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International Immunology, Vol. 15, No. 8, pp. 975-985, August 2003
© 2003 Japanese Society for Immunology

Chronic GVH prevents anergy in bone marrow self-reactive B cells: a selective increase in post-endoplasmic reticulum processing and trafficking to the cell surface of autoreactive IgM receptors

Nili Feuerstein1, Debra Shivers1, Fangqi Chen2, Robert A. Eisenberg2 and Terri H. Finkel1,3

1 Division of Rheumatology, The Children’s Hospital of Philadelphia, andDepartments of 2 Medicine and 3 Pediatrics, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA

Correspondence to: Nili Feuerstein, Division of Rheumatology, The Children’s Hospital of Philadelphia, 1107 ARC, Philadelphia, PA 19104, USA. E-mail: feuerstein{at}email.chop.edu
Transmitting editor: S. Izui

B cell autoreactivity is a component of chronic graft versus host (GVH) disease in humans and mice. Chronic GVH driven by I-A disparity results in loss of B cell tolerance in Ig/sHEL tolerant mice. In these mice, B cell anergy is characterized by down-modulation of sIgM mediated by intracellular retention in the endoplasmic reticulum (ER) and/or a block in post-ER processing of IgM receptors. Here, we report that GVH induces a selective increase in post-ER processing of the µ chain and trafficking to the cell surface of IgM receptors in B cells that bind HEL self-antigen. The increase in sIgM was detectable as early as 6 days post-GVH, before the appearance of circulating autoantibodies, and was particularly prominent in B cells that up-regulated surface I-A. A further increase in sIgM was found at later time points, along with circulating anti-HEL autoantibodies and a marked decrease in serum-free HEL, but no significant change in the amounts of HEL bound to B cells in vivo. These findings suggest that (i) abrogation of ER retention of IgM receptors in self-reactive B cells is an early event triggered by allogeneic T cells and (ii) at later stages of GVH disease the appearance of autoantibodies reduces the availability of free autoantigen, which may further escalate anergy escape of self-reactive B cells, and lead to exacerbation and perpetuation of autoimmunity.

Keywords: autoimmunity, B lymphocyte, BCR, graft versus host disease


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