Genetic disorders with immune dysregulation

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.

Practice parameter for the diagnosis and management of primary immunodeficiency

“…IPEX syndrome is a rare systemic autoimmune disorder resulting from mutations in the forkhead box protein 3 (FOXP3) gene, which encodes the DNA-binding transcriptional regulator considered to be the master controller for CD4 1 CD25 1 Treg cells. 489,490 The lack of Treg cells leads to allergic and autoimmune manifestations, including severe eczema and food allergies with enteritis and early-onset endocrine autoimmunity, with diabetes and thyroiditis being most common. It is frequently fatal in the first year of life.…”

“…The FOXP3 gene encodes a crucial DNA-binding transcriptional regulator that is critically required for the differentiation and function of CD4 1 naturally occurring Treg cells and subsets of inducible Treg cells. 489,490 The genetic defects lead to a deficiency in a cell population that is required to regulate effector T cells, diminish inflammatory cytokine production, and mitigate against autoimmune processes.…”

“…These tests are available in specialized centers. 489,490 Summary statement 135. Initial treatment of IPEX syndrome should include immune suppression with a calcineurin inhibitor or mammalian target of rapamycin (MTOR) inhibitor.…”

“…The only potential definitive treatment for IPEX syndrome is HSCT. 490,494 Early treatment improves outcomes because autoimmune and endocrinologic manifestations can persist after transplantation. Myeloablative conditioning has been associated with transient reconstitution and mortality caused by graft failure, viral infections, and hemophagocytic syndromes.…”

From Primary Immunodeficiency to Autoimmunity: How Extreme Situations Highlight the Main Genetic Factors Involved in Autoimmune Disease

“…IL-2Rα, in conjunction with the β-chain and γ-chain, defines high affinity IL-2R, the receptor for IL-2 (being alpha chain the most specific subunit for IL-2), a cytokine fundamental for expanding and defining function of T regulatory cells (Tregs) in the periphery [43,44]. CD25 is constitutively expressed at the highest levels in these Tregs, allowing a fast response to IL-2 in the immune response, reducing immune function [45].…”