Lung Myeloid Dendritic Cells Coordinately Induce TH1 and TH17 Responses in Human Emphysema

Specialized immune cells in the lungs of patients with emphysema create an inflammatory environment that drives lung destruction in a characteristic autoimmune reaction. Dendritic Cells of Destruction Underlie Emphysema Tobacco smoke is never good for your lungs, and in some people it sets up a destructive process called emphysema. In this disease, air sacs that normally exchange carbon dioxide for oxygen become enlarged, ultimately losing their elastic recoil and physiological function. Breathing becomes labored. Even uninfected lungs with emphysema show signs of a complex immune response, with an accumulation of immune cells. To attack the difficult chicken-or-the-egg problem presented by this disease, Shan et al. sorted out which of these cells serve as the ringleaders in orchestrating this immune reaction and, in the process, found the telltale presence of T helper 17 (TH17) cells—a recently identified hallmark of autoimmune inflammation. Cigarette smoke causes irritation in the lung and activates a general defensive reaction via the innate immune system. When this system cannot restore tissue health, the more precise adaptive immune system comes into play. The authors of Shan et al. now show that specialized professional antigen-presenting cells—called dendritic cells—are recruited by a chemoattractant into the lung, where they induce naïve CD4 T cells to develop into TH1 cells. These immune agents then help cytotoxic T cells to target damaged host lung tissue for destruction. Also induced by the dendritic cells are TH17 cells. These specialized T lymphocytes normally protect the barriers between the body and the environment (the skin and the gut lining, for example), but they also congregate at sites in which the body is erroneously attacking itself, as in autoimmune diseases such as rheumatoid arthritis and colitis. The cytokine interleukin-17A secreted by the TH17 cells coordinates their contribution to destruction of the lung in emphysema by causing lung macrophages to secrete two critical molecules: CCL20, a chemoattractant for the dendritic cells, which then set up an inflammatory positive feedback loop, and matrix metalloproteinase 12 (MMP12), a potent enzyme that destroys a lung endogenous protective proteinase called α1-antitrypsin. In the industrialized world, the ultimate cause of emphysema is usually smoking, but in developing countries, smoke from cooking fires and pollution are important factors in the development of this disease, which is a leading cause of death worldwide. Even after removal of the respiratory irritant, the disease progression is only slowed and existing lung damage is irreversible. Medications can ease the shortness of breath but are not a cure. A lung transplant or partial lung removal is a last resort available only to a few fortunate individuals (see Cypel et al. in this issue). Identification of the cellular players—like the dendritic and TH17 cells described by Shan et al.—through which smoke causes lung destruction is a key to discovering drugs that effect damage control. Moreover, the injurious cellular cycles established in the emphysematous lung are likely not unique, and their elucidation will undoubtedly uncover clues to other immune-related diseases that are associated with smoking. Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.