Circulating Regulatory T Cell Subsets in Patients with Sarcoidosis

Abstract

Over recent years, many researchers have supported the autoimmune theory of sarcoidosis. The presence of uncontrolled inflammatory response on local and system levels in patients with sarcoidosis did not define that the immunoregulatory mechanisms could be affected. The aim of this study was to evaluate the distribution and the disturbance circulating Treg cell subsets in the peripheral blood in patients with sarcoidosis. Materials and methods: A prospective comparative study was performed in 2016–2018 (34 patients with sarcoidosis (men (67.6%), women (32.3%)) were examined). Healthy subjects—the control group (n = 40). The diagnosis of pulmonary sarcoidosis was performed according to the standard criteria. We used two ten-color combinations of antibodies for Treg immunophenotyping. The first one contained CD39–FITC, CD127–PE, CCR4–PE/Dazzle™ 594, CD25–PC5.5, CD161–PC7, CD4–APC, CD8–APC–AF700, CD3–APC/Cy7, HLA–DR–PacBlue, and CD45 RA–BV 510™, while the second consisted of CXCR3–Alexa Fluor 488, CD25–РЕ, CXCR5–РЕ/Dazzle™ 594, CCR4–PerСP/Сy5.5, CCR6–РЕ/Cy7, CD4–АPC, CD8 АPC–AF700, CD3–АPC/Cy7, CCR7–BV 421, and CD45 RA–BV 510. The flow cytometry data were analyzed by using Kaluza software v2.3. A statistical analysis was performed with Statistica 7.0 and GraphPad Prism 8 software packages. Results of the study: Primarily, we found that patients with sarcoidosis had decreased absolute numbers of Treg cells in circulation. We noted that the level of CCR7-expressing Tregs decreased in patients with sarcoidosis vs. the control group (65.55% (60.08; 70.60) vs. 76.93% (69.59; 79.86) with p < 0.001). We noticed that the relative numbers of CD45RA–CCR7+ Tregs decreased in patients with sarcoidosis (27.11% vs. 35.43%, p < 0.001), while the frequency of CD45 RA–CCR7– and CD45RA+ CCR7– Tregs increased compared to the control group (33.3% vs. 22.73% and 0.76% vs. 0.51% with p < 0.001 and p = 0.028, respectively). CXCR3-expressing Treg cell subsets—Th1-like CCR60078CXCR3+ Tregs and Th17.1-like CCR6+ CXCR3+ Tregs—significantly increased in patients with sarcoidosis vs. the control group (14.4% vs. 10.5% with p < 0.01 and 27.9% vs. 22.8% with p < 0.01, respectively). Furthermore, the levels of peripheral blood EM Th17-like Tregs significantly decreased in the sarcoidosis group vs. the control group (36.38% vs. 46.70% with p < 0.001). Finally, we found that CXCR5 expression was increased in CM Tregs cell subsets in patients with sarcoidosis. Conclusions: Our data indicated a decrease in circulating Tregs absolute numbers and several alterations in Treg cell subsets. Moreover, our results highlight the presence of increased levels of CM CXCR5+ follicular Tregs in the periphery that could be linked with the imbalance of follicular Th cell subsets and alterations in B cell, based on the immune response. The balance between the two functionally distinct Treg cell populations—Th1-like and Th17-like Tregs—could be used in sarcoidosis diagnosis and the determination of prognosis and disease outcomes. Furthermore, we want to declare that analysis of Treg numbers of phenotypes could fully characterize their functional activity in peripherally inflamed tissues.

Infectious Complications of Pulmonary Sarcoidosis

“…Tregs interacting with innate and adaptive immunity have been shown to limit acute lung inflammation, due to respiratory pathogens, and to provide lung protection [92]. A decrease in the absolute number of circulating Tregs and several alterations in Treg cell subsets have been reported in sarcoidosis [93], and more recently, the cross-talk of B-cells with regulatory T-follicular helper cells (Tfh) has been shown in sarcoidosis [94], suggesting that Tfh2-and Tfh17-like cells-the most effective cell type in supporting B-cell activity, particularly in antibody production-may play a role in the anti-infectious humoral response in sarcoidosis. In conclusion, although the references are not extensive on this topic, the humoral arm does not seem to be defective in sarcoidosis, except against still-unknown very-selective targets, explaining the stochastic occurrence of infections in sarcoidosis.…”

Sarcoidosis-related autoimmune inflammation in COVID-19 convalescent patients

“…Potentially, it may explain why a key role in the development of efficiently functioning Tfr cells is related to their thymic differentiation. Analyzing circulating Tfr cells in patients with sarcoidosis showed that within the total CD45RA–CCR7+ central memory Treg population, the proportion of CXCR5+ Tregs was increased, whereas the percentage of thymic CXCR5+ Tregs did not significantly differ from that in the control group ( 174 ). Moreover, d’Alessandro et al ( 162 ) showed that the level of peripheral blood CD4highCD25highCXCR5high Tfr cells was increased in sarcoidosis, while the level of alveolar Tfr cells correlated with the Scadding stages.…”

Imbalance of Lymphocyte Subsets and CD45RA-Expressing Cells in Intrathoracic Lymph Nodes, Alveolar Compartment and Bloodstream of Pulmonary Sarcoidosis Patients

“…Originally described as a Th1-driven disease, sarcoidosis involves a complex interplay of different immune cells. Cumulative evidence suggests that Th17, regulatory T helper (Th-reg) and follicular T helper (Tfh) cells also play a critical role in the pathogenesis [ 8 , 9 , 10 , 11 ]. As a result of the defective protective function of Th-reg cells in patients with autoimmune diseases, tissue tolerance is broken down, and ongoing immune responses do not decrease in a timely manner, as is the case in patients with inflammatory diseases [ 12 ].…”