Background:Systemic lupus erythematosus (SLE) is an autoimmune disease with disturbance of lymphocyte subpopulations1. Growing experimental and clinical evidence suggests that chronic inflammatory response induced by gut microbiome critically contribute to the development of SLE2 3.Objectives:To investigate the characteristics of gut microbiome and the associations between flora and peripheral lymphocyte subpopulations in SLE patients.Methods:A total of 19 SLE patients who fulfilled the 2019 American college of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria and 16 age- and sex- matched healthy controls (HC) were enrolled in this study. The peripheral T lymphocyte subsets of these participants were assessed by flow cytometry and the gut microbiota were investigated via 16s rRNA. Indicators of disease activity such as erythrocyte sedimentation rate (ESR), complement C3 and C4 were recorded at the same time. Mann-Whitney U test was applied to compare T lymphocyte subsets between SLE patients and HC. Spearman analysis was used for calculating correlation between T subsets and highly expressed differential flora as well as their correlation with disease activity indicators. All P-values reported herein were two-tailed and P-value<0.05 was taken as statistically significant.Results:SLE patients had higher proportions of Th17 cells (P=0.020) and γδT cells (P=0.018) but lower levels of Treg cells (P=0.001), Tfh cells (P=0.018) and Naïve CD4+T cells (P=0.004) (Figure 1a-e). The diversity and relative abundance of intestinal flora in patients with SLE were significantly different from those in HCs. Detailly, the α-diversity was decreased in SLE (P<0.05) (Figure 2a-c). Compared with HC, 11 species of flora were discovered to be distinctly different(P<0.05) (Figure 2d-e). Moreover, there was a significant positive correlation between Treg levels and Ruminococcus2 (P=0.042), Th17 and Megamonas (P=0.009), γδT and Streptococcus (P=0.004) as well as Megamonas (P=0.003), Tfh and Bacteroides (P=0.040). Whereas Th1 levels and Bifidobacterium were negatively correlated in these participants (P=0.005). As for clinical disease measures, there were negative correlations not only between ESR and Treg cells (P=0.031) but also C4 and the amount of Unclassified Ruminococcaceae (P=0.032).Conclusion:Abnormality of T cell subsets, especially the level of Naïve CD4+T, γδT, Tfh, Treg, and Th17 cells contributes to the occurrence and progression of SLE, which may be related to the disturbance of gut microbiota. Therefore it is necessary to attach importance to the alteration of gut microbiota to prevent the outbreak of inflammation and maybe they can be identified as biomarkers predicting disease activity.References:[1]Katsuyama T, Tsokos GC, Moulton VR. Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus. Front Immunol 2018;9:1088. doi: 10.3389/fimmu.2018.01088 [published Online First: 2018/06/06][2]López P, de Paz B, Rodríguez-Carrio J, et al. Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients. Sci Rep 2016;6:24072. doi: 10.1038/srep24072 [published Online First: 2016/04/06][3]Esmaeili SA, Mahmoudi M, Momtazi AA, et al. Tolerogenic probiotics: potential immunoregulators in Systemic Lupus Erythematosus. J Cell Physiol 2017;232(8):1994-2007. doi: 10.1002/jcp.25748 [published Online First: 2016/12/21]Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared.
BackgroundPrimary Sjögren’s syndrome (pSS) is one of the more common rheumatological diseases. Despite continued advances, the use of conventional drugs or biologic agents in patients with pSS did not provide expected efficacy and a targeted treatment of pSS is not available at present. We have shown that absolute number of peripheral CD4+CD25+FOP3+regulatory T cells (Tregs) decreased in pSS patients. And rapamycin is an inhibitor of mTOR that can decrease Th17 cells but increase regulatory T cells (Treg cells).ObjectivesTo observe the effect of rapamycin on Th17/Treg cell balance in patients with refractory pSS.MethodsTwenty-eight refractory SS patients (26 women and 2 men) and 93 health controls were enrolled, with a mean duration of 76.64±49.66 months and mean age of 52.39±10.62 years. They fulfilled the 2002 PSS international classification criteria and were treated with glucocorticoid and immunosuppressant for more than one year, but had not yet reached the disease relief. After the eligible patients are given rapamycin in combination with conventional therapy at 0, 12, 24 weeks, we respectively collect the clinical symptoms, blood routine, urine routine, ESR, the absolute number of Th17 and Treg cells, the ratio of Th17/Treg, and the dosage of corticosteroids and immunosuppressant. Alleviation criteria: no clinical symptoms, inflammation normal range, no organ damage.ResultsThe absolute number of Treg cells decreased significantly in peripheral blood of pSS patients compared with that of healthy controls. By rapamycin combined with conventional therapy, flow cytometry showed the absolute number of Treg cells in refractory SS patients was increased from 25.51 cells/µl (at week 0) to 27.88 cells/µl (at 12 weeks) and 29.6 cells/µl (at 24 weeks) (P>0.05) respectively. The ratio of Th17/Treg decreased from 0.38 (at week 0) to 0.21 (at 12 weeks) and 0.22 (at 24 weeks) (P>0.05). There was no significant difference in the usage of prednisone, whereas 5 patients gradually stopped using CTX at 24 weeks. Also, the dose of hydroxychloroquine and leflunomide were markedly diminished.ConclusionsOur results suggest that rapamycin combined with the conventional treatment greatly alleviated symptoms of patients with pSS, and gradually reduced the use of DMARDs. The absolute number of peripheral Tregs decreased in pSS patients and restored by this combined therapy. It still needs to be further confirmed by large sample studies.References[1] Ferro F, Marcucci E, Orlandi M, Baldini C, Bartoloni-Bocci E. One year in review 2017: primary Sjögren’s syndrome. Clin Exp Rheumatol2017Mar–Apr;35(2):179–191. Epub 2017 Mar 15. Review.PMID: 28337967.[2] Zheng Y. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. [J].Immunity2009;30(6):832–844.AcknowledgementsWuruijie contributed collection of information of outpatients. Wuqi contributed contacted and bought reagents.Disclosure of InterestNone declared
Background:Takayasu arteritis (TA) refers to chronic progressive non-specific inflammation that involves the aorta and its main branches, causing stenosis and occlusion of arteries in different parts, and ischemic manifestations in the corresponding parts. A variety of immune dysfunctions are involved in the occurrence and development of TA(1)Recent studies have shown that Th17/Treg imbalance plays an important role in the pathogenesis of Takayasu’s arteritis, in which T help 17 cells (Th17) cells are up-regulated in TA patients(2). Th17 cells are closely related to Treg cells during differentiation. There are few studies on the expression level of CD4+CD25+FOX3+T lymphocyte (Treg) cells. This study aims to study the clinical significance of Treg cell expression in peripheral blood of patients with Takayasu’s arteritis.Objectives:To analyze the levels of circulating lymphocyte subsets and serum cytokines in patients with takayasu arteritis (TA), and explore the relationship between their changes and TA disease activity.Methods:A total of 46 TA patients and 43 gender-age-matched healthy controls were enrolled. According to the NIH standard, 30 patients were in active disease. Flow cytometry was used to detect the absolute numbers and ratios of Th1, Th2, Th17 and Treg cells in peripheral blood of all subjects. Magnetic bead-based multiplex immunoassay was used to detect cytokines and statistical analysis was performed.Results:Compared with the healthy controls, the absolute number and proportion of peripheral Treg cells of TA patients significantly decreased while those of Th17 cells increased significantly, leading to the increased ratio of Th17 / Treg. Compared with the inactive group, the TA active group had significantly increased IL-6 and TNF-α, and there was no significant difference in the expression of Th17 cells and Treg cells.Conclusion:In peripheral blood of TA patients, Treg cells decreased, while Th17 cells increased as compared with healthay controls, leading to an imbalance between Th17 and Treg cells. The levels of IL-6 and TNF-α were related to disease activity.References:[1]Russo, R.A.G. and M.M. Katsicas, Takayasu Arteritis. Front Pediatr, 2018. 6: p. 265.[2]Misra, D.P., S. Chaurasia, and R. Misra. Increased Circulating Th17 Cells, Serum IL-17A, and IL-23 in Takayasu Arteritis. Autoimmune Dis, 2016. 2016: p. 7841718.Figure 1.Characteristics of the absolute numbers and proportions of Th1cells,Th2cells,Th17 cells and CD4Treg cells in the PB of patients with TA.(A-C)The levels of Th17 cells and the ratio of Th1/Treg,Th2/Treg,Th17/Treg in PB were significantly increased in patients with TA (n=46). The absolute number and the proportion of CD4Treg cells were significantly decreased in TA(n=46). (D-F) The absolute number of Th2 cells and ratio of Th2/Treg in PB were significantly decreased in active patients with TA (n=30).Neither the absolute number nor proporation of Th1, Th17 and Treg cells was altered significantly between active TA patients(n=30) and inactive TA patients(n=16).*P<0.05; **P<0.001. P<0.05 was considered statistically significant.TA,takayasu arteritis;PB peripheral blood;Tregs, regulatory Tcells.Figure 2.Characteristics of serum concentrations of cytokine (including IL-6, IL-10, IL-17 and TNF-α) between active TA patients(n=30) and inactive TA patients(n=16).(A,D)In terms of cytokines, the concentration of IL-6 and TNF-α was significantly up-regulated,(B,C)but no significant changes in IL-10, and IL-17 were found.*P<0.05; **P<0.001. P < 0.05 was considered statistically significant.Disclosure of Interests:None declared
Background:Rheumatoid arthritis (RA) is an aggressive immune-mediated joint disease with synovial inflammation and joint destruction characterized by abnormal immune responses to self-antigens1. An imbalance in pro- and anti-inflammatory lymphocyte subsets has been considered to contribute to the pathogenesis of RA2. However, the detailed lymphocyte statuses of RA patients are required clarified and the effect of immunomodulatory therapy on the lymphocyte subsets is unclear3.Objectives:To investigate the status of lymphocyte subsets in peripheral blood (PB) of RA patients at relatively large-sample size and the changes of them after our immune regulatory combination treatment.Methods:This cross-sectional study enrolled 3016 patients with RA who met the ACR’s revised RA diagnostic classification in 1987 as well as 206 healthy controls (HCs). Among these participations, 1415 patients have received the treatment of immunomodulatory drugs (IMiDs) such as low-dose interleukin-2, rapamycin, metformin, retinoic acid etc. Flow cytometry (FCM) was used to measure the levels of PB lymphocyte subgroups and CD4+T subsets in RA patients before and after the treatments and HCs. Data were expressed as mean ± standard deviation to the distribution. Independent-samples T test and paired-samples T test were applied.Pvalue <0.05 were considered statistically significant.Results:Compared with HCs, patients with RA had a lower absolute numbers of total T, CD8+T, NK and Tregs (P<0.05), decreased percentages of NK, Th1, Th2 and Th17 (P<0.05), but higher ratios of Teffs/Tregs such as Th1/Tregs and Th17/Tregs (P<0.05), indicating a disturbance of immune systems (Figure 1). After receiving combined immunomodulatory therapy, the absolute numbers of T, B, CD4+T, CD8+T, NK, Th1, Th17 and Tregs were dramatically increased (P<0.05) and the percentages of B, Th1, CD4+T and Tregs were also increased (P<0.05). Although these subsets increased globally, the ratio of Teffs/Tregs such as Th2/Tregs and Th17/Tregs tended to decrease, suggesting a rebalance of immune systems(Figure 2).Conclusion:Impaired peripheral lymphocytes especially insufficiency of Tregs might played an important role in pathogenesis of RA. Immunoregulatory combination therapies could promote the proliferation and functional recovery of Tregs in patients and help to alleviate disease activity.References:[1]Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. (1474-547X (Electronic))[2]Kondo Y, Yokosawa M, Kaneko S, et al. Review: Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis. (2326-5205 (Electronic))[3]Fonseka CY, Rao DA, Raychaudhuri S. Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis. (1879-0372 (Electronic))Acknowledgments:None.Disclosure of Interests:None declared
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