Regulation of B-cell tolerance by complement C4
© BioMed Central Ltd 2004
Published: 13 September 2004
Systemic lupus erythematosus (SLE) is a B-cell-dependent autoimmune disease characterized by autoantibodies specific for nuclear antigens such as dsDNA and histones. Apoptotic blebs released from dying cells are thought to represent a major source of autoantigen. The cellular and molecular basis for SLE is not known but a major risk factor is deficiency in products of natural immunity. For example, individuals deficient in serum complement proteins C1q or C4 almost always develop lupus. This presents a paradox as the complement system is known to mediate pathogenesis in SLE. In addition to its known role in inflammation, the complement system participates in humoral antibody responses via enhancement of B-lymphocyte activation, germinal center survival and maintenance of long-term effector responses.
Two nonmutually exclusive hypotheses for a protective role of complement are termed the clearance hypothesis and the B-cell tolerance hypothesis. The former proposes that complement (and natural immunity) protects by clearance of apoptotic blebs and sequesters them from the adaptive immune system. The tolerance hypothesis proposes that complement and natural immunity act in concert to localize lupus-antigens to sites within the primary and secondary lymphoid compartments where developing B cells undergo negative selection. To examine directly a role for complement C4 in protection from self-reactive B cells, we have bred the deficient mice with mice bearing rearranged immunoglobulin heavy chain and light chain anti-chromatin transgenes (Tg) (termed 564) specific for chromatin. On a normal C4-sufficient background, the self-reactive Tg B cells are blocked at the immature or transitional stage of development. By contrast, in the absence of C4, the self-reactive B cells continue to develop and enter the mature compartment. Moreover, they appear to secrete self-reactive antibody of both IgM and IgG isotypes. These results identify a functional role for C4 in regulation of self-reactive B cells and support the B-cell tolerance hypothesis.