ABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of multiple autoantibodies. The exact cause of SLE is unclear, but the emergence of disease appears to depend on environmental factors that initiate and/or contribute to pathogenic autoimmunity in genetically-prone individuals. Candidate initiating factors include female sex hormones and infection with viruses and/or bacteria. Characteristics of SLE are a number of profound B cell abnormalities that may either reflect the composite impact of genetic factors or secondary events to other primary immunologic abnormalities. Perturbations of B cell maturation may permit the generation, activation, differentiation and positive selection of B cells that secrete pathogenic autoantibodies. Such autoantibodies may be for intrinsic autoantigens or neoautoantigens that become accessible to the immune system during disease activity. In addition, SLE-prone individuals may have an abnormality in generation and/or maintenance of their functional repertoire of B cells expressing specific Ig genes or may be subjected to conditions that bias specific immunoglobulin variable region (IgV) usage, thereby predisposing to the development of autoantibodies. Furthermore, mechanisms contributing to somatic hypermutation of Ig or subsequent B cell selection may be intrinsically abnormal in patients with SLE and thus permit the preferential emergence of high avidity autoantibodies. Finally, intrinsic B cell overreactivity to normal antigenic stimulation may provide the drive for pathogenic autoantibody formation even though B cell maturation, repertoire generation, maintenance, somatic hypermutation and subsequent selection are not mechanisitically abnormal. For example, intrinsic B cell overactivity could overwhelm the normal mechansims that protect against autoimmunity and thereby permit the escape of pathogenic autoantibody producing B cell progeny.
