Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development
| Autor: | John P. Manis, Nils Landegren, Jared H. Rowe, Daniel Eriksson, Marita Bosticardo, K. Ching, Pietro Luigi Poliani, Ld Notarangelo, A. Barbieri, Olle Kämpe, L. M. Ott de Bruin, S. G. Lin |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lymphocyte Immunology Cell Biology Hematology Biology Immune dysregulation medicine.disease_cause Biochemistry Phenotype Recombination-activating gene Autoimmunity 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure Immune system Immunoglobulin M biology.protein medicine Antibody |
| Zdroj: | Blood. 132:281-292 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2017-12-820985 |
| Popis: | 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 naive 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|