No abstract

Currently, chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The determination of immune mechanisms of inflammation in the disease presents an important challenge for fundamental medical research. According to modern views, Toll-like receptors (TLRs), among which TLR2 and TLR4 play a key role, are one of the essential components of inflammatory process in COPD. This review focuses on following aspects: the role of TLR2 and TLR4 in the initiation of inflammatory process in COPD; the mechanisms of influence of various exogenous factors (cigarette smoke, suspended particulate matter, and bacteria) on the expression of TLR2 and TLR4; the contribution of these TLRs to the T-helper (Th) immune response development in COPD, in particular to the Th17 immune response, which contributes to the progression of the disease and therapeutic implications of TLR2 and TLR4 in COPD.

Introduction. The prevalence and gain in the incidence of chronic obstructive pulmonary disease (COPD) is a reason to search for new approaches to the diagnosis of its progression. Air pollution causes an additional burden on COPD patients, contributing to the progression of this pathology. The study of mechanisms of its impact on the inflammatory response in COPD is an urgent task. The aim is to establish the dynamics of expression of interleukin-4 (IL-4), IL-6 and their membrane receptors (IL-4R, IL-6R) in blood T-helpers during COPD progression in patients living in areas with the high technogenic load. Material and methods. Vladivostok was chosen as a region with significant technogenic air pollution - the amount of air pollutants is 59.9 thousand tons per year, with 80% related to vehicle emissions; the surface layer of air is characterized by a predominance of particles less than 10 µm, which are the most pathogenic for the respiratory system. Patients with stable mild (36), moderate (52 ) and severe COPD (24) patients living in Vladivostok for at least 5 years were examined. The control group consisted of healthy volunteers living in the same area (32cases). The levels of IL-4, IL-6 in plasma and the number of T-helper cells expressing IL-4R and IL-6R were determined by flow cytometry. Results. A decline in serum IL-4 concentration and an increase in serum IL-6 level in COPD patients living under constant air pollution has been found. A decrease in IL-4R expression in blood T-helpers at all COPD stages and the gain in IL-6R synthesis in blood T-helpers during the progression of COPD were established. Conclusion. Data on the expression of IL-6R and IL-4R on circulating T-helpers can be used to diagnose the progression of COPD in patients living in urbanized areas.

Introduction — Currently, chronic obstructive pulmonary disease (COPD) is a global public health problem. However, molecular mechanisms of the development of this pathology are still poorly understood. The aim is to establish mechanisms of cytokine regulation of T-helper (Th) immune pathway in patients with COPD of varying severity. Material and Methods — The study included 112 patients with stable COPD (mild, moderate and severe grade) and 32 healthy volunteers (control group). We investigated serum cytokine levels (tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin 4 (IL-4), IL-6, IL-10, IL-17A) and the percentage of circulating Th cells (CD4+) expressing membrane receptor to IL-6 (IL-6R or CD126+), using flow cytometry. The levels of transforming growth factor-β1 (TGF-β1) and IL-21 were detected by ELISA. The direction of immune response in COPD patients was determined depending on the prevalence of cytokines playing a crucial role in the formation of certain Th cells type (Th1, Th17). Results — Th1-associated cytokine profile was expressed at the initial stage of COPD; the Th17-associated cytokine profile begins to prevail at severe COPD. Among COPD patients with Th1-associated cytokine profile, a statistically significant increase in the number of CD4+CD126+ cells in comparison with the control group was identified only in severe COPD. In the group of COPD patients with Th17-associated cytokine profile, an increase in the number of CD4+CD126+ cells were observed at all severity stages of the pathology. Conclusion — Moderate and severe COPD are characterized by the predominance of Th17-associated cytokine profile leading to chronic inflammation. The increase in IL-6R expression levels in circulating CD4+ cells serves as the mechanism for enhancing Th17-associated response in COPD.

Objective. According to modern views, the differences in the clinical course of chronic obstructive pulmonary disease (COPD) are associated with certain types of T-helper (Th) immune response. Recent data have shown that toll-like receptor 2 (TLR2) is involved in the development of Th immune response. However, TLR2-mediated regulation of Th subpopulation balance in COPD needs to be elucidated. The aim of our work is to determine the mechanisms of TLR2-mediated regulation of Th immune response in COPD of varying severity. Methods. The study included 323 smokers/ex-smokers with stable COPD (GOLD I, GOLD II, and GOLD III) and 97 healthy nonsmokers (control group). Serum levels of Th1 (TNF- α and IFN- γ ), Th2 (IL-4), Th17 (IL-6 and IL-17A), Treg (IL-10) cytokines, and the percentage of peripheral blood Th cells expressing TLR2 (CD4+CD282+) were assessed by flow cytometry. Serum concentrations of IL-21 (Th17) and TGF-β1 (Treg) were measured using the ELISA method. The predominant Th cytokine profile in serum was determined by calculating the ratios between levels of Th1 and Th17 cytokines. Spearman’s correlation test was performed. Results. Patients with COPD GOLD II and III with Th1 and Th17 cytokine profiles exhibited an increase in the percentage of CD4+CD282+ cells compared to the control group. In COPD GOLD I–III, positive correlations between CD4+CD282+ cell frequency and Th17 cytokine levels (IL-6, IL-17A, and IL-21) were found. In COPD GOLD I, IL-10 concentration was negatively correlated with the percentages of studied cells; in COPD GOLD II, a positive correlation between these parameters was noted. Conclusions. Enhanced TLR2 expression on CD4+ cells shifts cytokine profile toward Th17 phenotype that plays a crucial role in COPD progression. The level of TLR2 expression on peripheral blood CD4+ cells may be considered as a biomarker for diagnosing and predicting the progression of COPD.