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dc.contributor.authorChinnasamy, Prameladevi
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 78-12(E), Section: B.;Advisors: Nicholas E. S. Sibinga.
dc.description.abstractAllograft inflammatory factor-1 (AIF1), also known as IBA1, is a 17 KDa protein identified as an inflammatory molecule in multiple clinically relevant conditions, including alloimmune, autoimmune, metabolic, and vascular diseases. Despite increased AIF1 expression in infiltrating cells in rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE, an animal model for multiple sclerosis in humans), and single nucleotide polymorphisms associated with several autoimmune diseases, the pathogenetic significance of AIF1 in these inflammatory disease settings remains unclear. In addition, several reports link sequence variants at the AIF1 locus to obesity, adipose inflammation, and diabetes in human populations. Thus, I have investigated the functional role of AIF1 in EAE, RA, and metabolic diseases including obesity and type 2 diabetes using AIF1-deficient mice we have generated in our laboratory.;In the EAE model, I observed that AIF1-deficient mice developed less severe disease than controls after myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization. These findings correlated with reduced CNS leukocyte infiltration and demyelination; spinal cords from AIF1-deficient mice contained fewer CD4 T cells and microglia and more CD8 T cells. These mice also showed significantly less splenic CD4 T-cell expansion and activation, plus decreased pro-inflammatory cytokine expression. Overall, our findings identify AIF1 as a potent molecule that promotes expansion and activation of CD4 T cells, plus elaboration of a pro-inflammatory cytokine milieu, in MOG35-55-induced EAE.;To elucidate the role of AIF1 in collagen-induced arthritis (an animal model for RA), I immunized AIF1-deficient and control mice with chicken collagen. AIF1-deficient mice showed protection against disease activity, with decreased paw swelling, reduced inflammatory monocytes (CD11b+Gr1+) in the spleen, and lower levels of IgG1 and IgG3 anti-collagen antibodies in the serum. However, AIF1 deficiency did not affect overall B and T cell populations, markers of early activation, or total monocytes, macrophages, or dendritic cells in spleens of immunized mice and proinflammatory cytokine expression in CII rechallenged splenocytes and lymph node cells. Together, these observations suggest that AIF1 promotes collagen-induced arthritis, possibly by contributing to an isotype-specific autoantibody response.;Furthermore, I assessed a possible causal role of AIF1 in obesity and type 2 diabetes using mouse models, and found that genetic inactivation of AIF1 expression prevents high fat diet-induced obesity, limited expansion of white adipose depots, and decreased lipid accumulation within brown adipose tissues. This protection appeared to reflect increased basal metabolic activity, with no significant changes in core body temperature or physical activity. At the tissue level, I found that AIF1 deficiency promoted gene expression associated with thermogenesis and adipogenesis in brown adipose tissues and beiging in white adipose tissues, without impairment of basal white adipogenic gene expression. Mechanistically, loss of AIF1 in brown adipocytes permitted increased [3adrenergic signaling, and in white adipocytes, canonical protein kinase A (PKA) signaling, both of which can stimulate phosphorylation of PKA substrates and promote thermogenesis. Further, the increase in basal metabolism due to loss of AIF1 improved glucose homeostasis and insulin sensitivity, correlated with reduced inflammatory infiltrates and increased M2 vs. M1 macrophage marker expression in epididymal adipose tissue, and protected against hepatosteatosis.;Overall, my findings provide new insights into the function of AIF1 in EAE, collagen-induced arthritis, and mouse models of obesity and type 2 diabetes, and lead us to propose that strategies to block AIF1 function could provide novel therapeutic approaches to prevent or ameliorate clinical autoimmune and metabolic diseases.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.titlePleiotropic Functions of the Allograft Inflammatory Factor-1 Protein in Autoimmune and Metabolic Disorders

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