres of IC deposits in the renal mesangium, whereas vessel wall IC deposits were reduced.DBA/1 mice deficient for the FcR?-chain (lack of the activating receptors Fc?RI, Fc?III and Fc?RI) or Fc?RIII 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 Fc?RIII mice. Female Hg-treated Fc?RIIB 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 Fc?-chain, and in DBA/1 mice lacking either the Fc?- chain or specifically the Fc?RIII compared to wt mice. This indicates that Fc?RIII is the receptor important for the in HgIA characteristic serum IgG1 response. On the other hand, Hg-treated Fc?RIIB 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 Fc?RIII deficient mice. In contrast, the total Th2 and Th17 profile increased in both wt and Fc?RIII deficient mice. However, during Hg treatment IL-21 mRNA expression was significantly reduced in Fc?RIII deficient mice compared with wt mice. The increased Th1 profile in the wt mice could not be attributed to an increase of IFN-? secretion from the major IFN-? cell source, NK cells.We conclude that Fc?RIII 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 Fc?RIII. The expression of Fc?RIII 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 Fc?RIIB. The increase of serum IgG1 in HgIA is dependent on Fc?RIII which is likely to be mediated by the low expression of IL- 21 in mice deficient for Fc?RIII. In contrast, lack of Fc?RIIB increases both the serum IgG1 and IgE response.