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Title: Autoimmunity in obesity and myocarditis
Author: Selli, Mehmet Emrah
ISNI:       0000 0004 6057 9173
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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Autoimmunity is responsible for a wide spectrum of degenerative diseases, including metabolic disorders such as type I diabetes. If the triggering antigen or antigens can be identified, immune tolerization with peptides may be an effective therapy. Mitochondrial heat shock protein 60 (HSP60) has been implicated as an autoantigen in several diseases. Furthermore, ectopic HSP60 over expression was recently linked to human obesity and could therefore act as an autoantigen causing obesity-related metabolic dysfuntion. Using high fat fed C57BL6 mice as a' model, we observed increased circulating HSP60 levels and both T cell and B cell (antibody) responses against HSP60. Hence, HSP60 does indeed appear to be one of the mystery autoantigens triggering the early T and B cell responses during obesity. Furthermore, using previously-defined, immunodominant murine HSP60 peptide combinations in a dose escalation protocol we attempted peptide therapy. Peptide therapy did not significantly reduce T or B cell responses to HSP60 but nevertheless significantly improved glucose tolerance and circulating LDLlVLDL. HSP60 peptide therapy could therefore be helpful in reversing the metabolic consequences of obesity. Myocarditis is defined as damage to heart muscle coupled with an inflammatory infiltrate and left ventricular dysfunction. Clinically, the acute phase is usually caused by viral cardiac damage but it can progress to chronic myocarditis when autoimmunity develops. Exposure of intracellular cardiac proteins, especially cardiac a-myosin, has been implicated. Autoimmunity to a-myosin may arise because it is not expressed in the thymus and therefore tolerance does not develop. We developed a humanised HLA-DR4 transgenic mouse model of a-myosin induced autoimmune myocarditis. Moreover, we were able to downregulate autoimmune responses against a-myosin, reduce inflammatory cell infiltration and improve left ventricular cardiac function using tolerogenic peptide combinations determined from epitope prediction studies. In summary, our findings provide proof of principle for peptide therapy to treat obesity-associated metabolic complications and autoimmune myocarditis.
Supervisor: Newby, Andrew; Wraith, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available