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      Human Inborn Errors of Immunity: an Expanding Universe

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          Abstract

          Molecular, cellular, and clinical studies of human inborn errors of immunity have revolutionized our understanding of their pathogenesis, considerably broadened their spectrum of immunological and clinical phenotypes, and enabled successful targeted therapeutic interventions. These studies have also been of great scientific merit, challenging a number of immunological notions initially established in inbred mice, while revealing previously unrecognized mechanisms of host defense by leukocytes and other cells, and of both innate and adaptive tolerance to self.

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          Projection of an immunological self shadow within the thymus by the aire protein.

          Mark S. Anderson, Emily S Venanzi, Ludger Klein … (2002)
          Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
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            A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.

            Stefan Feske, Yousang Gwack, Murali Prakriya … (2006)
            Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.
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              Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

              Stuart G. Tangye, Waleed Al-Herz, Aziz Bousfiha … (2020)
              We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101688624
                Journal ID (pubmed-jr-id): 45516
                Journal ID (nlm-ta): Sci Immunol
                Journal ID (iso-abbrev): Sci Immunol
                Title: Science immunology
                ISSN (Electronic): 2470-9468
                Publication date Nihms-submitted: 31 October 2020
                Publication date (Print): 10 July 2020
                Publication date PMC-release: 10 January 2021
                Volume: 5
                Issue: 49
                Electronic Location Identifier: eabb1662
                Affiliations
                [1 ]Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
                [2 ]Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
                [3 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
                [4 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch INSERM, Necker Hospital for Sick Children, Paris, France, EU.
                [5 ]Paris University, Imagine Institute, Paris, France, EU.
                [6 ]Pediatrics Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France, EU.
                [7 ]Howard Hughes Medical Institute, New York, NY 10065, USA.
                Author notes

                Author contributions: All authors (LDN, RB, JLC, HS) equally contributed to writing of the manuscript.

                [^]

                Equally contributed

                [* ]Corresponding author: Luigi D. Notarangelo, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 5-3950, 10 Center Drive, Bethesda, MD 20892, USA, Ph: (301)-761-7550, luigi.notarangelo2@ 123456nih.gov
                Article
                Accession ID: PMC7647049 Pmcid ID: PMC7647049 Pmc-uid ID: 7647049 Manuscript ID: nihpa1641282
                DOI: 10.1126/sciimmunol.abb1662
                PMC ID: 7647049
                PubMed ID: 32651211
                SO-VID: c7030682-09b2-4175-9535-b6dc66ae451e
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