B cell biology, apoptosis, and autoantibodies to phospholipids.

Systemic autoimmune diseases are characterised by the development of a relatively narrow spectrum of autoantibodies. These are of considerable diagnostic value. In addition, in some diseases, including anti-phospholipid syndrome, these autoantibodies can be directly pathogenic. Understanding how these autoantibodies are formed represents an important avenue towards understanding the pathogenesis of systemic autoimmune disease itself. The minimum requirements for production of autoantibodies are self-reactive B cells and the availability of autoantigen. In other words, their formation is determined by factors that shape the B cell repertoire and the distribution and immunogenicity of the relevant autoantigens. On the B cell side, the propensity to produce autoantibodies depends on the fidelity of B cell self-tolerance mechanisms, B cell differentiation and selection into different peripheral compartments. These processes are interdependent, because both selection into different peripheral and mechanisms of B cell self-tolerance are influenced by signalling through the B cell receptor (BCR). On the antigen supply side, apoptotic cells appear to be a crucial source of antigenic targets of systemic autoimmunity, and elaborate mechanisms exist to ensure that apoptotic corpses undergo efficient disposal and do not become immunogenic. Several defects have been described where the disposal of apoptotic cells is compromised leading to their accumulation in parenchymal organs. These may become immunogenic resulting in autoantibody formation. The mechanisms that lead to progression from accumulation of autoantigen, in the form of apoptotic corpses, to the production of autoantibodies by self-reactive B cells within different parts of the peripheral repertoire are discussed.