UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice

Recent advances in genetic analyses have significantly refined human type 1 diabetes (T1D) associated loci. The goal of such effort is to identify the causal genes and have a complete understanding of the molecular pathways that independently or interactively influence cellular processes leading to the destruction of insulin producing pancreatic beta cells. UBASH3A has been suggested as the underlying gene for a human T1D associated region on chromosome 21. To further evaluate the role of UBASH3A in T1D, we targeted Ubash3a in NOD mice using zinc-finger nuclease mediated mutagenesis. In both 10-week-old females and males, significantly more advanced insulitis was observed in UBASH3A-deficient than in wild-type NOD mice. Consistently, UBASH3A-deficient NOD mice developed accelerated T1D in both sexes, which was associated with increased accumulation of beta -cell autoreactive T cells in the spleen and pancreatic lymph node. Adoptive transfer of splenic T cells into NOD.Rag1(-/-) mice demonstrated that UBASH3A deficiency in T cells was sufficient to promote T1D development. Our results provide strong evidence to further support a role of UBASH3A in T1D. In addition to T1D, UBASH3A deficiency also promoted salivary gland inflammation in females, demonstrating its broad impact on autoimmunity.