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Modulation of Autoimmunity by TLR9 in the Chronic Graft-vs-Host Model of Systemic Lupus Erythematosus¹

Zhongjie Ma^*, Fangqi Chen^*, Michael P. Madaio^2,, Philip L. Cohen^*, and Robert A. Eisenberg^3,*

^* Division of Rheumatology and Renal Electrolyte and Hypertension, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104

Chronic graft-vs-host (cGVH) disease is induced in nonautoimmune mice by the transfer of alloreactive T cells that recognize foreign MHC class II. It closely resembles systemic lupus erythematosus, with antinuclear Abs and immune-mediated nephritis. Recent work has implicated TLRs, particularly TLR9, in the recognition of certain autoantigens in vitro and in vivo. To explore further the role of TLR9 in systemic autoimmunity, we induced cGVH disease in C57BL/6 (B6) mice lacking TLR9, including B6 mice expressing the anti-DNA-encoding IgH transgenes 3H9 or 56R (B6.3H9.TLR9^–/–, B6.56R.TLR9^–/–). We found that cGVH disease caused breakdown of B cell tolerance to chromatin and DNA in TLR9^–/– recipients of alloreactive cells, yet that nephritis was less severe and that some autoantibody titers were lower compared with B6-cGVH controls. Spleen lymphocyte analysis showed that cGVH disease strikingly depleted marginal zone B cells in B6 mice, but did not influence T cell subsets in either B6 or B6-TLR9^–/– hosts. B6.56R.TLR9^–/– mice had less spontaneous production of autoantibodies than B6.56R mice, but there were no significant differences between B6.56R and B6.56R.TLR9^–/– postinduction of cGVH disease. Taken together, these results suggested that TLR9 may worsen some aspects of systemic autoimmunity while alleviating others.

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 by the Arthritis Foundation, Alliance for Lupus Research, Lupus Research Institute, Lupus Foundation of South New Jersey, Department of Veterans Affairs, and National Institutes of Health Grants R01-AR-34156, U19-AI-46358, R01-AI063626-22, and RO1-DK53088.

² Current address: Section of Nephrology and Kidney Transplantation, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140.

³ Address correspondence and reprint requests to Dr. Robert A. Eisenberg, Division of Rheumatology, 756 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160. E-mail address: raemd{at}mail.med.upenn.edu

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; cGVH, chronic graft-vs-host; RF, rheumatoid factor.

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