Mechanisms of Autoimmune Emphysema

Although cigarette smoking is implicated in the pathogenesis of emphysema, the precise mechanisms of chronic progressive alveolar septal destruction are not well understood. Here we show in a novel animal model (1) that immune competent, but not athymic, nude rats injected intraperitoneally with xenogeneic endothelial cells produce antibodies against endothelial cells and develop emphysema. Anti–endothelial cell antibodies cause endothelial cell apoptosis in vitro. TUNEL assay and activated caspase-3 Western blot and immunostaining showed more cells undergoing cell death in immunized animal lungs than in control rat lungs. There is a significant up-regulation of matrix metalloproteases (MMPs) MMP-9 and MMP-2 in the lungs of immunized animals when compared with control rat lungs. Anti–endothelial cell antibodies recognize several endothelial cell epitopes, including vascular endothelial growth factor receptor (VEGFR)-2 and angiotensin-converting enzyme (ACE). Mice injected with anti–endothelial cell serum also develop emphysema. Lung morphometry of mice injected with anti–endothelial cell antibody showed 20% enlargement of alveolar airspaces over a 5-wk period as compared with normal rat serum–injected controls. Immunization also causes accumulation of CD4⁺ T cells in the lung. Adoptive transfer of a pathogenic, spleen-derived CD4⁺ cell population into naive immune-competent animals also results in emphysema. Moreover, adoptive transfer of CD4⁺ spleen cells into secondary syngeneic rats resulted in emphysema, even though these secondary rats had not been immunized with human umbilical vein endothelial cells (HUVEC). In this study, we show for the first time that humoral and CD4⁺ cell–dependent mechanisms are sufficient to trigger the development of emphysema. Our data demonstrate that pathogenic CD4⁺ T lymphocytes are necessary and sufficient in breaking a regulatory tolerance and causing emphysema in naive immune-competent rats, suggesting the involvement of autoimmune mechanisms in alveolar septal cell destruction.