Abstract
A major goal for the treatment of patients with systemic lupus erythematosus with cytotoxic therapies is the induction of long-term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects of cyclophosphamide on the selection of the re-emerging B cell repertoire in wild type mice and transgenic mice that express the H chain of an anti-DNA antibody. The reconstituting B cell repertoire in wild type mice contained an increased frequency of DNA-reactive B cells; in heavy chain transgenic mice, the reconstituting repertoire was characterized by an increased frequency of mature, high affinity DNA-reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in serum levels of BAFF. Treatment of transgene-expressing mice with a BAFF blocking agent or with DNase to reduce exposure to autoantigen limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, not only is negative selection of high affinity DNA-reactive B cells impaired by increased BAFF, but also that B cells escaping negative selection are positively selected by autoantigen. There are significant implications for therapy.
Highlights
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies against a vast array of self antigens, most notably double stranded DNA [1]
To begin to address this important issue, we studied the effects of CY-induced B cell depletion on the selection of DNA-reactive B cells in wild type (WT) BALB/c mice and in the R4A Tg BALB/c mouse that expresses the heavy chain of a pathogenic anti-DNA antibody
CY-induced B cell depletion was almost complete on day 3 with a greater than 95% reduction in splenic B cells (Figure 1 A&B and Table 1)
Summary
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies against a vast array of self antigens, most notably double stranded (ds) DNA [1]. The B cell repertoire is purged of potentially pathogenic autoreactive B cells at multiple developmental checkpoints; in SLE patients, many of these checkpoints are breached and autoreactive B cells become part of the mature, immunocompetent and activated B cell repertoire [2,3,4]. Initial studies of human SLE patients and lupus-prone mouse strains suggested that B cell depletion usually given together with CY ameliorates disease activity in a subset of patients [9,10], but two large randomized, placebo controlled studies of B cell depletion with anti-CD20 antibody failed to show efficacy at 12 months. There remains a lack of critical information about how autoreactive B cells reconstitute following B cell depletion, especially in light of the observation that serum levels of BAFF rise following B cell depletion [11] in an attempt to restore B cell homeostasis. A reduction in the elevated levels of BAFF that result from B cell depletion or a decrease in antigen availability diminished the expansion of these autoreactive B cells
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