Investigation of the IL-23 response to wheat gliadin, the primary etiologic agent in celiac disease.
AuthorHarris, Kristina Michelle
AdvisorMann, Dean L.
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AbstractCeliac disease (CD) is an autoimmune disease of the small intestine that affects nearly 1% of the general population in the U.S. and in Europe. CD is unique because it is currently the only form of autoimmunity in which both the major genetic (90% HLA-DQ2+, the others HLA-DQ8) and etiologic factors (dietary glutens) for susceptibility are known. Still, the HLA association is thought to account for only 40% of the genetic requirement, and does not explain why most individuals that carry these alleles and consume dietary glutens on a regular basis never develop CD. IL-23 is a recently described cytokine thought to participate in both the innate and adaptive arms of the immune system. While the downstream effects of IL-23 on TH17 cells and their role in disease pathogenesis have been the primary focus of autoimmune research, the agents that initiate its production in the context of autoimmunity remain elusive. Thus, this dissertation investigated the IL-23 response induced by wheat gliadin, the major etiologic agent in CD. The results establish that enzymatically digested gliadin stimulates significantly greater production of IL-23, IL-1beta and TNFalpha and reduced levels of IL-1ra from CD patients compared to HLA-DQ2+ healthy controls, providing the first evidence that IL-23 is involved in the pathogenesis of CD. In addition, CD16+ monocytes were identified as the primary source of IL-23 induced by gliadin and were found to be overrepresented in CD patients, implicating this subset in the disease process. Moreover, these studies present convincing evidence that IL-1 cytokines control IL-23 production in human monocytes and in addition, offer insight on cytokine-dependent and FcR-mediated regulation of IL-1beta and IL-1ra secretion in myeloid-derived cell populations. These novel findings identify a functional role for a number of candidate genes that have been associated with CD and provide information that will guide studies of innate immune pathways in other inflammatory diseases. Importantly, the results of this study may lead to the discovery of therapeutic targets for this disease and other conditions characterized by an imbalance in the ratio of IL-1beta/IL-1ra and/or elevated levels of IL-23, as the two are likely synonymous.
DescriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2008
Health Sciences, Immunology