Chapter 23 - Immune Dysregulation Leading to Chronic Autoimmunity

Abstract

A number of Mendelian disorders of chronic autoimmunity have been identified. These diseases result from defects in pathways regulating central and peripheral T cell tolerance. Central tolerance refers to mechanisms that prevent the development of autoreactive lymphocytes in generative lymphoid organs, such as the thymus for T cells and bone marrow for B cells. The best example of a defect in central tolerance occurs with mutations affecting the autoimmune regulator gene (AIRE). AIRE is a transcription factor that drives expression of self-antigens in the thymus so that autoreactive T cells can be deleted through negative selection. Defects in AIRE give rise to autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome. Although central tolerance is essential for immune regulation, this is not the only mechanism of immune regulation. Peripheral tolerance refers to mechanisms to prevent activation of self-reactive T and B cells that escape central tolerance. The best-characterized defect in peripheral tolerance occurs due to mutations affecting the transcription factor FOXP3. Loss of this transcription factor results in failure in the development and function of T regulatory (Treg) cells that are critical to peripheral tolerance. Defects in FOXP3 result in the disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). A number of other gene defects that affect Treg cell function also give rise to an IPEX-like phenotype, including loss-of-function mutations in CD25, STAT5b, and ITCH, and gain-of-function mutations in STAT1.