A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences wi...

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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 119; číslo 31; s. e2120028119
Hlavní autoři:	Girdhar, Khyati, Huang, Qian, Chow, I-Ting, Vatanen, Tommi, Brady, Claudia, Raisingani, Amol, Autissier, Patrick, Atkinson, Mark A, Kwok, William W, Kahn, C Ronald, Altindis, Emrah
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 02.08.2022
Témata:	Animals Autoantibodies - immunology Bacteroidetes CD8-Positive T-Lymphocytes Child Diabetes Mellitus, Type 1 - pathology Female Gastrointestinal Microbiome Humans Insulin - genetics Mice Mice, Inbred NOD Mice, SCID Molecular Mimicry Peptides - chemistry Parabacteroides distasonis molecular mimicry type 1 diabetes gut microbiome insB:9-23 epitope
ISSN:	1091-6490, 1091-6490
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Abstract	Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the peptide, found in the normal human gut commensal , activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8 T cells, while decreasing FoxP3 regulatory T cells. Western blot analysis identified -reacting antibodies in sera of NOD mice colonized with and human T1D patients. Furthermore, adoptive transfer of splenocytes from -treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis.
AbstractList	Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the hprt4-18 peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8+ T cells, while decreasing FoxP3+ regulatory T cells. Western blot analysis identified P. distasonis-reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis-treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the hprt4-18 peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis.Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the hprt4-18 peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8+ T cells, while decreasing FoxP3+ regulatory T cells. Western blot analysis identified P. distasonis-reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis-treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the hprt4-18 peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis. Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the peptide, found in the normal human gut commensal , activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8 T cells, while decreasing FoxP3 regulatory T cells. Western blot analysis identified -reacting antibodies in sera of NOD mice colonized with and human T1D patients. Furthermore, adoptive transfer of splenocytes from -treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis.
Author	Altindis, Emrah Kwok, William W Brady, Claudia Raisingani, Amol Atkinson, Mark A Huang, Qian Vatanen, Tommi Kahn, C Ronald Autissier, Patrick Girdhar, Khyati Chow, I-Ting
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Snippet	Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the...
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SubjectTerms	Animals Autoantibodies - immunology Bacteroidetes CD8-Positive T-Lymphocytes Child Diabetes Mellitus, Type 1 - pathology Female Gastrointestinal Microbiome Humans Insulin - genetics Mice Mice, Inbred NOD Mice, SCID Molecular Mimicry Peptides - chemistry
Title	A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes
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