PAPER B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells

Systemic lupus erythematosus (SLE) is a complex disease characterizedby numerous autoantibodies and clinical involvement in multiple organ systems. Autoantibodies are usually present in serum for years before the onset of clinical disease. Autoimmunity begins with a limited number of autoantibodiesand evolves to become progressivelymore diverse. Eventually clinical disease ensues. The immunological events triggering the onset of clinical manifestations have not yet been de ned. While undoubtedly T cells and dendritic cells appear to play major roles in SLE, a central role for B cells in the pathogenesis of this disease has been brought to the fore in the last few years by work performed both in mice and humans by multiple laboratories.As a result, there is little doubt about the importance of B cells in the development of SLE. Yet much remains to be learned about their role in the ongoing disease process and the merit of targeting B cells for the treatment of SLE. This article will review the role of B cells in human SLE as well as the currently available data on the treatment of SLE by depleting B cells with anti-CD20 (rituximab). Lupus (2004) 13, 381–390. Key words: B cell subsets; clinical trials; review; rituximab; SLE B cells in SLE Several lines of evidence strongly suggest a primary role for B cells in systemic lupus erythematosus. Thus, the development of SLE is completely prevented in mice lacking B cells.1,2 The importance of primary B cell abnormalities is also strongly supported by genetic studies. For example, intrinsic B cell defects are necessary for the development of SLE in both NZB/ NZW F1 mice and MRL-lpr/lpr mice.3–6 Speci cally, B cell hyper-responsiveness is genetically determined in the NZB/NZW derived NZM2410 lupus strain by several recessive loci including Sle1, which mediates the loss of tolerance to nuclear antigens, and Sle2, which lowers the activation threshold of B cells. Moreover, manipulating the expression of molecules that modulate immunoglobulin mediated signaling and in uence B cell tolerance can produce SLE-like phenotypes. Examples of such molecules includ