Abstract
The goal of this study was to determine how B-cell-activating factor of the TNF family (BAFF) availability influences selection of the autoreactive B-cell repertoire in NZB/W and NZW/BXSB lupus-prone mice bearing the site-directed heavy-chain transgene 3H9 that encodes for anti-dsDNA and anti-cardiolipin (CL) autoantibodies. We used a bone marrow chimera system in which autoreactive 3H9 transgenic B cells were allowed to mature in competition with wild-type cells and could be identified by green fluorescent protein. The light-chain repertoire associated with the 3H9 heavy chain in naive and antigen-activated B-cell subsets was assessed using single-cell polymerase chain reaction. We found that deletion of autoreactive transgenic B cells occurred in the bone marrow of both strains regardless of BAFF availability, and there were only modest and physiologically non-relevant effects on the naive B-cell repertoire. BAFF inhibition had different effects on selection of the germinal center repertoire in the two strains. In the NZW/BXSB strain, BAFF inhibition phenocopied the loss of one TLR7 allele in that it influenced the selection of 3H9-encoded autoreactive B cells in the germinal center but did not prevent somatic mutation. In the NZB/W strain, BAFF inhibition did not alter the selection of 3H9-encoded B cells in the germinal center, but it influenced selection of a subset of germinal center cells into the plasma cell compartment. Our data underscore the complexity of regulation of the autoreactive B-cell repertoire by BAFF and may help to explain the heterogeneity of responses observed after BAFF inhibition in humans.
Highlights
Systemic lupus erythematosus (SLE)is an autoimmune disorder in which loss of tolerance to nucleic acids and their binding proteins leads to the production of autoantibodies that cause systemic inflammation and organ damage
B-cell–activating factor of the tumor necrosis factor (TNF) family (BAFF)-R-Ig–treated female NZB/W mice (F B/W 3H9 BAFF receptor (BAFF-R)-Ig) developed high titer anti-dsDNA antibodies by 18 wks posttransplantation that were no different from untreated female 3H9 NZB/W mice (F B/W 3H9, Figure 1B) [21,22]
Phenotypic analysis of spleen B cells indicated that BAFF-R-Ig–treated mice had significant depletion of B cells compared with untreated 3H9 chimeras with sparing of the T1, germinal centers (GCs) and plasma cell subsets in both strains (Figure 2)
Summary
Is an autoimmune disorder in which loss of tolerance to nucleic acids and their binding proteins leads to the production of autoantibodies that cause systemic inflammation and organ damage. Both intrinsic and extrinsic defects in B-cell tolerance can contribute to the generation of autoantibodies in SLE [1]. Innate signals may enhance autoreactive responses in a T cell–independent fashion [9]. Understanding how these defects contribute to autoantibody production in individual patients will enable therapy to be directed to the appropriate B-cell stage and subset
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