title: Loss of Peripheral Tolerance in Emphysema. Phenotypes, Exacerbations, and Disease Progression.
abstract: Heterogeneity in the development and progression of cigarette smoke-induced lung diseases strongly argues for a need to improve the clinical and phenotypic characterization of patients with chronic obstructive lung disease and emphysema. Smokers with emphysema are at a much higher risk for accelerated loss of lung function, increased cardiovascular morbidity, and development of lung cancer. Recent evidence in human translational studies and animal models suggests that emphysema is associated with activation of specialized antigen-presenting cells and that cigarette smoke can disrupt the induction of immune tolerance in the lungs. Quantitative assessment of cytokines expressed by autoreactive T lymphocytes in response to human lung elastin fragments has shown a strong positive correlation between T helper Type 1 (Th1) and Th17 cells' immune responses and emphysema. In search of factors that could reduce the threshold for induction of autoimmune inflammation, we have discovered that cleavage of complement protein 3 (C3) generates bioactive molecules (e.g., C3a) and activates lung antigen-presenting cells. The autocrine and paracrine function of C3a and its receptor are required in T cell-mediated inflammatory responses to cigarette smoke in both human and preclinical models of emphysema. Targeting upstream molecules that reduce the potential for generation of autoreactive T cells could lead to the development of novel therapeutics to prevent progression of emphysema in smokers.
authors.affiliation: 1 Department of Medicine.
authors.forename: Sivasubramanium
authors.initials: S
authors.lastname: Bhavani
authors.affiliation: 1 Department of Medicine.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yuan
authors.affiliation: 1 Department of Medicine.
authors.forename: Ran
authors.initials: R
authors.lastname: You
authors.affiliation: 1 Department of Medicine.
authors.forename: Ming
authors.initials: M
authors.lastname: Shan
authors.affiliation: 1 Department of Medicine.|2 Department of Pathology and Immunology, and.|3 Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas; and.|4 Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Corry
authors.affiliation: 1 Department of Medicine.|2 Department of Pathology and Immunology, and.|3 Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas; and.|4 Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, Texas.
authors.forename: Farrah
authors.identifier: http://orcid.org/0000-0001-5343-103X
authors.initials: F
authors.lastname: Kheradmand
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015926:Complement C3a / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D061166:Peripheral Tolerance / Q000276:immunology*; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D011656:Pulmonary Emphysema / Q000276:immunology*; D012907:Smoking / Q000009:adverse effects; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; D015926:Complement C3a
keywords: C3a; T cells; complement proteins; emphysema