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Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex...

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Autores principales: Durinovic-Belló, I, Wu, R P, Gersuk, V H, Sanda, S, Shilling, H G, Nepom, G T
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845516/
https://www.ncbi.nlm.nih.gov/pubmed/20054344
http://dx.doi.org/10.1038/gene.2009.108
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author Durinovic-Belló, I
Wu, R P
Gersuk, V H
Sanda, S
Shilling, H G
Nepom, G T
author_facet Durinovic-Belló, I
Wu, R P
Gersuk, V H
Sanda, S
Shilling, H G
Nepom, G T
author_sort Durinovic-Belló, I
collection PubMed
description Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens.
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spelling pubmed-28455162010-03-29 Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin Durinovic-Belló, I Wu, R P Gersuk, V H Sanda, S Shilling, H G Nepom, G T Genes Immun Short Communications Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens. Nature Publishing Group 2010-01-07 2010-03 /pmc/articles/PMC2845516/ /pubmed/20054344 http://dx.doi.org/10.1038/gene.2009.108 Text en Copyright 2010, Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Licence. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Short Communications
Durinovic-Belló, I
Wu, R P
Gersuk, V H
Sanda, S
Shilling, H G
Nepom, G T
Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin
title Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin
title_full Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin
title_fullStr Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin
title_full_unstemmed Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin
title_short Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin
title_sort insulin gene vntr genotype associates with frequency and phenotype of the autoimmune response to proinsulin
topic Short Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845516/
https://www.ncbi.nlm.nih.gov/pubmed/20054344
http://dx.doi.org/10.1038/gene.2009.108
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