scholarly journals A Systems Immunology Approach Identifies Cytokine-Induced STAT Signaling Pathways Critical to Rheumatoid Arthritis Disease Activity and Treatment Response

2019 ◽  
Author(s):  
Jason Ptacek ◽  
Rachael E. Hawtin ◽  
Dongmei Sun ◽  
Brent Louie ◽  
Erik Evensen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Disease Activity ◽  
Signaling Pathways ◽  
Treatment Response ◽  
Immune Cell ◽  
Rheumatoid Arthritis Disease ◽  
Immune Cell Subsets ◽  
Systems Immunology ◽  
Stat Signaling

AbstractRheumatoid arthritis (RA), a chronic autoimmune disease characterized by circulating autoantibodies, involves many cytokine-mediated signaling pathways in multiple immune cell subsets. Most studies of immune cells in RA have limitations, such as analysis of a small number of cell subsets or pathways, and limited longitudinal data on patient phenotypes. In this study, we used an innovative systems immunology approach to simultaneously quantify up to 882 signaling nodes (Jak/STAT signaling readouts modulated by cytokines and other stimuli) in 21 immune cell subsets. We studied 194 RA patients and 41 controls, including 146 well-characterized RA patients prior to, and 6 months after, initiation of methotrexate or biologic agents from the Treatment Efficacy and Toxicity in RA Database and Repository (TETRAD). There was strikingly attenuated signaling capacity in RA patients in IFNα stimulation followed by measurement of phosphorylated STAT1 [IFNα→p-STAT1] in six immune cell subsets. Multiple nodes showed negative association with disease activity, including IFNα→STAT5 signaling in naive and memory B cells. In contrast, IL-6-induced STAT1 and STAT3 activation in central memory CD4-negative T cells showed a positive association with disease activity. Multiple nodes were associated with treatment response, including IFNα→STAT1 in monocytes and IL-6→STAT3 in CD4+ naive T cells. Decision tree analysis identified a model combining these two nodes as a high-performing classifier of treatment response to TNF inhibitors. Our study provides novel information on RA disease mechanisms and serves as a framework for the discovery and validation of biomarkers of treatment response in RA.

scholarly journals Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244187
Author(s):  
Jason Ptacek ◽  
Rachael E. Hawtin ◽  
Dongmei Sun ◽  
Brent Louie ◽  
Erik Evensen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Treatment Response ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Peripheral Blood Mononuclear ◽  
Immune Cell Subsets ◽  
Systems Immunology ◽  
Stat Signaling ◽  
Multiple Cell

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.

scholarly journals OP0128 DISTINCT FEATURES OF HLA-DR+ AND HLA-DR- PD-1HI CXCR5- T PERIPHERAL HELPER CELLS IN SEROPOSITIVE RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 84.2-84
Author(s):  
H. Yamada ◽  
T. Sasaki ◽  
K. Suzuki ◽  
M. Takeshita ◽  
S. Tanemura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Disease Activity ◽  
Plasma Cells ◽  
Immune Cell ◽  
Effector Memory ◽  
Chugai Pharmaceutical ◽  
Effector Memory T Cells ◽  
Hla Dr ◽  
Immune Cell Subsets

Background:PD-1hi CXCR5- T peripheral helper (Tph) cells are newly identified pathogenic CD4+ helper T cells in rheumatoid arthritis (RA). Since Tph cells have been emerged quite recently, the characteristics of Tph cells as a biomarker of RA are not fully understood.Objectives:The aim of the study is to evaluate how useful Tph cells in peripheral bloods are when compared to other immune cell subsets, and to clarify which Tph subset most accurately reflects the disease activity of RA.Methods:The RA patients who visited our rheumatology department between January 2000 and February 2017, and met the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria were included. We first assessed correlation with 40 immune cell subsets and the disease activity of RA. Next, the proportions of these immune cells were compared between RA and healthy controls (HCs). We also investigated the immune cell subsets which reflected the time course change of the disease activity after the methotrexate (MTX) treatment. The study protocol was approved by the ethics committee at Keio University School of Medicine.Results:Thirty-four seropositive RA, 12 seronegative RA and 34 HCs were included. The Immune cell subsets which showed correlation with DAS28-ESR (r> 0.2 or r> -0.2) were activated CD4 T cells (r= 0.31), HLA-DR+Th1 cells (r= 0.20), HLA-DR+Th1-17 cells (r= 0.25), Tfh1-17 cells (r= -0.25), HLA-DR+Tph cells (r= 0.22), CD3+CD8+naïve T cells (r= -0.25), CD3+CD8+effector memory T cells (r= -0.26), plasma cells (r= 0.40) and CD14++CD16+intermediate monocyte (r= 0.23). The proportions of HLA-DR+Th1 cells (2.3% vs. 5.7%), HLA-DR+Th1-17 cells (0.7% vs. 2.2%), Tfh1-17 cells (1.7% vs. 2.0%), HLA-DR+Tph cells (0.02% vs. 0.1%), CD3+CD8+effector memory T cells (16.6% vs 25.7%), plasma cells (0.04% vs. 0.17%) were statistically higher in the patients with RA compared to HCs. While the proportion of Tph cells showed weak correlation with DAS28-ESR (r= 0.18), that was extremely higher in RA (0.08% vs. 0.25%). Interestingly, when assessing the correlations with the disease activity in seropositive and seronegative RA separately, the proportions of Tph cells (r= 0.52) and HLA-DR+Tph cells (r= 0.50) were highly reflected in seropositive RA, but not in seronegative RA. Regarding the disease activity after the MTX treatment, the change of proportion of Tph cells between week 0 and 52 significantly reflected the change of DAS28-ESR (r= 0.75, p= 0.025), but not HLA-DR+Tph cells because of the non-specific reduction by the MTX treatment. Rather, HLA-DR-Tph cells significantly reflected the change of DAS28-ESR while receiving the MTX treatment (r= 0.76, p= 0.021).Conclusion:Tph cells and HLA-DR+Tph cells highly reflected the disease activity of seropositive RA. However, after the treatment, the proportion of HLA-DR+Tph cells decreased independent from the disease activity, and that of HLA-DR-Tph cells more accurately reflected the change of the disease activity during the treatment.References:[1]Rao DA, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542:110-114.Disclosure of Interests:Hiroki Yamada: None declared, Takanori Sasaki: None declared, Katsuya Suzuki: None declared, Masaru Takeshita: None declared, Shuhei Tanemura Employee of: I am employed by Mitsubishi Tanabe Pharma Corporation, Noriyasu Seki Employee of: I am employed by Mitsubishi Tanabe Pharma Corporation, Hideto Tsujimoto Employee of: I am employed by Mitsubishi Tanabe Pharma Corporation, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.

scholarly journals The relationship of blood CDC42 level with Th1 cells, Th17 cells, inflammation markers, disease risk/activity, and treatment efficacy of rheumatoid arthritis

2021 ◽  
Author(s):  
Yongji Li ◽  
Wendi Yang ◽  
Feng Wang
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Treatment Response ◽  
Treatment Efficacy ◽  
Th17 Cells ◽  
Immune Cell ◽  
Disease Risk ◽  
Th1 Cells ◽  
Clinical Role ◽  
Reactive Protein

Abstract Background Cell division control protein 42 (CDC42) is reported to be involved in multiple inflammation processes by regulating T cell differentiation, maintaining immune cell homeostasis, and altering their function, while no relevant studies explored its clinical role in patients with rheumatoid arthritis (RA). Therefore, this study aimed to explore the correlation of CDC42 with Th1 and Th17 cells and its association with disease risk, activity, and treatment outcomes of RA. Methods After the enrollment of 95 active RA patients and 50 healthy subjects (HC), their CDC42, Th1 cells, and Th17 cells were assayed by RT-qPCR and flow cytometry, accordingly. For RA patients only, CDC42 was also detected at W6, and W12 after treatment. The treatment response and remission status were evaluated at W12. Results Compared to HC, CDC42 was reduced (P < 0.001), while Th1 cells (P = 0.021) and Th17 cells (P < 0.001) were increased in RA patients. Besides, CDC42 was negatively correlated with Th17 cells (P < 0.001), erythrocyte sedimentation rate (ESR) (P = 0.012), C-reactive protein (P = 0.002), and disease activity score in 28 joints (DAS28) (P = 0.007), but did not relate to Th1 cells or other disease features (all P > 0.05) in RA patients. Furthermore, CDC42 was elevated during treatment in RA patients (P < 0.001). Moreover, CDC42 increment at W12 correlated with treatment response (P = 0.004). Besides, CDC42 elevation at W0 (P = 0.038), W6 (P = 0.001), and W12 (P < 0.001) also linked with treatment remission. Conclusion CDC42 has the potential to serve as a biomarker to monitor disease activity and treatment efficacy in patients with RA.

Quantification and phenotype of regulatory T cells in rheumatoid arthritis according to Disease Activity Score-28

Autoimmunity ◽  
2009 ◽  
pp. 1-1
Author(s):  
Jose Miguel Sempere-Ortells ◽  
Vicente Perez-Garcia ◽  
Gema Marin-Alberca ◽  
Alejandra Peris-Pertusa ◽  
Jose Miguel Benito ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Disease Activity Score ◽  
Activity Score

scholarly journals Immune Monitoring during Therapy Reveals Activitory and Regulatory Immune Responses in High-Risk Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2096
Author(s):  
Celina L. Szanto ◽  
Annelisa M. Cornel ◽  
Sara M. Tamminga ◽  
Eveline M. Delemarre ◽  
Coco C. H. de Koning ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Nk Cells ◽  
Immune Cell ◽  
High Dose Chemotherapy ◽  
Immune Monitoring ◽  
High Dose ◽  
Effector Cells ◽  
Gm Csf ◽  
Immune Cell Subsets

Despite intensive treatment, including consolidation immunotherapy (IT), prognosis of high-risk neuroblastoma (HR-NBL) is poor. Immune status of patients over the course of treatment, and thus immunological features potentially explaining therapy efficacy, are largely unknown. In this study, the dynamics of immune cell subsets and their function were explored in 25 HR-NBL patients at diagnosis, during induction chemotherapy, before high-dose chemotherapy, and during IT. The dynamics of immune cells varied largely between patients. IL-2- and GM-CSF-containing IT cycles resulted in significant expansion of effector cells (NK-cells in IL-2 cycles, neutrophils and monocytes in GM-CSF cycles). Nonetheless, the cytotoxic phenotype of NK-cells was majorly disturbed at the start of IT, and both IL-2 and GM-CSF IT cycles induced preferential expansion of suppressive regulatory T-cells. Interestingly, proliferative capacity of purified patient T-cells was impaired at diagnosis as well as during therapy. This study indicates the presence of both immune-enhancing as well as regulatory responses in HR-NBL patients during (immuno)therapy. Especially the double-edged effects observed in IL-2-containing IT cycles are interesting, as this potentially explains the absence of clinical benefit of IL-2 addition to IT cycles. This suggests that there is a need to combine anti-GD2 with more specific immune-enhancing strategies to improve IT outcome in HR-NBL.

scholarly journals Change in dietary inflammatory index score is associated with control of long-term rheumatoid arthritis disease activity in a Japanese cohort: the TOMORROW study

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Yoshinari Matsumoto ◽  
Nitin Shivappa ◽  
Yuko Sugioka ◽  
Masahiro Tada ◽  
Tadashi Okano ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Quantitative Measure ◽  
Inflammatory Change ◽  
Multivariable Logistic Regression Analysis ◽  
Dietary Inflammatory Index ◽  
Low Disease Activity ◽  
Inflammatory Index ◽  
Rheumatoid Arthritis Disease ◽  
Anti Inflammatory

Abstract Background The dietary inflammatory index (DII®), a quantitative measure of the inflammatory potential of daily food and nutrient intake, and associations between a variety of health outcomes have been reported. However, the association between DII score and disease activity of rheumatoid arthritis (RA) is unclear. Therefore, this study was designed to test whether higher DII score contributes to disease activity and as a corollary, whether reducing DII score helps to achieve or maintain low disease activity or remission in patients with RA. Methods We performed a cross-sectional and longitudinal analysis using 6 years of data (from 2011 to 2017) in TOMORROW, a cohort study consisting of 208 RA patients and 205 gender- and age-matched controls started in 2010. Disease activity of RA patients was assessed annually using DAS28-ESR (disease activity score 28 joints and the erythrocyte sedimentation rate) as a composite measure based on arthritic symptoms in 28 joints plus global health assessment and ESR. Dietary data were collected in 2011 and 2017 using the brief-type self-administered diet history questionnaire (BDHQ). Energy-adjusted DII (E-DII™) score was calculated using 26 nutrients derived from the BDHQ. Data were analyzed with two-group comparisons, correlation analysis, and multivariable logistic regression analysis. Results One hundred and seventy-seven RA patients and 183 controls, for whom clinical and dietary survey data were available, were analyzed. RA patients had significantly higher E-DII (pro-inflammatory) score compared to controls both in 2011 and 2017 (p < 0.05). In RA patients, E-DII score was not a factor associated with significant change in disease activity. However, anti-inflammatory change in E-DII score was associated maintaining low disease activity (DAS28-ESR ≤ 3.2) or less for 6 years (OR 3.46, 95% CI 0.33–8.98, p = 0.011). Conclusions The diets of RA patients had a higher inflammatory potential than controls. Although E-DII score was not a factor associated with significant disease activity change, anti-inflammatory change in E-DII score appeared to be associated with maintaining low disease activity in patients with RA. Trial registration UMIN Clinical Trials Registry, UMIN000003876. Registered 7 Aug 2010—retrospectively registered.

scholarly journals Different Rating of Global Rheumatoid Arthritis Disease Activity in Rheumatoid Arthritis Patients With Multiple Morbidities

2017 ◽  
Vol 69 (4) ◽  
pp. 720-727 ◽  
Author(s):  
Helga Radner ◽  
Kazuki Yoshida ◽  
Sara Tedeschi ◽  
Paul Studenic ◽  
Michelle Frits ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Rheumatoid Arthritis Disease Activity ◽  
Rheumatoid Arthritis Disease ◽  
Multiple Morbidities

scholarly journals Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110113
Author(s):  
Sheng-Xiao Zhang ◽  
Jia Wang ◽  
Cai-Hong Wang ◽  
Rui-Huan Jia ◽  
Ming Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Side Effects ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Fold Increase ◽  
Plain Language ◽  
T Subsets

Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs ( p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values ( p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

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