Maha Al-Riyami, Oman
Sultan Qaboos University Biochemistry DepartmentPresenter of 1 Presentation
CLONAL MOSAICISM IN AUTOREACTIVE T CELLS IN DIABETIC NOD MICE
Abstract
Background and Aims
Type 1 Diabetes (T1D) caused by an autoimmune targeted destruction of the insulin-producing beta cells. The concordance for T1D in monozygotic twins and in the inbred NOD mice is far from 100%, despite genetic identity and shared environment during incidence peak years. This suggests stochastic determinants such as the never explored, post-zygotic mutations in the expanding antigen-specific T cell lineages, by analogy to their role in the expanding tumor lineage in cancer. We investigated somatic mutations as part of the cause of diabetes.
Methods
We used comparative genomic hybridization to identifiy somatic copy-number aberrations (CNAs) in DNA of memory CD4+ T cells from pancreatic lymph-nodes of diabetic NOD mice. To confirm the CNAs, we used the gold standard approach for CNA quantification, Multiplex ligation-dependent probe amplification. As controls, we examined DNA from lymphocytes expanded during normal host defense in mice infected with Leishmania major parasite. Also, we sequenced the TCR to determine the coloniality of these CD4+ memory cells.
Results
We found lymphocyte-exclusive mosaic somatic CNAs with highly non-random independent involvement of the same genes across different mice, some with an autoimmunity association. Lymphocytes involved in host defense were fewer and significantly smaller compared to those in autoreactive cells. Low T cell clonality for our samples suggests a pre-thymic formation of these CNAs.
Conclusions
Here, we explored a novel, unexplored phenomenon of a potential causal contribution of PZMs in autoreactive T cells in T1D pathogenesis. Our findings challenge the classical notions of autoimmunity and open conceptual avenues toward individualized prevention and therapeutics.