LAUSR

Generation of enormous antigen receptor repertoire diversity through random VDJ recombination is the cornerstone of the adaptive immune system, but it comes at the cost of generating large numbers of selfreactive lymphocytes with potential for pathogenesis. It has long been appreciated that a series of elegant tolerance mechanisms are employed by lymphocytes to prevent autoimmune disease. Several of these are broadly analogous in T and B cells, including deletion in response to strong antigen signals delivered early during development, a requirement for costimulation in addition to antigen recognition to license immune responses by mature lymphocytes, and functional unresponsiveness of mature selfreactive lymphocytes (“anergy”). In addition, there are several unique mechanisms that distinguish T and B cell tolerance, such as receptor editing in central B cell tolerance and the generation of regulatory T cells. These mechanisms were discovered and molecularly dissected in large part through the development and study of BCR and TCR transgenic animals and other genetic mouse models. Newer insights are emerging through study of both mouse and human immunology and through cuttingedge analyses of unusual patient phenotypes. In this issue of Immunological Reviews, contributors describe work that has built on this classic literature to further define the biochemical, transcriptional, and epigenetic molecular mechanisms that mediate central and peripheral T and B cell tolerance (Kurosaki, Pelanda, Zikherman, Tsubata, Getahun). Selected reviews highlight how abnormalities in signals received by and propagated in lymphocytes can breach these tolerance checkpoints to produce autoimmune disease in mice and humans (Weiss, Kuchroo, Deenick, Acharya and Jackson). These include discussion of rare germline gainoffunction mutations in signaling molecules identified in familial autoimmune syndromes (Weiss, Deenick). Two other reviews describe the discovery of new pathogenic T and B cell populations in mouse models and human autoimmunity (Tph— Rao, ABCs— Pernis). Finally, Reed describes an exciting new role for somatic mutations in the evolution of pathogenic B cell clones in human autoimmunity. Together, the issue highlights the leading edges of our understanding of tolerance and autoimmunity both in model systems and patients. We hope that this will illuminate opportunities for further investigation of basic tolerance mechanisms and novel approaches to therapeutic intervention and reveal unexpected features of human autoimmune pathogenesis. Below, we provide an overview of the areas covered in this issue.