TIGIT reverses IFN-α-promoted Th1-like Tregs via in-sequence effects dependent on STAT4.

OBJECTIVES: The induction direction of interferon (IFN)-α in T-cell phenotype and function varies depending on the activation state of the cell and the time of stimulation. To assess the effects of elevated IFN-α on regulatory T cells (Tregs) in systemic lupus erythematosus (SLE) patients, we investigated the differentiation of Th1-like Tregs under in-sequence and out-of-sequence conditions and the reversal effect of activating TIGIT on immune suppression. METHODS: Phenotypes and activation levels of Tregs from SLE patients and healthy controls were analyzed using flow cytometry. In vitro culture conditions based on the sequence of TCR activation and IFN-α stimulation simulated in-sequence or out-of-sequence effects. CD4+T cells and Tregs were cultured under the above conditions with or without TIGIT agonist. Expression of related characteristic markers and phosphorylation levels of AKT, mTOR, and STATs were detected using flow cytometry and ELISA. RESULTS: The frequency of Th1-like Tregs and activation levels of Tregs increased, but TIGIT expression in Tregs decreased in SLE patients. IFN-α promoted the conversation of Tregs to Th1-like Tregs while reducing immunosuppressive function under in-sequence conditions. The STAT4 pathway, but not the STAT1 pathway, was crucial for the IFN-α-mediated in-sequence effects. Reactivation of TIGIT reversed Th1 polarization of Tregs by suppressing AKT/mTOR and STAT4 signaling. CONCLUSIONS: Our findings suggest that IFN-α mediated in-sequence effects on Tregs may be responsible for the expansion of Th1-like Tregs in SLE. TIGIT can restore immune suppression damage in Tregs and represents a potential therapeutic target for SLE.

Competitive binding of transcription factors underlies flexibility of T peripheral helper cells and T follicular helper cells in SLE.

OBJECTIVE: Peripheral helper T (Tph) cells interact with B cells and promote immune responses at sites of ectopic lymphoid structures (ELSs). To assess the characteristics of Tph cells, we investigated the phenotype of T helper (Th) cells in patients with SLE and the underlying competitive binding mechanisms using cytokine-mediated signal transducer and activator of transcription (STAT) factors. METHODS: Peripheral blood mononuclear cells from SLE patients and healthy controls were analysed for phenotypic identification. Serum cytokine levels were detected using Luminex assays. In vitro culture was performed to assess cytokine-induced conversion of phenotypes and transcriptional regulation using flow cytometry and PCR. Chromatin immunoprecipitation was used to evaluate STAT binding and histone modifications. RESULTS: CXCR5-PD-1+Tph-like cells were increased in SLE patients and showed strong association with disease activity and renal involvement. Serum IFN-α levels were increased and associated with Tph frequency. IFN-α promoted the differentiation of IL-10-producing CXCR5-PD-1+Tph-like cells, increased the responsiveness of IL-2 and induced the conversion of Tfh-like cells to Tph-like cells. STAT5 gained a competitive advantage and bound to the BCL6 locus at the expense of STAT1, accompanied by suppression of H3K4me3. Finally, anti-IFNAR1 decreased the differentiation of Tph-like cells, thereby suppressing the generation of CD38highCD27highplasmablasts. CONCLUSION: Tph cells might be crucial makers to effectively reflect disease activity level in SLE patients. The finding that synergy of IFN-α and IL-2 increases Tph cells through competitive transcriptional regulation could be one of the mechanisms responsible for pathological formation of ELSs and helpful for selection of individualized therapeutic approaches for SLE.

A systematic review and meta-analysis: effects of glucocorticoids on rheumatoid arthritis and systemic lupus erythematosus.

BACKGROUND: Meta-analysis was performed to explore the efficacy of glucocorticoids in the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), to provide a theoretical basis for the clinical treatment of patients. METHODS: Relevant literatures from the establishment of the database to December 31, 2020, were searched from databases such as PubMed. The literatures with randomized controlled trial of the clinical efficacy of glucocorticoids in the treatment of RA and SLE were screened for meta-analysis. RESULTS: Eleven documents were included, including 1,298 participants. It was found that the cardiovascular system [mean difference (MD) =1.23; 95% confidence interval (CI): 0.64 to 2.34; Z=0.62; P=0.53], respiratory system (MD =1.87; 95% CI: -0.66 to 5.29; Z=1.18; P=0.24), nervous system (MD =1.22; 95% CI: 0.25-5.84; Z=0.25; P=0.8), visual impairment (MD =1.41; 95% CI: 0.79-2.52; Z=1.15; P=0.25), endocrine system (MD =8.53; 95% CI: 2.71-26.88; Z=3.66; P=0.0003), digestive system (MD =1.41; 95% CI: 0.76-2.63; Z=1.09; P=0.28), genitourinary system (MD =1.06; 95% CI: 0.35-3.17; Z=0.1; P=0.92), blood system (MD =2.96; 95% CI: 0.62-14.26; Z=1.35; P=0.18), Z=0.48; P=0.63), infection status (MD =1.36; 95% CI: 0.98-1.87; Z=1.86; P=0.06), clinical efficacy (MD =1.79; 95% CI: 1.27-2.52; Z=3.32; P=0.0009), pain (MD =1.16; 95% CI: 0.76-1.78; Z=0.68; P=0.5), and joint swelling score (MD =0.03; 95% CI: -0.38 to 0.45; Z=0.15; P=0.88) of experimental group after treatment were all superior versus controls. However, the skin and mucous membranes (MD =0.87; 95% CI: 0.55-1.37; Z=0.61; P=0.54), musculoskeletal (MD =0.85; 95% CI: 0.43-1.66; Z=0.48; P=0.63), radiation injury (MD =-1.93; 95% CI: -3.68 to -0.18; Z=2.17; P=0.03), and C-reactive protein (CRP) level (MD =-8.66; 95% CI: -10.16 to -7.16; Z=11.34; P<0.00001) of experimental group were inferior to those of control group. DISCUSSION: Glucocorticoids in the treatment of RA and SLE can improve the clinical efficacy, but it was easy to cause multiple system adverse reactions. Therefore, the clinical treatment should follow the doctor's advice.

Serum vascular endothelial growth factor as a biomarker for prognosis of minor ischemic stroke.

Objectives Although vascular endothelial growth factor (VEGF) is a well-known molecule involved with neuronal survival and angiogenesis. there are no prospective studies directed at evaluating a potential association between serum VEGF and minor ischemic stroke. The goal of this study was to investigate the utility of serum VEGF as an index for assessing the 90-day prognosis of minor ischemic stroke patients. Methods Records of acute minor stroke patients (N = 225) and those of age- and gender-matched healthy control subjects (N = 225) were prospectively reviewed. Clinical, laboratory, and imaging data were evaluated. Serum samples collected from these stroke patients immediately after admission were assessed for VEGF levels and compared with those of control subjects. Results Serum VEGF levels were significantly increased in stroke patients (40.01 ±â€¯16.48 pg/mL) as compared with those of controls (32.98 ±â€¯10.35 pg/mL). No statistically significant differences in serum VEGF levels were obtained among the three stroke subtypes analyzed in this study (large-artery atherosclerosis, small-artery occlusion and other types of brain infarction). Multivariate regression analysis revealed that serum VEGF levels and cerebral artery stenosis ≥ 50 % were independently associated with an unfavorable outcome. Unfavorable outcome rates were significantly greater in stroke patients showing VEGF levels in the upper quartiles of the distribution, and these VEGF levels were found to serve as a significant predictor of unfavorable outcomes in these minor ischemic stroke patients. Conclusion Increased serum VEGF may serve as an independent predictor of an unfavorable outcome in minor ischemic stroke.