19 Ann. N.Y. Acad. Sci. 1050: 19–33 (2005). © 2005 New York Academy of Sciences. doi: 10.1196/annals.1313.003 B Lymphocytes Are Required for Development and Treatment of Autoimmune Diseases PIERRE YOUINOU, CHRISTOPHE JAMIN, JACQUES-OLIVIER PERS, CHRISTIAN BERTHOU, ALAIN SARAUX, AND YVES RENAUDINEAU Brest University Medical School, Brest, France ABSTRACT: Recent studies have revealed that B cells serve extraordinarily di- verse functions within the immune system in addition to antibody production. These functions contribute to autoimmunity. They initiate the development of lymphoid architecture and regulate dendritic and T-cell function through cytokine production. Receptor editing is also essential to prevent autoimmunity. Both abnormalities in the distribution of B-cell subsets and the benefits of ablative B-cell therapy of autoimmune states confirm their importance. Results from transgenic models have demonstrated that the sensitivity of B cells to antigen receptor cross-linking correlates to autoimmunity, with particular reference to negative signaling by CD5 and CD22. These mechanisms maintain tolerance by recruiting src-homology 2 domain-containing protein tyrosine phosphatase-1. These findings open new prospects for immunotherapy of autoimmune diseases. KEYWORDS: B lymphocyte; autoimmune disease; dendritic cell; T lymphocyte; B-cell antigen receptor; CD5 Major advances recently have revived and refined our understanding of autoreactive B cells. 1 Humoral abnormalities, most notably in systemic lupus erythematosus (SLE), have even been explained by intrinsic B-cell hyperactivity. 2 New works have indeed incorporated B lymphocytes in the afferent arm of the immune response rather than confined them in the efferent phase. For example, according to Klinman and Steinberg, 3 connective tissue diseases (CTD) clearly arise from polyclonal B-cell activation. In this respect, it is not surprising that characteristics suggestive of the breakdown of normal antibody (Ab) regulation have been identified in the relatives of patients 4–6 with SLE, rheumatoid arthritis (RA), or primary Sjögren’s syndrome (pSS) that might predispose the family members to full-blown diseases similar to that of their probands. The finding of enhanced immunoglobulin (Ig) production in response to mitogens is consistent with this propensity for IgG production in the peripheral blood of relatives. Address for correspondence: Professor Pierre Youinou, Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest Cedex, France. Voice: +33-298-22- 33-84; fax: +33-298-22-38-47. youinou@univ-brest.fr