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Mature B Cells Preferentially Lose Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus¹

Arpita Choudhury^*, Philip L. Cohen^*, and Robert A. Eisenberg^2,*

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

Chronic graft-vs-host (cGVH) disease is a well-characterized systemic lupus erythematosus (SLE) model. Induction of cGVH in anti-DNA H chain knockin (3H9KI) transgenic mice results in specific activation of anti-dsDNA B cells. In this study, we show that B cells from 3H9KI mice were activated by cGVH even when adoptively transferred into irradiated JHT–/– recipients that lack endogenous B cells. This process of activation was reflected by high autoantibody titers and changes in phenotypic markers. We have used this system to characterize the particular B cell subsets that were responsible for secreting autoantibodies during cGVH response. We isolated splenic B cell subsets based on their expression of specific cell surface markers and used them in our adoptive transfer studies. We found that mature B cells were the most vulnerable to the allostimulus and were the major source of autoantibodies compared with immature B cells. The greater susceptibility of mature B cells to become activated and thereby lose tolerance was unanticipated and has implications for maintenance of peripheral tolerance and for the development of autoimmunity. Furthermore, of the mature B cells, marginal zone B cells were particularly responsible for mounting the initial response to the cGVH stimulus. This observation underscores the critical role of marginal zone B cells in activation and production of autoantibodies.

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 National Institutes of Health Grants R01-AR34156, R01-AI063626, and U19-AI-46358; the Lupus Research Institute, Alliance for Lupus Research, U.S. Department of Veteran Affairs, and the Lupus Foundation of South Jersey. A.C. was supported by a postdoctoral fellowship from the Arthritis Foundation.

² Address correspondence and reprint requests to Dr. Robert A. Eisenberg, Division of Rheumatology, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail address: raemd{at}mail.med.upenn.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; GVH, graft-vs-host; cGVH, chronic GVH; bm12, B6.C-H2^bm12/KhEg mice; B6, C57BL/6; KI, knockin; tg, transgene; MZ, marginal zone; FO, follicular; MFI, mean fluorescence intensity.