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

Yi-Guang Chen; Ashley E Ciecko; Shamim Khaja; Michael Grzybowski; Aron M Geurts; Scott M Lieberman

doi:10.1038/s41598-020-68956-6

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

Journal article

Open access

Peer reviewed

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

Yi-Guang Chen, Ashley E Ciecko, Shamim Khaja, Michael Grzybowski, Aron M Geurts and Scott M Lieberman

Scientific reports, Vol.10(1), pp.12019-12019

07/21/2020

DOI: 10.1038/s41598-020-68956-6

PMCID: PMC7374577

PMID: 32694640

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https://doi.org/10.1038/s41598-020-68956-6View

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Abstract

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.

Adoptive Transfer

Animals

Autoimmunity

CD4-Positive T-Lymphocytes - immunology

CD4-Positive T-Lymphocytes - metabolism

CD8-Positive T-Lymphocytes - immunology

CD8-Positive T-Lymphocytes - metabolism

Diabetes Mellitus, Type 1 - genetics

Diabetes Mellitus, Type 1 - immunology

Diabetes Mellitus, Type 1 - metabolism

Disease Models, Animal

Female

Genetic Predisposition to Disease - genetics

Insulin-Secreting Cells - metabolism

Male

Mice

Mice, Inbred NOD

Mice, Knockout

Mutagenesis - drug effects

Receptors, Antigen, T-Cell - deficiency

Receptors, Antigen, T-Cell - genetics

Sialadenitis - metabolism

Zinc Finger Nucleases - pharmacology

Details

Title: Subtitle: UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice
Creators: Yi-Guang Chen - Medical College of Wisconsin
Ashley E Ciecko - Medical College of Wisconsin
Shamim Khaja - Medical College of Wisconsin
Michael Grzybowski - Medical College of Wisconsin
Aron M Geurts - Medical College of Wisconsin
Scott M Lieberman - University of Iowa
Resource Type: Journal article
Publication Details: Scientific reports, Vol.10(1), pp.12019-12019
DOI: 10.1038/s41598-020-68956-6
PMID: 32694640
PMCID: PMC7374577
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: R01 DK121747 / NIDDK NIH HHS DK097605 / NIH HHS R01 DK107541 / NIDDK NIH HHS EY027731 / NIH HHS R21 AI144360 / NIAID NIH HHS DP3 DK097605 / NIDDK NIH HHS R01 EY027731 / NEI NIH HHS
Language: English
Date published: 07/21/2020
Academic Unit: Stead Family Department of Pediatrics; Rheumatology, Allergy, and Immunology
Record Identifier: 9984353841802771

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