Abstract
We summarize the clinical presentation and molecular basis of a unique group of congenital immunodeficiency disorders in which defects in immune tolerance mechanisms result in severe autoimmunity. Patients with severe, familial forms of multi-organ autoimmunity have been recognized and clinically described for more than 40 years (Clin Exp Immunol 1: 119-128, 1966; Clin Exp Immunol 2: 19-30, 1967). Some are characterized primarily by autoimmunity and others by autoimmunity combined with susceptibility to specific infectious organisms. The first mechanistic understanding of these disorders began to emerge approximately 10 years ago with the initial identification of causative genes. As a result, our understanding of how immune tolerance is established and maintained in humans has expanded dramatically. Data generated over the last 3-4 years including identification of additional gene defects and functional characterization of each identified gene product in human and animal models have added clarity. This, in turn, has improved our ability to diagnose and effectively treat these severe, life-threatening disorders. Inherited disorders characterized by immune dysregulation have dramatically expanded our understanding of immune tolerance mechanisms in humans. Recognition and diagnosis of these disorders in the clinic allows timely initiation of life-saving therapies that may prevent death or irreversible damage to vital organs.
MeSH terms
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AIRE Protein
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Animals
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Autoimmunity* / genetics
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Autoimmunity* / immunology
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Diagnostic Techniques and Procedures
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Female
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Genetic Diseases, X-Linked* / diagnosis
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Genetic Diseases, X-Linked* / genetics
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Genetic Diseases, X-Linked* / immunology
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Genetic Diseases, X-Linked* / therapy
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Humans
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Immune Tolerance / genetics
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Immune Tolerance / immunology
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Immunologic Deficiency Syndromes* / diagnosis
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Immunologic Deficiency Syndromes* / genetics
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Immunologic Deficiency Syndromes* / immunology
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Immunologic Deficiency Syndromes* / therapy
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Interleukin-10 / deficiency
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Interleukin-2 Receptor alpha Subunit / deficiency
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Male
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Mice
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Polyendocrinopathies, Autoimmune* / diagnosis
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Polyendocrinopathies, Autoimmune* / genetics
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Polyendocrinopathies, Autoimmune* / immunology
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Polyendocrinopathies, Autoimmune* / therapy
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Receptors, Interleukin-10 / deficiency
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Repressor Proteins / deficiency
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STAT5 Transcription Factor / deficiency
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T-Lymphocytes, Regulatory / immunology
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Transcription Factors / genetics
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Transcription Factors / immunology
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Ubiquitin-Protein Ligases / deficiency
Substances
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FOXP3 protein, human
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Forkhead Transcription Factors
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IL2RA protein, human
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Interleukin-2 Receptor alpha Subunit
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Receptors, Interleukin-10
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Repressor Proteins
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STAT5 Transcription Factor
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STAT5B protein, human
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Transcription Factors
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Interleukin-10
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ITCH protein, human
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Ubiquitin-Protein Ligases