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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.

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


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.

[Available on 2019-07-19]

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