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Hypomorphic Rag1mutations alter the preimmune repertoire at early stages of lymphoid development

Authors :
Ott de Bruin, L.M.
Bosticardo, M.
Barbieri, A.
Lin, S.G.
Rowe, J.H.
Poliani, P.L.
Ching, K.
Eriksson, D.
Landegren, N.
Kämpe, O.
Manis, J.P.
Notarangelo, L.D.
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