Here, the leaky severe combined immunodeficiency (SCID) phenotype and relative loss of AIRE expression permits the survival of a few T cells with autoimmune

potential. However, some self-reactive T cells escape thymic selection and must be removed in the periphery. The mechanisms for removal of these cells are different than for central tolerance, and probably involve a number of different pathways, including the development of regulatory T cells (Tregs), among others. Here, the study of mutations in the X-chromosome gene for the forkheard box P3 (FoxP3) transcription factor has led to a clearer understanding of the essential role of Tregs in CHIR-99021 tolerance. FoxP3 is essential for the development of CD25+ Tregs. Its loss leads to the clinical condition called immune dysregulation, polyendocrinopathy

and enteropathy, X-linked (IPEX) manifested by early-onset type 1 diabetes mellitus, severe enteropathy, eczema, anaemia, thrombocytopenia, hypothyroidism and other organ-specific AZD8055 molecular weight tissue damage [3–5]. The lack of Tregs in this syndrome explains many facets of the immune-mediated tissue destruction which occurs. Normal B cell development also includes stages in which potentially autoimmune

B cell clones can be eliminated; these steps include the bone marrow and peripheral tissues. B cell receptors of naive B cells do not contain somatic hypermutations, and any diversity that is present is due to random immunoglobulin (Ig) V(D)J gene recombination events. However, early immature B cells in the bone marrow are often both autoreactive and polyreactive, having the capacity to bind to many antigens. Thus random recombination normally leads to the production of numerous deleterious B cells, unless Cytidine deaminase these are eliminated. As autoreactive cells are much less common in the peripheral blood, it is clear that mechanisms for their removal are generally successful [6]. However, with regard to T cell clonal elimination, both central and peripheral checkpoints appear to be operative to remove autoimmune B cells in blood. If new emigrant B cells in peripheral blood do express autoimmune potential, a failure of central tolerance is suggested; if mature naive B cells in this compartment contain autoimmune potential, peripheral checkpoints have failed. Again, using selected defects in primary immune deficiency, it has been possible to analyse the molecular requirements for these checkpoints in humans.