Analysis of PD-1 and Tim-3 expression on CD4+ T cells of patients with rheumatoid arthritis; negative association with DAS28

Abstract

Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4 T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3/PD-1/CD4 T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1/CD4 and Tim-3/PD-1/CD4 T cells was significantly higher in patients with RA compared to that in controls (p = 0.0013 and p = 0.050, respectively). The percentage of Tim-3/CD4 T cells was similar in patients and controls (p = 0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p = 0.0121, p = 0.0417, and p = 0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3/CD4 cells and DAS28 of RA patients (r = - 0.4696, p = 0.0493). Similarly, the percentage of Tim-3/PD-1/CD4 T cells was also revealed an inverse correlation with DAS28 (r = - 0.5268, p = 0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r = 0.6418, p = 0.0023) and IL-17 (r = 0.4683, p = 0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.

Expression analysis of PD‐1 and Tim‐3 immune checkpoint receptors in patients with vitiligo; positive association with disease activity

“…In agreement with our study, up‐regulation of Tim‐3 mRNA has been reported in both CD4 + and CD8 + T cells of CNS‐resident cells during EAE . In addition, we have also previously shown a significant elevation of PD‐1 and Tim‐3 on peripheral blood CD4 + T cells of patients with RA and asthma . Controversial findings have also been reported in systemic lupus erythematosus .…”

“…[23,38] In addition, we have also previously shown a significant elevation of PD-1 and Tim-3 on peripheral blood CD4 + T cells of patients with RA and asthma. [39,40] Controversial findings have also been reported in systemic lupus erythematosus. [41] To more explore the expression profile of PD-1 and Tim-3 immune checkpoints in CD8 + T cells, we also looked at the mRNA expression of these molecules in We found positive correlations between mRNA and protein expression of Tim-3 and PD-1 with disease activity.…”

CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?

“…Much like transplantation, the management of autoimmune diseases frequently involves systemic immunosuppression, and the role of CD4 T-cells in autoimmune pathology has long been recognized (138,139). Conversely, a negative correlation between CD4 inhibitory receptor expression and disease severity has been observed in a rheumatoid arthritis (RA) population (140), although this has not been a consistent finding (141) (142)(143)(144). Additionally, persistent stimulation of CD4 T-cells with endogenous peptides resulted in loss of cytokine production and proliferation, upregulation of inhibitory markers, and delayed onset of autoimmune diabetes (145).…”

Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer

“… 22 , 53 Blocking TIM-3 increases the production of IFNγ by lymphocytes, but it is unclear as to what forms the molecular basis of this action. 54 In patients with gastric, colorectal, liver, and pancreatic cancers, TIM-3 tumor expression correlated with tumor invasion, reduced survival, and metastasis; thus, TIM-3 can be implicated in carcinogenesis. 55 …”