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

LM Ott de Bruin, M Bosticardo, A Barbieri… - Blood, The Journal …, 2018 - ashpublications.org
LM Ott de Bruin, M Bosticardo, A Barbieri, SG Lin, JH Rowe, PL Poliani, K Ching, D Eriksson…
Blood, The Journal of the American Society of Hematology, 2018ashpublications.org
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 …
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.
ashpublications.org