Type 1 diabetes (T1D) is an autoimmune disease resulting in destruction of pancreatic beta cells by infiltrating self-reactive T-cells into the islets. The concordance rate of T1D is far from 100% in monozygotic twins and in the inbred NOD mice, despite genetic identity and shared environment during the years of peak incidence. This suggests stochastic determinants such as, somatic mutations in the expanding autoantigen-specific T cell lineages, parallel to what is seen in the expanding tumor lineages in cancer.

Here, using comparative genomic hybridization (CGH), we found that ∼67% of our study subjects (newly diagnosed patients with T1D) carry somatic copy number aberrations (CNAs) in proinsulin- reactive CD3+ T cell clones. Some of the mutated genes reoccurred independently in cells from two or three different patients which is a substantial evidence for a pathogenic contribution. These include genes with T cell expression and a proliferation or regulatory function, such as IKZF1, CHD7 and SMARCA2. Moreover, we identified genes, such as SAMD1 and CASZ1 that were previously identified in T cells of diabetic NOD mice and also have a proliferative and a regulatory function. The level of TCR clonality of the tested lymphocytes shows that these somatic mutations can occur both pre- and post- to the thymic selection. CNAs in T cells involved in host defense (reaction to Tetanus Toxoid) obtained from the same patients were significantly smaller in size. Our data provide evidence of a potential role of somatic mutations in the pathogenesis of T1D and, potentially, other autoimmune diseases.


M. Al-Riyami: None. L. Marchand: None. C. Polychronakos: Employee; Self; MaiDa Gene Technology, Zhoushan, Zhejiang Province, China.


Canadian Institutes of Health Research (MOP-137050); Canadian Diabetes Association (OG-3-11-3429CP); Sultan Qaboos University (to M.A-R.)

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