All ETDs from UAB

Advisory Committee Chair

Steven R Duncan

Advisory Committee Members

Troy D Randall

Susan L Bellis

Jessy S Deshane

Amit Gaggar

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Immune dysregulation is a hallmark of various chronic lung diseases such as Chronic Obstructive Pulmonary Diseases (COPD) and Idiopathic Pulmonary Fibrosis (IPF). Previous studies in our lab have shown evidences of autoimmunity such as increases in autoantibodies, abnormal T cell profile, immune complex deposition and the presence of ectopic lymphoid structures in the lung of these patients. This thesis consolidates two separate projects about various aberrant immune responses in these diseases. The first project identified Glucose-Regulated-Protein 78 (GRP78) as the common autoantigen in COPD and characterized how GRP78 autoantibodies may increase COPD mortality via its atherogenic effects. I demonstrated that circulating IgG autoantibodies to Glucose Regulated Protein 78 (GRP78), a heat shock protein, were significantly associated with carotid intima-medial thickness- a surrogate marker of atherosclerosis, in COPD patients. Moreover, IgG autoantibodies against a particular GRP78 peptide segment (GRP78 246-260) isolated from COPD plasma, induced human aortic endothelial cells to produce proinflammatory mediators, including IL-8, potentially contributing to atherosclerosis. These data raised possibilities that autoantibody reduction might ameliorate vascular disease in this high-risk population. The second project studied how an abnormal population of T cells- the “terminally-differentiated” CD27null CD4+ T cells may contribute to IPF pathogenesis. CD27, a TNF receptor ubiquitously present on naïve T-cells, is costimulatory molecule important for the generation of T cell memory response. Since IPF is characterized by accumulation of lung extracellular matrix protein (ECM) produced by fibroblasts, I sought to determine how the lack of CD27 in CD4+ T cells may affect fibroblast activity. I demonstrated that CD70, the sole ligand for CD27, is expressed in human fibroblasts and characterized CD70 expression in these cells. TGF-β1, the most potent fibrotic cytokine, increased CD70 expression, and CD70 cross-linkage diminished ECM production. These effects were mediated by AKT and interconnected pathways and were abrogated by prior CD70 knockdown. This response was also strong enough to reverse the pro-fibrotic effect of TGF-β1 in vitro and in ex-vivo human skin fibrosis models. These data suggested the CD27/CD70 axis in lymphocyte-fibroblast interaction is a homeostatic mechanism to regulate fibroblast ECM, thereby inhibiting excessive fibrosis, and may illuminate novel fibrosis treatment.



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