title: Tolerance and autoimmunity in primary immunodeficiency disease: a comprehensive review.
abstract: The immune system has evolved to respond to pathogens (nonself) and unresponsive to self-antigens (tolerance). During the development of T and B cells in the thymus and bone marrow, respectively, self-reactive T and B cells are deleted by a process of apoptosis (both T and B cells) and become unresponsive to self-antigen by receptor editing (for B cells). However, few self-reactive T cells are leaked into the periphery. A number of mechanisms are responsible to ensure that self-reactive T and B cells remain unresponsive to self-antigens. In the central tolerance, major mechanisms include apoptosis (for T cells) and receptor editing (for B cells), and in the peripheral tolerance, a major mechanism appears to be regulated by Treg cells. In T cell central tolerance, one of the most important molecules is a transcription factor, autoimmune regulator, which is selectively expressed in medullary thymic epithelial cells (mTECs) and constitutively regulates the transcription of hundreds of self-antigens in mTECs, thereby inducing central tolerance, negative selection, and Treg differentiation from some self-reactive thymocytes. Primary immunodeficiency diseases are a group of monogenic diseases where mutations of certain genes have resulted in the loss of central and/or peripheral tolerance. As a result autoimmunity and autoimmune diseases are common among patients with primary immunodeficiency diseases. Here, we have provided a comprehensive review of the mechanisms of central and peripheral tolerance and autoimmune manifestations and mechanisms of autoimmunity in primary immunodeficiency diseases.
authors.affiliation: Programs in Primary Immunodeficiency and Aging and Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies, Division of Basic and Clinical Immunology, Medical sciences I, C-240, University of California at Irvine, Irvine, CA, 92697, USA, sgupta@uci.edu.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Gupta
authors.forename: Ankmalika Gupta
authors.initials: AG
authors.lastname: Louis
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D061167:Central Tolerance; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D061166:Peripheral Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*