Genetic differences in immune reactivity to mercuric chloride (HgCl2): immunosuppression of H-2d mice is mediated by interferon-gamma (IFN-γ)

Abstract

SUMMARYUpon treatment with HgCl 2 , H-2 s mice, such as B10.S, develop an activation of B lymphocytes that depends, at least partially, on activation of T helper type 2 (Th2) cells and results in increased serum levels of IgG1 and IgE, appearance of IgG autoantibodies, and development of immune glomerulonephritis and vasculitis. Results of previous studies and of experiments presented here indicate that the B cell activation and systemic autoimmune disease fail to develop in MHC-congenic B10.D2 (H-2 d ) and B10.BR (H-2 k ) mice treated with HgCl 2 , although B10.D2 T cells showed signs of activation by and specificity for HgCl 2 comparable to those seen in strain B10.S. Here, we report that following HgCl 2 injections the antibody response to sheep erythrocytes is normal in B10.S, but suppressed in B10.D2 mice. This suppression was prevented by MoAb to mouse IFN-g. Conversely, treatment of B10.D2 mice with murine recombinant IFN-g (rIFN-g) was able to reproduce the immunosuppression seen after HgCl 2 treatment. In B10.S mice, it took administration of both rIFN-g and HgCl 2 to suppress the antisheep erythrocyte response. Although rIFN-g diminished the increase in IgE serum levels of HgCl 2 -treated B10.S mice, it failed to prevent their autoantibody production and immune glomerulonephritis. These findings further strengthen the concept that B10.S mice react to HgCl 2 by preferential activation of their Th2 cells producing IL-4, whereas B10.D2 mice react to HgCl 2 by preferential activation of their Th1 cells, which produce IFN-g and thus suppress antibody responses.

Amelioration of Mercury-Induced Autoimmunity by 4-1BB

“…Thus restoration observed by anti-4-1BB therapy was not merely due to a tilt of balance between Th2 to Th1. The results described in the current study therefore proposes a unique condition in which anti-4-1BB mAb by its actions (presumably due to high IFN-␥ expression and other unknown factors) overrides the regulatory capacity of IFN-␥, which is believed to orchestrate the induction phase of mercury autoimmunity (30,33,34), Based on the results described in the present study, we propose that the levels of IFN-␥ following exposure to mercury (mercury/rat IgG group) appear to be insufficient to cause disturbances in humoral immunity as revealed by comparable B cell numbers among PBS-and rat IgG-treated mice. Alterations in B cell function was only seen when IFN-␥ levels were elevated as seen in the anti-4-1BB treated group that prevented among others the development of autoantibody production, tissue Ig deposition leading to protection against the disease.…”

“…Alterations in B cell function was only seen when IFN-␥ levels were elevated as seen in the anti-4-1BB treated group that prevented among others the development of autoantibody production, tissue Ig deposition leading to protection against the disease. In summary, our results indicate that high levels of IFN-␥ in anti-4-1BB group appear to override the regulatory role of IFN-␥, which is believed to operate in the early induction phase of mercury autoimmunity (30,33,34) to target B cell function and form the chief basis of anti-4-1BB mAb-mediated immunotherapy. This conclusion further draws its support from the data that in vivo neutralization of IFN-␥ profoundly restored anti-4-1BB-mediated loss of B cell numbers.…”

“…30,33). However, in susceptible mice when treated with mercury and IFN-␥, only a few parameters of autoimmunity were resolved (34) despite reports that early IFN-␥ is a key regulator of mercury-induced autoimmunity (reviewed in Ref. 30).…”

Cytokine Regulation of a Rodent Model of Mercuric Chloride-Induced Autoimmunity

“…In one study by Doth and colleagues, the effect of recombinant interferon (rIFN)-y pretreatment prior to HgCI2 injections was assessed in susceptible B1O.S mice (H-2s). In resistant B1.D2 mice (H-2d), HgCl2 induces an IFN-yLdependent suppression of antibody formation to sheep red blood cells (40). To investigate whether this immunosuppression was responsible for resistance to HgCI2, rIFN-y was administered to B10.S mice prior to HgCI2 treatment.…”

“…To investigate whether this immunosuppression was responsible for resistance to HgCI2, rIFN-y was administered to B10.S mice prior to HgCI2 treatment. This pretreatment led to reductions in serum IgE levels and anti-SRBC antibody levels but filled to prevent ANoA production and immune glomerulonephritis in B1O.S mice (40). Conversely, mAb neutrlization of IFN-,y in resistant B10.D2 mice alleviated the mercury-induced immunosuppression but could not convert the mice to a mercury-susceptible phenotype (40).…”