Inborn Errors of Immunity (IEI) Breaking Immune Homeostasis and Tolerance: A Key Role for T Regulatory Cells

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Background

Monogenic diseases of the immune system, also known as inborn errors of immunity (IEI), are caused by single-gene mutations resulting in immune deficiency and/or dysregulation. Classical IEI includes Primary Immunodeficiencies (PID) affecting both cellular and humoral immunity, such as X-linked severe combined immunodeficiency (SCID). Predominant antibody deficiencies include B cell deficiencies (i.e., X- linked agammaglobulinemia) and common variable immunodeficiency disorders (CVID). Examples of IEI that primarily cause autoimmune or autoinflammatory manifestations, are named Primary Immune Regulatory disorders (PIRD). The spectrum of immune dysregulation in PIRD is wide, encompassing deficiencies in humoral, cellular and innate immunity which may ultimately lead to systemic autoinflammation and/or organ specific autoimmunity, prevailing the inability to fight infections. IEI exemplifying the latter include defects in molecules essential for the development, survival and/or function of regulatory T (Treg) cells, the T cell subset involved in the control of peripheral tolerance.

Treg cell defects (Tregopathies) currently encompass diseases commonly resulting from loss-of-function (LOF) mutations of genes encoding proteins that control the function of thymus-derived forkhead box p3 (FOXP3) regulatory T (tTreg) cells. The prototype of Tregopathies is the immunodysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome, secondary to loss-of-function mutations in FOXP3, the Treg cell master transcription factor. In addition to FOXP3, other genes encoding for cytokine receptors, intracellular signaling or coinhibitory molecules can alter the number or function of regulatory T cells, leading to immune dysregulation.

The availability of metabolites and the engagement of specific pathways interconnect with signaling events and epigenetic regulators to balance T cell activation, differentiation and function. LOF mutations of genes that control chromatin accessibility and histone modifications impact on the faithful execution of lineage-restricting transcription programs during T cell activation, leading to multiorgan disorders and immune dysregulation, as observed in Kabuki syndrome and in Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) syndrome. Moreover, epigenetic alterations, such as DNA methylation and histone modifications, may be envisioned as potential mechanisms implicated in some genetically yet undefined cases (i.e., CVID patients) and account for immune dysregulation by affecting the differentiation or function of Treg cells.

Therefore, this Research Topic aims to promote a better understanding of the underlying mechanisms breaking immune tolerance in IEI; this may clarify the pathways interconnecting autoimmunity and primary immunodeficiency thus contributing to the development of novel therapeutics.

In this Research Topic, we aim to bring together researchers and clinicians to focus on the role of Treg cells and other regulatory subsets in IEI. We invite authors for original articles, reviews and opinions. Topics of interest in this special edition include, but are not limited to, the following sub-topics:

• Immune regulatory defects and their pathophysiological origins in diverse Tregopathies;
• Genetic variants of epigenetic enzymes affecting Treg cell generation and function;
• Metabolic alterations in IEI and their impact on the faithful execution of lineage-restricting transcription
programs controlling FOXP3 transcription;
• Mutations in FOXP3 and their contribution to immune dysregulation in IEI;
• Overview of novel techniques to detect epigenetic alterations in IEI;
• LOF mutations of TFs key for the epigenetic and metabolic control of immune tolerance;
• The clinical spectrum and molecular treatments of patients diagnosed with diverse Tregopathies;

Keywords: Primary immunodeficiency, inborn errors of immunity, epigenetic alteration, regulatory T cells, metabolic enzymes, immune dysregulation, peripheral tolerance, autoimmune disease., primary immune regulatory disorders

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