title: Experimental evidence that mutated-self peptides derived from mitochondrial DNA somatic mutations have the potential to trigger autoimmunity.
abstract: Autoimmune disease is a critical health concern, whose etiology remains enigmatic. We hypothesized that immune responses to somatically mutated self proteins could have a role in the development of autoimmune disease. IFN-γ secretion by T cells stimulated with mitochondrial peptides encoded by published mitochondrial DNA was monitored to test the hypothesis. Human peripheral blood mononuclear cells (PBMCs) of healthy controls and autoimmune patients were assessed for their responses to the self peptides and mutated-self peptides differing from self by one amino acid. None of the self peptides but some of the mutated-self peptides elicited an immune response in healthy controls. In some autoimmune patients, PBMCs responded not only to some of the mutated-self peptides, but also to some of the self peptides, suggesting that there is a breach of self-tolerance in these patients. Although PBMCs from healthy controls failed to respond to self peptides when stimulated with self, the mutated-self peptide could elicit a response to the self peptide upon re-stimulation in vitro, suggesting that priming with mutated-self peptides elicits a cross-reactive response with self. The data raise the possibility that DNA somatic mutations are one of the events that trigger and/or sustain T cell responses in autoimmune diseases.
authors: Department of Kinesiology and Health Science, York University, Canada. Electronic address: lina.chen@mail.utoronto.ca.
authors: Lina
authors: L
authors: Chen
authors: Department of Kinesiology and Health Science, York University, Canada.
authors: Bhargavi
authors: B
authors: Duvvuri
authors: Department of Mathematics and Statistics, York University, Canada.
authors: Jörg
authors: J
authors: Grigull
authors: Department of Kinesiology and Health Science, York University, Canada.
authors: Roni
authors: R
authors: Jamnik
authors: University Health Network and University of Toronto, Canada.
authors: Joan E
authors: JE
authors: Wither
authors: Department of Kinesiology and Health Science, York University, Canada.
authors: Gillian E
authors: GE
authors: Wu
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015551:Autoimmunity / Q000187:drug effects*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003429:Cross Reactions; D004272:DNA, Mitochondrial / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000276:immunology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D017634:Self Tolerance; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D001324:Autoantigens; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D010455:Peptides
keywords: Autoimmunity; Cross-reactivity; Self-tolerance; Self–nonself discrimination; Somatic mutation