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Amelioration of Mercury-Induced Autoimmunity by 4-1BB¹

Dass S. Vinay^*, Jung D. Kim^*, and Byoung S. Kwon^2,*,

^* Louisiana State University Eye Center, Louisiana State University Health Science Center School of Medicine, New Orleans, LA 70112; and Immunomodulation Research Center and Department of Biological Sciences, University of Ulsan, Ulsan, Korea

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-. 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-2^s) 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- production due to anti-4-1BB mAb treatment appears to be responsible for the observed B cell defects because neutralization of IFN- 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--dependent manner and thus, preventing the development of autoantibody production and tissue Ig deposition.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by U.S. Public Health Service Grants R01EY013325 (to B.S.K.), KRF-2005-201-E00008, KRF-2005-084-E00001, Ulsan Technopark Fund, Science Research Center funds to the Immunomodulation Research Center, University of Ulsan, and grants from Korea Science and Engineering Fund.

² Address correspondence and reprint requests to Dr. Byoung S. Kwon, Immunomodulation Research Center, University of Ulsan, 29 Mukeo Dong Nam-Ku, Ulsan 680-749, Korea. E-mail address: bkwon{at}lsuhsc.edu

³ Abbreviations used in this paper: 4-1BBL, 4-1BB ligand; ANoA, antinucleolar Ab; PNA, peanut agglutinin; MZ, marginal zone.