Censoring self-specific B cells

Any one of 50 human VH regions can be included in the final rearranged immunoglobulin as B cell precursors mature. Although this process is essentially random, VH regions are not uniformly distributed among mature, IgG-secreting plasma cells, because these cells are subject to both positive and negative selection as they mature. In particular, B cells expressing the VH4-34 segment are dramatically underrepresented among plasma cells. Unlike most immunoglobulins, which acquire their antigen-specificity of a mature B cell receptor only after rearrangement and somatic mutation, those carrying the VH4-34 almost uniformly recognize a ubiquitous self-structure, an erythrocyte carbohydrate antigen. Here, Pugh-Bernard and colleagues have followed the fate of VH4-34-expressing cells in the blood, marrow, and tonsils of healthy individuals and people with systemic lupus erythematosus (SLE). They show that while mature VH4-34-expressing plasma cells are rare in healthy subjects, there is no barrier to their differentiation in culture. Interestingly, individuals with SLE possess such cells, suggesting that some normal protective mechanisms that suppress self-reactive B cells are missing in this autoimmune condition. Since VH4-34-containing antibodies recognize bacterial carbohydrates in addition to the erythrocyte self-epitope, the authors suggest that VH4-34 has survived because it acts as pattern recognition receptor, as discussed in the current Perspective series on multi-ligand receptors. Although their expression must be limited in duration so that they do not induce chronic autoimmunity, these antibodies may play a valuable role as a the rapid host response to bacterial infections. Evidently, the ability of the immune system to censor these B cells at multiple levels is efficient enough that immature B cells expressing this sequence can be tolerated.

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