A Novel Mouse with B Cells but Lacking Serum Antibody Reveals an Antibody-independent Role for B Cells in Murine Lupus

Abstract

The precise role of B cells in systemic autoimmunity is incompletely understood. Although B cells are necessary for expression of disease (Chan, O., and M.J. Shlomchik. 1998. J. Immunol. 160:51–59, and Shlomchik, M.J., M.P. Madaio, D. Ni, M. Trounstine, and D. Huszar. 1994. J. Exp. Med. 180:1295–1306), it is unclear whether autoantibody production, antigen presentation, and/or other B cell functions are required for the complete pathologic phenotype. To address this issue, two experimental approaches were used. In the first, the individual contributions of circulating antibodies and B cells were analyzed using MRL/MpJ-Faslpr (MRL/lpr) mice that expressed a mutant transgene encoding surface immunoglobulin (Ig), but which did not permit the secretion of circulating Ig. These mice developed nephritis, characterized by cellular infiltration within the kidney, indicating that B cells themselves, without soluble autoantibody production, exert a pathogenic role. The results indicate that, independent of serum autoantibody, functional B cells expressing surface Ig are essential for disease expression, either by serving as antigen-presenting cells for antigen-specific, autoreactive T cells, or by contributing directly to local inflammation.

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

“…Fourth, although B cell-deficient MRL-lpr/lpr mice do not develop nephritis or vasculitis (51), MRLlpr/lpr mice bearing B cells that are incapable of secreting Ig (and, hence, harbor no circulating autoantibodies) do develop such disease (albeit in a milder form than that developed by wild-type MRL-lpr/lpr mice) (52). Thus, B cells clearly effect a disease-promoting function that is independent of their ability to produce autoantibodies but may be dependent upon the ability of B cells to promote the activation of autoreactive T cells (52,53).…”

“…Thus, B cells clearly effect a disease-promoting function that is independent of their ability to produce autoantibodies but may be dependent upon the ability of B cells to promote the activation of autoreactive T cells (52,53). By extension, the effects of BAFF overexpression on the precocious development of glomerular disease in B6.Sle1 and B6.Nba2 mice may relate more to the effects of BAFF on B cell numbers ( Figure 1D) than to its effects on circulating autoantibody levels.…”

Class switching and consecutive loss of dsDNA‐reactive B1a B cells from the peritoneal cavity during murine lupus development

“…Furthermore, B cells act as APC and cytokine producers and are indispensable for the development of lupus [1].…”

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

“…1C). Thus, although B6.NZBc13 MC mice exhibit abnormal B-cell activation, B-cell subset distribution, and DC expansion, T-cell activation and autoantibody production are inhibited by co-transfer of control B6.Thy1 a IgH a cells BM cells in B6.NZBc13 MC mice.Autoreactive B cells initiate the cellular abnormalities observed in B6.NZBc13 mice Autoreactive B cells and/or autoantibodies have been shown to play an important role in the generation of the abnormal cellular phenotypes in several other strains of lupus-prone mice [8,10]. Therefore we questioned whether the replacement of the normal B-cell repertoire with a non-autoreactive Ig Tg would normalize these phenotypes in B6.NZBc13 mice.…”