THE PROTOTYPIC TH2 AUTOIMMUNITY INDUCED BY MERCURY IS DEPENDENT ON IFN-GAMMA AND NOT TH1 TH2 IMBALANCE/

Imbalances of Th1- and Th2-type responses have been postulated to be a predisposing factor for both humoral and cellular mediated autoimmune diseases. To further define their roles in systemic autoimmunity, IL- 9 and IFN-gamma gene knockout mice were studied for susceptibility to the prototypic Th2-mediated mercury-induced autoimmunity, A predominan t Th2-type response following HgCl2 treatment of wild-type B10.S mice was confirmed by the findings of a significant increase in splenic IL- 4 and hypergammaglobulinemia primarily of the IgG1 isotype, without an increase in IFN-gamma levels, paradoxically, IL-4-deficient mice deve loped the characteristic anti-nucleolar autoantibodies and tissue depo sition of immune complexes, while IFN-gamma-deficient mice had very lo w autoantibody levels and essentially normal immunohistology. Studies to define defects in Ab responses of IFN-gamma-deficient mice, using t he T-dependent Ag (4-hydroxy-3-nitrophenyl)acetyl, revealed an attenua ted IgG response to low and to a lesser extent high doses of (4-hydrox y-3-nitrophenyl)acetyl-hemocyanin maintenance of affinity maturation, These results indicate that Th1/Th2 imbalance does not directly play a role in susceptibility to mercury-induced autoimmunity, and suggest t hat the dependence on Th1-type responses in certain autoimmune disease s is due to the requirement for IFN-gamma for Ab production to weakly antigenic self molecules.