Imbalance in B cell and T Follicular Helper Cell Subsets in Pulmonary Sarcoidosis

Abstract

Sarcoidosis is a systemic granulomatous disease that develops due to the Th1, Th17 and Treg lymphocytes disturbance. There is an assumption, that B cells and follicular T-helper (Tfh) cells may play an important role in this disorder, as well as in several other autoimmune diseases. The aim of this study was to determine CD19+ B cells subset distribution in the peripheral blood and to define disturbance in the circulating Tfh cells subsets in patients with sarcoidosis. The prospective comparative study was performed in 2016-2018, where peripheral blood B cell subsets and circulating Tfh cell subsets were analyzed in 37 patients with primarily diagnosed sarcoidosis and 35 healthy donors using multicolor flow cytometry. In the results of our study we found the altered distribution of peripheral B cell subsets with a predominance of "naïve" (IgD + CD27−) and activated B cell (Bm2 and Bm2′) subsets and a decreased frequency of memory cell (IgD+ CD27+ and IgD− CD27+) in peripheral blood of sarcoidosis patients was demonstrated. Moreover, we found that in sarcoidosis patients there are increased levels of B cell subsets, which were previously shown to display regulatory capacities (CD24+++ CD38+++ and CD5 + CD27−). Next, a significantly higher proportion of CXCR5-expressing CD45RA − CCR7+ th cells in patients with sarcoidosis in comparison to the healthy controls was revealed, that represents the expansion of this memory Th cell subset in the disease. This is the first study to demonstrate the association between the development of sarcoidosis and imbalance of circulating Tfh cells, especially CCR4− and CXCR3-expressing Tfh subsets. Finally, based on our data we can assume that B cells and Tfh2-and Tfh17-like cells-most effective cell type in supporting B-cell activity, particularly in antibody production-may be involved in the occurrence and development of sarcoidosis and in several other autoimmune conditions. Therefore, we can consider these results as a new evidence of the autoimmune mechanisms in the sarcoidosis development.

Key Players and Biomarkers of the Adaptive Immune System in the Pathogenesis of Sarcoidosis

“…Increased numbers of B lymphocytes and their progeny, plasma cells, have been observed in areas surrounding granulomas [ 74 ]. A recent study noted a higher frequency of peripheral blood B cells in patients with Stage II sarcoidosis compared to healthy controls but noted a reduction in CD19 + CD27 + IgD − class switched and CD19 + CD27 + IgD + unswitched memory B cell frequencies in active sarcoidosis [ 75 ]. Furthermore, the frequency of activated CD19 + IgD + CD38 + naïve B cells rose in sarcoidosis compared to inactive disease or healthy controls [ 75 ].…”

“…The same study noted a change in the T follicular helper (Tfh) cell population which are the CD4 + T-cells responsible for helper T-cell-dependent antibody responses [ 75 ]. Tfh cells provide contact-dependent and cytokine signals to B cells within germinal centers of lymph node follicles and are identified by high expression of C-X-C Chemokine Receptor Type 5 (CXCR5), a cell membrane receptor necessary for the migration of Tfh cells to B cell-rich lymph node follicles [ 75 ]. CXCR3 − CCR6 − Tfh2 and CXCR3 − CCR6 + Tfh17 cells increased, while CXCR3 + CCR6 − Tfh1 and CXCR3 + CCR6 + CCR4 − Tfh17.1-like cells decreased in sarcoidosis patients [ 75 ].…”

“…Tfh cells provide contact-dependent and cytokine signals to B cells within germinal centers of lymph node follicles and are identified by high expression of C-X-C Chemokine Receptor Type 5 (CXCR5), a cell membrane receptor necessary for the migration of Tfh cells to B cell-rich lymph node follicles [ 75 ]. CXCR3 − CCR6 − Tfh2 and CXCR3 − CCR6 + Tfh17 cells increased, while CXCR3 + CCR6 − Tfh1 and CXCR3 + CCR6 + CCR4 − Tfh17.1-like cells decreased in sarcoidosis patients [ 75 ]. It has been shown that Tfh2 and Tfh17 CD4 + T-cells can activate and induce IgM, IgG, and IgA secretion in naïve B cells through IL-21 production, while Tfh1 cells can trigger apoptosis in activated naïve B cells [ 76 ].…”

“…Although the role of Tfh cells in the pathogenesis of sarcoidosis is not well understood, the predominant Tfh subsets may explain the skew in B cells toward an activated naïve phenotype as well as the hypergammaglobulinemia of sarcoidosis [ 76 , 77 ]. Additionally, a Tfh2/Tfh17 dominance has been observed in several other autoimmune diseases [ 75 ].…”

“…The study also found a significant increase in the percentage of CD5 + CD27 − and CD24 +++ CD38 +++ IL-10 producing regulatory B (Breg) cells [ 75 ]. IL-10 is a suppressive cytokine that turn off the TH1 response and thus facilitates non-inflammatory, fibrotic repair.…”