A Novel Animal Model of Emphysema Induced by Anti-Elastin Autoimmunity

Abstract

Loss of immune tolerance to self-antigens can promote chronic inflammation and disrupt the normal function of multiple organs, including the lungs. Degradation of elastin, a highly insoluble protein and a significant component of the lung structural matrix, generates proinflammatory molecules. Elastin fragments (EFs) have been detected in the serum of smokers with emphysema, and elastin-specific T cells have also been detected in the peripheral blood of smokers with emphysema. However, an animal model that could recapitulate T cell–specific autoimmune responses by initiating and sustaining inflammation in the lungs is lacking. In this study, we report an animal model of autoimmune emphysema mediated by the loss of tolerance to elastin. Mice immunized with a combination of human EFs plus rat EFs but not mouse EFs showed increased infiltration of innate and adaptive immune cells to the lungs and developed emphysema. We cloned and expanded mouse elastin-specific CD4+ T cells from the lung and spleen of immunized mice. Finally, we identified TCR sequences from the autoreactive T cell clones, suggesting possible pathogenic TCRs that can cause loss of immune tolerance against elastin. This new autoimmune model of emphysema provides a useful tool to examine the immunological factors that promote loss of immune tolerance to self.

Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

“…These models may be more relevant for the initial assessment of alveolar damage mechanisms. Recently, Gu et al [178] demonstrated the use of a murine model of anti-elastin autoimmunity resulting in emphysema that could be used to examine the role of immune tolerance in diseases, such as COPD, and enhance the clinical relevance of elastase-based models.…”