Background-Tobacco related lung diseases including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide. Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory viral infections and may result in respiratory failure in those with advanced lung disease.

Over the past few decades, neutrophils and macrophages had co-occupied center stage as the critical innate immune cells underlying the pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease and lung parenchymal destruction (i.e., emphysema). While chronic exposure to smoke facilitates the recruitment of innate immune cells into the lung, a clear role for adaptive immunity in emphysema has emerged. Evidence from human studies specifically point to a role for recruitment and activation of pathogenic lymphocytes and lung antigen-presenting cells in emphysema; similarly, animal models have confirmed a significant role for autoimumnity in progressive smoke-induced emphysema. Increased numbers of activated antigen-presenting cells, Th1 and Th17 cells, have been associated with smoke-induced lung inflammation and production of the canonical cytokines of these cells, IFN-γ and IL-17, correlates with disease severity. These exciting new breakthroughs could open new avenues for developing effective new therapies for smoke-induced emphysema.

Cross-sectional studies have suggested a role for activation of adaptive immunity in smokers with emphysema, but the clinical application of these findings has not been explored. Here we examined the utility of detecting autoreactive T cells as a screening tool for emphysema in an at-risk population of smokers. We followed 156 former and current (ever)-smokers for 2 years to assess whether peripheral blood CD4 T cell cytokine responses to lung elastin fragments (EFs) could discriminate between those with and without emphysema, and to evaluate the relevance of autoreactive T cells to predict changes during follow-up in lung physiological parameters. Volunteers underwent baseline complete phenotypic assessment with pulmonary function tests, quantitative chest CT, yearly 6-min walk distance (6MWD) testing, and annual measurement of CD4 T cell cytokine responses to EFs. The areas under the receiver operating characteristic curve to predict emphysema for interferon gamma (IFN-γ), and interleukin 6 (IL-6) responses to EFs were 0.81 (95% CI of 0.74–0.88) and 0.79 (95% CI of 0.72–0.86) respectively. We developed a dual cytokine enzyme-linked immunocell spot assay, the γ-6 Spot, using CD4 T cell IFN-γ and IL-6 responses and found that it discriminated emphysema with 90% sensitivity. After adjusting for potential confounders, the presence of autoreactive T cells was predictive of a decrease in 6MWD over 2 years (decline in 6MWD, −19 m per fold change in IFN-γ; P = 0.026, and −26 m per fold change in IL-6; P = 0.003). In support of the human association studies, we cloned CD4 T cells with characteristic T helper (Th)1 and Th17 responses to EFs in the peripheral blood of ever-smokers with emphysema, confirming antigenicity of lung elastin in this population. These findings collectively suggest that the EF-specific autoreactive CD4 T cell assay, γ-6 Spot, could provide a non-invasive diagnostic tool with potential application to large-scale screening to discriminate emphysema in ever-smokers, and predict early relevant physiological outcomes in those at risk.

This paper studies best finitely supported approximations of one-dimensional probability measures with respect to the L r -Kantorovich (or transport) distance, where either the locations or the weights of the approximations' atoms are prescribed. Necessary and sufficient optimality conditions are established, and the rate of convergence (as the number of atoms goes to infinity) is discussed. In view of emerging mathematical and statistical applications, special attention is given to the case of best uniform approximations (i.e., all atoms having equal weight). The approach developed in this paper is elementary; it is based on best approximations of (monotone) L r -functions by step functions, and thus different from, yet naturally complementary to, the classical Voronoi partition approach.Keywords. Constrained approximation, best uniform approximation, asymptotically best approximation, Kantorovich distance, balanced function, quantile function.When endowed with the metric d r , the space P r is separable and complete, and d r (µ n , µ) → 0 implies that µ n → µ weakly. Note that P r ⊃ P s and d r ≤ d s whenever r < s. On P s , the metrics d r and d s are not equivalent, as the example of µ n = (1 − n −s )δ 0 + n −s δ n shows, for which d s (µ n , δ 0 ) ≡ 1, and yet lim n→∞ d r (µ n , δ 0 ) = 0 for all r < s, and hence µ n → δ 0 weakly. The reader is referred to [12,32] for details on the mathematical background of the Kantorovich distance, and to [17,32] for a discussion of its usefulness in the study of mass transportation and quantization problems.

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