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Hypomorphic Rag1mutations alter the preimmune repertoire at early stages of lymphoid development
- Source :
- Blood; July 2018, Vol. 132 Issue: 3 p281-292, 12p
- Publication Year :
- 2018
-
Abstract
- Hypomorphic RAG1mutations 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 Rag1mutations 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 Vand Trb Vgene usage in early progenitors, with a bias for productive Ighand Trbrearrangements after selection occurred and increased apoptosis of B-cell progenitors. Rearrangement at the Igklocus was impaired, and polyreactive immunoglobulin M antibodies were detected. This study provides novel insights into how hypomorphic Rag1mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.
Details
- Language :
- English
- ISSN :
- 00064971 and 15280020
- Volume :
- 132
- Issue :
- 3
- Database :
- Supplemental Index
- Journal :
- Blood
- Publication Type :
- Periodical
- Accession number :
- ejs56976325
- Full Text :
- https://doi.org/10.1182/blood-2017-12-820985