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dc.contributor.advisorHaskins, Kathryn
dc.contributor.advisorSlansky, Jill
dc.contributor.authorWiles, Timothy Aaron
dc.contributor.committeememberDavidson, Howard
dc.contributor.committeememberJacobelli, Jordan
dc.contributor.committeememberReisdorph, Nichole
dc.contributor.committeememberWysocki, Lawrence
dc.date.accessioned2017-01-06T22:35:02Z
dc.date.available2017-01-06T22:35:02Z
dc.date.submitted2016
dc.descriptionIncludes bibliographical references.
dc.descriptionFall
dc.description.abstractAutoimmunity arises from a failure of the immune system to establish or maintain self-tolerance. In the thymus, developing T cells are exposed to self-peptides derived from genetically encoded proteins, and self-reactive T cells are either deleted or develop a regulatory phenotype before venturing into the periphery. Post-translational modification (PTM) of self-peptides in the periphery may lead to the generation of neo-epitopes that are not displayed in the thymus. T cells specific for these modified peptides can bypass central tolerance mechanisms and escape into the periphery where they may potentially contribute to an autoimmune response. PTM of proteins is well documented in several autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, celiac disease), but has been little characterized in autoimmune diabetes. To facilitate the identification of autoantigens relevant to this disease, we have used a panel of islet-reactive, diabetogenic CD4 T cell clones isolated from spontaneously diabetic NOD mice. In this work, we demonstrate that the antigen for one of these clones, BDC-6.9, is a member of a novel class of post-translationally modified peptides we term hybrid insulin peptides (HIPs). The BDC-6.9 antigen, 6.9HIP, is formed by fusion of a normal cleavage product of islet amyloid polypeptide to the C-terminus of an insulin C-peptide fragment. Characterization of the CD4 T cell response to this antigen in the NOD mouse suggests an important role for HIPs as antigens in autoimmune diabetes. These findings hold great potential for improving our understanding of the etiology and pathogenesis of autoimmune diabetes, promoting the development of disease biomarkers, and informing the design of disease interventions.
dc.identifierWiles_ucdenveramc_1639D_10385.pdf
dc.identifier.schemaETD Data Dictionary 1.1
dc.identifier.urihttp://hdl.handle.net/10968/1760
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.subjectCD4 T cells
dc.subject.meshT-Lymphocytes
dc.subject.meshMice, Inbred NOD
dc.subject.meshAutoantigens
dc.subject.meshDiabetes Mellitus, Type 1
dc.subject.meshPeptides
dc.subject.meshInsulin
dc.titleIdentification of a novel post-translationally modified antigen in the NOD mouse model of autoimmune diabetes
dc.typeThesis
thesis.degree.disciplineImmunology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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