Progressive B Cell Loss in Revertant X-SCID
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ORIGINAL ARTICLE
Progressive B Cell Loss in Revertant X-SCID Connie H. Lin 1 & Hye Sun Kuehn 2 & Timothy J. Thauland 1 & Christine M. Lee 3 & Suk See De Ravin 4 & Harry L. Malech 4 & Timothy J. Keyes 5 & Astraea Jager 5 & Kara L. Davis 5 & Maria I. Garcia-Lloret 1 & Sergio D. Rosenzweig 2 & Manish J. Butte 1 Received: 23 March 2019 / Accepted: 6 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract We report the case of a patient with X-linked severe combined immunodeficiency (X-SCID) who survived for over 20 years without hematopoietic stem cell transplantation (HSCT) because of a somatic reversion mutation. An important feature of this rare case included the strategy to validate the pathogenicity of a variant of the IL2RG gene when the T and B cell lineages comprised only revertant cells. We studied the X-inactivation of sorted T cells from the mother to show that the pathogenic variant was indeed the cause of his SCID. One interesting feature was a progressive loss of B cells over 20 years. CyTOF (cytometry time of flight) analysis of bone marrow offered a potential explanation of the B cell failure, with expansions of progenitor populations that suggest a developmental block. Another interesting feature was that the patient bore extensive granulomatous disease and skin cancers that contained T cells, despite severe T cell lymphopenia in the blood. Finally, the patient had a few hundred T cells on presentation but his TCRs comprised a very limited repertoire, supporting the important conclusion that repertoire size trumps numbers of T cells. Keywords SCID . IL2RG . somatic reversion . B cells . T cells
Introduction X-linked severe combined immunodeficiency (X-SCID) is a disorder characterized by pathogenic variants affecting the IL2RG gene, which encodes the common gamma chain (γc) protein, also known as CD132 [1]. It is one of the most common genetic causes of SCID, accounting for about 30% of cases [2]. In this disorder, the developing immune system cannot appropriately respond to cytokines that signal through * Manish J. Butte [email protected] 1
Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of California Los Angeles, Los Angeles, CA 90095, USA
2
Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA
3
Department of Pathology, University of California Los Angeles, Los Angeles, CA 90095, USA
4
Laboratory of Clinical Immunology and Microbiology, National Institutes of Health, NIAID, Bethesda, MD, USA
5
Department of Pediatrics, Division of Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA 90435, USA
the γc chain: IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The result is a characteristic phenotype lacking T cells and NK cells but often with B cells present. Without allogeneic hematopoietic stem cell transplantation (HSCT) or gene therapy, XSCID is thought to be uniformly fatal. However, several cases of revertant mutations have been described in X-SCID patients
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