Elevated circulating CD14lowCD16+ monocyte subset in primary biliary cirrhosis correlates with liver injury and promotes Th1 polarization

Abstract

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease in which monocytes/macrophages infiltration and skewed T helper type (Th) 1 and Th17 cell responses participate in the development of the disease. Human peripheral blood monocytes are heterogeneous and can be divided into classical CD14CD16, intermediate CD14CD16, and nonclassical CD14CD16 monocyte subsets. Compared to classical monocytes, CD16 monocytes are generally termed pro-inflammatory monocytes and play an important pathogenic role in autoimmune diseases. However, little is known about the immunophenotype and immunopathogenic role of peripheral blood CD16 monocytes in PBC. Thus, we investigated the phenotype and function of these circulating monocyte subsets from PBC patients. The frequencies of circulating CD14CD16 and CD14CD16 subpopulation were increased in disease compared with healthy controls. Among them, CD14CD16 monocyte subset positively correlated with disease progress, liver damage indicators and serum C-reactive protein, respectively. Furthermore, the frequencies of Th1 and Th17 cells were upregulated and CD14CD16 monocyte subset was also positively associated with Th1 cell frequency in PBC. Using a vitro coculture model, we further found that CD14CD16 monocytes promoted Th1 cell polarization compared to classical monocytes. Interleukin-12 (IL-12) and direct contact of patient CD4T cell and CD14CD16 monocytes, were responsible for CD14CD16 monocytes promotion of Th1 cells polarization in PBC. Our study demonstrated that the enhanced CD14CD16 monocyte subset participated in fostering liver damage and inflammatory responses, and promoted Th1 cells skewing in PBC.

Mass Cytometry Studies of Patients With Autoimmune Endocrine Diseases Reveal Distinct Disease-Specific Alterations in Immune Cell Subsets

“…Patients with HT were also characterized by an increased frequency of CD86 + non-classical Mo, which has been previously reported in patients with other autoimmune diseases including multiple sclerosis (37), systemic lupus erythematous (38), and primary biliary cirrhosis (39). Variations in sample material, separation protocols, detection methodology and definition of Mo subsets might explain why we did not detect a parallel reduction of classical Mo as observed in other studies (38,39).…”

Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells

“…Studies have documented that IL-12 is not only able to induce the differentiation of CD4 + naïve T cells into Th1 cells but is also able to drive the polarization of regulatory T cells into Th1-like cells and paralyze their activity by reducing their suppressive capacity [13,14]. [22], and data have demonstrated that in patients with PBC circulating monocytes are increased in frequency and absolute number and are able to produce significantly increased levels of pro-inflammatory cytokines when challenged with different TLR ligands [16,33]. Therefore, the absence of difference in IL-12 production from -24-PBC monocytes that was detected in our in vitro experiments could possibly be explained by the fact that equal numbers of cells were used as with the healthy control samples.…”

“…In patients with PBC elevated levels of circulating CD14 low CD16 + monocytes have been reported, and these elevations correlated with increased liver injury and Th1 polarization [16]. Therefore, we studied the ability of monocytes from patients with PBC to produce IL- cytokine have been used across studies, from 10ng/ml to 50ng/ml, to drive the polarization of naïve CD4 + T cells into Th1 cells [19][20][21].…”

“…In patients with PBC, in addition to Th1/Th17 cells, monocyte/macrophage infiltration is also evident, and recent studies have reported a significant increase in CD14 low CD16 + monocytes which positively correlates with Th1 cell frequency [16]. CD14 low CD16 + monocytes were also found to promote Th1 differentiation of PBC CD4 + T cells by IL-12 and direct cell contact [16].…”

“…3) forming IL-35, which is believed to have a role in controlling the immune response during active inflammation [1].IL-12 is produced by antigen presenting cells such as monocytes/macrophages, dendritic cells and B cells in response to infection [15]. In patients with PBC, in addition to Th1/Th17 cells, monocyte/macrophage infiltration is also evident, and recent studies have reported a significant increase in CD14 low CD16 + monocytes which positively correlates with Th1 cell frequency [16]. CD14 low CD16 + monocytes were also found to promote Th1 differentiation of PBC CD4 + T cells by IL-12 and direct cell contact [16].…”