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Journal article
T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes
Genes, v 12(6), p852
01 Jun 2021
PMID: 34205929
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/D-u) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/D-u and a susceptible allele of the Ubd promoter, we demonstrate that germline knockout of Tcrb-V13S1A1, which encodes the V beta 13a T cell receptor beta chain, completely prevents diabetes. Using the RT1B/D-u-identical LEW.1W rat, which does not develop T1D despite also having the same Tcrb-V13S1A1 beta chain gene but a different allele at the Ubd locus, we show that knockout of the Ubash3a regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the V beta 13a TCR and its class II RT1(u) ligand suggests a mechanism by which a germline TCR beta chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the V beta 13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity.
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Details
- Title
- T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes
- Creators
- John P. Mordes - University of Massachusetts Medical SchoolLaura Cort - Drexel UniversityZhijun Liu - University of Massachusetts Medical SchoolRyan Eberwine - Drexel UniversityElizabeth P. Blankenhorn - Drexel UniversityBrian G. Pierce - Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA.
- Publication Details
- Genes, v 12(6), p852
- Publisher
- Mdpi
- Number of pages
- 12
- Grant note
- AI088480 / NIH/NIAID R21 grant R01-GM126299 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1-16-ICTS-086 / American Diabetes Association
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000666667500001
- Scopus ID
- 2-s2.0-85107960236
- Other Identifier
- 991019169897604721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity