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Blood. 2018 Jul 19;132(3):281-292. doi: 10.1182/blood-2017-12-820985. Epub 2018 May 9.

Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development.

Author information

1
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
2
Department of Pediatric Immunology, Wilhelmina Children's Hospital, Utrecht University Medical Center, Utrecht, The Netherlands.
3
Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
4
Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.
5
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.
6
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; and.
7
Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.

Abstract

Hypomorphic RAG1 mutations allowing residual T- and B-cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T- and B-cell repertoire. To examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with mutations equivalent to those found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells and preserved serum immunoglobulin but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI. By using high-throughput sequencing, we identified marked skewing of Igh V and Trb V gene usage in early progenitors, with a bias for productive Igh and Trb rearrangements after selection occurred and increased apoptosis of B-cell progenitors. Rearrangement at the Igk locus was impaired, and polyreactive immunoglobulin M antibodies were detected. This study provides novel insights into how hypomorphic Rag1 mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.

PMID:
29743177
PMCID:
PMC6053949
[Available on 2019-07-19]
DOI:
10.1182/blood-2017-12-820985

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