Hypomorphic
| Autor: | L M, Ott de Bruin, M, Bosticardo, A, Barbieri, S G, Lin, J H, Rowe, P L, Poliani, K, Ching, D, Eriksson, N, Landegren, O, Kämpe, J P, Manis, L D, Notarangelo |
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| Rok vydání: | 2017 |
| Předmět: |
Gene Editing
B-Lymphocytes Immunobiology and Immunotherapy Genes RAG-1 Lymphopoiesis T-Lymphocytes Cell Differentiation Mice Transgenic V(D)J Recombination Immunity Humoral Immunophenotyping Mice Phenotype Gene Expression Regulation Mutation Animals Genetic Predisposition to Disease Disease Susceptibility Alleles Biomarkers |
| Zdroj: | Blood. 132(3) |
| ISSN: | 1528-0020 |
| 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 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. |
| Databáze: | OpenAIRE |
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