Amelioration of mercury-induced autoimmunity by 4-1BB.
In certain strains of mice, subtoxic doses of HgCl2 (mercuric chloride; mercury) induce a complex autoimmune condition characterized by the production of antinucleolar IgG Abs, lymphoproliferation, increased serum levels of IgG1/IgE Abs, and deposition of renal immune complexes. 4-1BB is an important T cell costimulatory molecule that has been implicated in T cell proliferation and cytokine production, especially production of IFN-gamma. To elucidate T cell control mediated by the 4-1BB signaling pathway in this syndrome, we assessed the effect of administering agonistic anti-4-1BB mAb on mercury-induced autoimmunity. Groups of A.SW mice (H-2s) received mercury/control Ig or mercury/anti-4-1BB or PBS alone. Anti-4-1BB mAb treatment resulted in a dramatic reduction of mercury-induced antinucleolar Ab titers, serum IgG1/IgE induction, and renal Ig deposition. These effects may be related to the present finding that anti-4-1BB mAb decreases B cell numbers and function. The anti-4-1BB mAb-treated mercury group also showed a marked reduction in Th2-type cytokines but an increase in Th1-type cytokines and chemokines. Increased IFN-gamma production due to anti-4-1BB mAb treatment appears to be responsible for the observed B cell defects because neutralization of IFN-gamma in vivo substantially restored B cell numbers and partly restored IgG1/IgE. Collectively, our results indicate that 4-1BB mAb can down-regulate mercury-induced autoimmunity by affecting B cell function in an IFN-gamma-dependent manner and thus, preventing the development of autoantibody production and tissue Ig deposition.
Vinay
Dass S
DS
Louisiana State University Eye Center, Louisiana State University Health Science Center School of Medicine, New Orleans, LA 70112, USA.
Kim
Jung D
JD
Kwon
Byoung S
BS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001323:Autoantibodies; D001327:Autoimmune Diseases / Q000139:chemically induced; D015551:Autoimmunity / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D007136:Immunoglobulins; D007371:Interferon-gamma / Q000494:pharmacology; D018655:Lymphocyte Count; D008627:Mercuric Chloride / Q000009:adverse effects*; D008628:Mercury; D051379:Mice; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007136:Immunoglobulins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D008627:Mercuric Chloride; D007371:Interferon-gamma; D008628:Mercury