The presence of autoantibodies is a feature of most systemic autoimmune diseases. In fact, the discovery of characteristic autoantibodies served to classify many inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), mixed connective tissue disease, and antiphospholipid syndrome, as autoimmune diseases. The production of autoantibodies in these conditions is thought to occur because of immune dysregulation with a resultant break in tolerance. However, autoreactivity also occurs under normal circumstances and is then presumed to be beneficial. Some autoantibodies, such as anti–doublestranded DNA (anti-dsDNA), anti-Ro/SSA, and anticardiolipin antibodies, have been shown to be of pathogenic importance, whereas others are associated with autoimmune diseases but are not necessarily pathogenic. It is important to recognize that persistence of autoantibodies in systemic autoimmune diseases represents a break in tolerance, regardless of whether they are pathogenic. Despite intensive work on the characterization of autoantigens, the cellular basis of their production, and the strong associations of certain autoantibodies with particular class II major histocompatibility complex molecules (1, 2), little is known about the usage of immunoglobulin variable (Ig V)–region genes, and specifically by autoantibodies, in autoimmune conditions. Although intrinsic perturbances of B cell function are considered to be essential features of autoimmune diseases, such as

SLE, a number of influences extrinsic to B cells can also contribute to the emergence of autoimmunity (Table 1). Despite evidence of the pathogenic role of autoantibodies, the mechanisms that lead to their production remain enigmatic. The observation that certain autoantibodies are frequently encoded by a limited number of IgV-region gene segments suggests that biases in the development of the Ig repertoire might play a role in the tendency to develop these autoantibodies. Whether the usage of these specific gene segments differs between healthy individuals and patients with systemic autoimmune disorders remains a matter of controversy. Recent approaches have made it possible to address these issues and to estimate the differential impact of molecular and selective influences in shaping the Ig V gene repertoire in healthy subjects and patients with autoimmune diseases.