UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice. Sci Rep 2020 Jul 21;10(1):12019
Date
07/23/2020Pubmed ID
32694640Pubmed Central ID
PMC7374577DOI
10.1038/s41598-020-68956-6Scopus ID
2-s2.0-85088288172 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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 β 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 β-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.
Author List
Chen YG, Ciecko AE, Khaja S, Grzybowski M, Geurts AM, Lieberman SMAuthors
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinAron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adoptive TransferAnimals
Autoimmunity
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Diabetes Mellitus, Type 1
Disease Models, Animal
Female
Genetic Predisposition to Disease
Insulin-Secreting Cells
Male
Mice
Mice, Inbred NOD
Mice, Knockout
Mutagenesis
Receptors, Antigen, T-Cell
Sialadenitis
Zinc Finger Nucleases
