Loss of peripheral tolerance in emphysema phenotypes, exacerbations, and disease progression

Sivasubramanium Bhavani, Xiaoyi Yuan, Ran You, Ming Shan, David Corry, Farrah Kheradmand

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)S164-S168
JournalAnnals of the American Thoracic Society
Volume12
DOIs
StatePublished - Nov 2015

Keywords

  • Autoimmunity
  • C3a
  • Complement proteins
  • Emphysema
  • T cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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