Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2017.198 Figure 1 Defects in lymphocyte development and central and peripheral tolerance Figure 1 | Defects in lymphocyte development and central and peripheral tolerance. a | VDJ recombination-activating protein (RAG) defects and impaired VDJ recombination lead to a restricted T cell receptor (TCR) repertoire, defects in autoimmune regulator (AIRE) cause a loss of negative selection, and both of these deficiencies result in various autoimmune syndromes characterized by regulatory T (Treg) cell lymphopenia or decreased Treg cell suppressive function. Disturbances of embryogenesis in the third and fourth pharyngeal pouches lead to DiGeorge syndrome, whereas mutations in AIRE cause autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is the result of deficiency in the transcription factor FOXP3, which causes a reduction in the number of Treg cells. CD4 lymphopenia is seen in all of these syndromes, as well as in the presence of mutations in DCLRE1C, and all of these manifestations can present as Omenn syndrome. b | RAG defects also lead to impaired VDJ recombination in B cells, thereby causing restrictions to the B cell receptor (BCR) repertoire. The consequences of RAG defects are B cell lymphopenia, inflammation, increased levels of B cell-activating factor (BAFF; also known as TNFSF13B) and immature B cells with a high degree of self-reactivity, which lead to increased levels of autoantibody production. CID, combined immunodeficiency; mTEC, medullary thymic epithelial cell; SCID, severe combined immunodeficiency. Schmidt, R. E. et al. (2017) Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2017.198