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Clonal copy-number mosaicism in T-lymphocytes in NOD mice

ABSTRACT: In Type 1 Diabetes (T1D), imperfect concordance in monozygotic twins and in males of the inbred NOD mouse model, despite genetic identity and shared environment during the years of peak incidence, points to stochastic determinants. One plausible such stochastic event, never explored, is post-zygotic genetic changes in the expanding antigen-specific autoreactive T-cell lineages. The contribution of such mutations in tumorigenesis is well established but little is known about potential role in autoimmunity. Here, with high-resolution comparative genomic hybridization (CGH) of DNA from memory CD4 T-cells from pancreatic lymph nodes of NOD mice, we found mosaic somatic copy-number aberrations (CNAs) with highly non-random independent involvement of the same gene(s) across different mice. A few CNAs were also found in lymphocytes expanded during normal host defense but were significantly smaller. Our data strongly support a causal role for post-zygotic mutations in autoreactive T-cells in T1D. They challenge the classical notions of autoimmune disease and open conceptual avenues towards individualized prevention and therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE114660 | GEO | 2019/09/13

REPOSITORIES: GEO

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