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-4 and IFN-gamma gene knockout mice were studied for susceptibility to the prototypic Th2-mediated mercury-induced autoimmunity. A predominant 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 developed the characteristic anti-nucleolar autoantibodies and tissue deposition of immune complexes, while IFN-gamma-deficient mice had very low autoantibody levels and essentially normal immunohistology. Studies to define defects in Ab responses of IFN-gamma-deficient mice, using the T-dependent Ag (4-hydroxy-3-nitrophenyl)acetyl, revealed an attenuated IgG response to low and to a lesser extent high doses of (4-hydroxy-3-nitrophenyl)acetyl-hemocyanin, but 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 that the dependence on Th1-type responses in certain autoimmune diseases is due to the requirement for IFN-gamma for Ab production to weakly antigenic self molecules.
Kono
D H
DH
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA. dkono@scripps.edu
Balomenos
D
D
Pearson
D L
DL
Park
M S
MS
Hildebrandt
B
B
Hultman
P
P
Pollard
K M
KM
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility; D004306:Dose-Response Relationship, Immunologic; D006241:Haptens / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008627:Mercuric Chloride / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009596:Nitrophenols / Q000276:immunology; D010648:Phenylacetates; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D006241:Haptens; D009596:Nitrophenols; D010648:Phenylacetates; C026242:4-hydroxy-5-nitrophenyl acetic acid; D015847:Interleukin-4; D008627:Mercuric Chloride; D007371:Interferon-gamma