1635-P: Recurrent Mosaicism in Memory T-Cells from Newly Diagnosed Patients with Type 1 Diabetes
Bibliographic record
Abstract
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. Disclosure M. Al-Riyami: None. L. Marchand: None. C. Polychronakos: Employee; Self; MaiDa Gene Technology, Zhoushan, Zhejiang Province, China. Funding 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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".