The recently recognized importance of B cells in systemic lupus erythematosus (SLE) raises the question as to whether those expressing CD5 predominate over the remaining B lymphocytes in the pathophysiology of this disease. Owing to their B B-cell receptor (BCR) polyspecificity, autoantibody production has been originally ascribed to CD5-positive B1 lymphocytes. Instead, it has since been established that high-affinity autoantibodies derive from CD5-negative B2 cells. Even worse, in the light of current findings, CD5-positive B cells have been considered to play a paradoxical role in preventing, rather than inducing, autoimmunity. In this context, there is evidence that the membrane expression of CD5 is regulated, and, to this end, a genetic mechanism has been described, based on the selection between exon 1A (E1A) and exon 1B (E1B). The full-length protein variant, encoded by E1A-cd5, translocates the phosphatase SHP-1 to the vicinity of the BCR, raises its threshold, and thereby limits the response of autoreactive B cells. In contrast, the truncated variant, encoded by E1B-cd5, remains in the cytoplasm, along with SHP1. Normally, EIB E1B is silenced by methylation and its product degraded in the proteosomes. Hence, a defect in the DNA methyl transfer favors the development of SLE, by preventing the effects of SHP-1.