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


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.

SUBMITTER: Ott de Bruin LM 

PROVIDER: S-EPMC6053949 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Hypomorphic <i>Rag1</i> mutations alter the preimmune repertoire at early stages of lymphoid development.

Ott de Bruin L M LM   Bosticardo M M   Barbieri A A   Lin S G SG   Rowe J H JH   Poliani P L PL   Ching K K   Eriksson D D   Landegren N N   Kämpe O O   Manis J P JP   Notarangelo L D LD  

Blood 20180509 3


Hypomorphic <i>RAG1</i> 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 <i>Rag1</i> 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. Immunologica  ...[more]

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