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 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.

Increased Serum Interleukin 22 in Patients with Rheumatoid Arthritis and Correlation with Disease Activity

2012 ◽  
Vol 39 (7) ◽  
pp. 1320-1325 ◽  
Author(s):  
LAURINDO FERREIRA da ROCHA ◽  
ÂNGELA LUZIA BRANCO PINTO DUARTE ◽  
ANDRÉA TAVARES DANTAS ◽  
HENRIQUE ATAÍDE MARIZ ◽  
IVAN da ROCHA PITTA ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Mononuclear Cells ◽  
Activity Index ◽  
Elevated Serum ◽  
Serum Levels ◽  
Peripheral Blood Mononuclear ◽  
Additional Tool ◽  
Bone Erosions ◽  
Interleukin 22

Objective.To analyze the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA).Methods.IL-22 serum levels were measured in 83 patients with established RA under treatment with disease-modifying antirheumatic drugs and in 30 healthy controls matched for age and sex. Patients were assessed for clinical and laboratory variables. Correlations of IL-22 serum levels with disease activity measures [Clinical Disease Activity Index (CDAI) and Disease Activity Score for 28 joints (DAS28)], serological markers, bone erosions, and demographic factors were assessed. Peripheral blood mononuclear cells (PBMC) from 30 patients with RA and 14 controls were purified and stimulatedin vitrowith phorbol myristate acetate (PMA)/ionomycin. IL-22 production by PBMC and in serum was investigated by ELISA.Results.IL-22 levels were increased in patients with RA compared with controls (mean 432.37 pg/ml and 67.45 pg/ml, respectively; p < 0.001). Levels of IL-22 correlated with DAS28 and CDAI measures. Rheumatoid factor (RF) positivity was correlated with higher levels of IL-22 in patients with RA (mean 575.08 pg/ml; p = 0.001). The presence of bone erosions was associated with high IL-22 levels (p = 0.0001). PBMC stimulated with PMA/ionomycin expressed higher levels of IL-22 in patients with RA than controls but this was not significant (mean 584.75 pg/ml and 295.57 pg/ml; p = 0.553).Conclusion.IL-22 is elevated in the serum of patients with established RA. Elevated serum IL-22 allows discrimination between patients with different clinical and laboratory measures and indicates the potential of IL-22 as an additional tool for assessment of activity in RA, particularly in patients with RF antibodies and longterm disease. IL-22 is associated with bone-destructive disease.

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.

scholarly journals No Correlation Exists between Disease Activity and the Expression of Killer-Cell Immunoglobulin-Like Receptors in Patients with Rheumatoid Arthritis

2007 ◽  
Vol 2007 ◽  
pp. 1-4 ◽  
Author(s):  
Toshiaki Kogure ◽  
Takeshi Tatsumi ◽  
Atsushi Niizawa ◽  
Hiroshi Fujinaga ◽  
Tomoyuki Ito ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Mononuclear Cells ◽  
Killer Cell ◽  
Joint Damage ◽  
Cross Sectional Study ◽  
Remarkable Change ◽  
Peripheral Blood Mononuclear ◽  
Cross Sectional ◽  
Inflammation Parameters

Objective. The genes for killer-cell immunoglobulin-like receptors (KIRs) have been cloned and their functions and expression in patients with rheumatoid arthritis (RA) have been partially clarified. However, the correlation between their expression and disease activity has not been analyzed in patients with RA. Thus, we measured KIR expression on lymphocytes in patients with RA, and assessed the correlation between KIR expression and disease activity.Patients and Methods. In the cross-sectional study, 15 patients (9 females and 6 males) who fulfilled the diagnostic criteria for RA were assessed. In the longitudinal study, patients who were followed-up for 3 months were assessed. CD158a/b expression on peripheral blood mononuclear cells (PBMC) of RA patients was analyzed using flow cytometry.Results. No significant correlation between KIR expression and CRP, ESR, or IgM-RF was observed. There was no remarkable change in the expression of KIRs between the baseline and after 3 months. Additionally, in the 5 patients whose expression of KIRs particularly changed, the time-related changes in the expression of KIRs were independent from those of inflammation parameters and IgM-RF.Conclusion. There was no correlation between KIR expression and disease activity; therefore, the clinical use of KIR expression should be limited, while unnatural KIR expression may be involved in the pathogenesis of RA, but not a recruitment of chronic inflammation to induce joint damage.

Galectin-9 expression correlates with efficacy of tacrolimus therapy in rheumatoid arthritis

2020 ◽  
Author(s):  
qiang shu ◽  
Jiao Sun ◽  
Yameng Sui ◽  
Yunqing Wang ◽  
Lijun Song ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Disease Activity ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
T Cell Subsets ◽  
Poor Responders ◽  
Immunological Parameters ◽  
Peripheral Blood Mononuclear

Abstract Background: The calcineurin inhibitor tacrolimus (TAC) is the second-line treatment for rheumatoid arthritis (RA). Galectin-9 (Gal-9) is a multifunctional immunomodulatory factor highly expressed in RA synovial tissues and synovial fluid. This study aimed to investigate the expression of Gal-9 and its correlation with disease activity and response to TAC in RA patients.Methods: Active RA patients were enrolled and treated with TAC alone or in combination with methotrexate and/or prednisone for 12 weeks in a prospective cohort study. Clinical and immunological parameters were recorded at baseline and at week 12. We measured Gal-9 expression in different subsets of peripheral blood mononuclear cells using flow cytometry and assayed Gal-9 levels in plasma. We also tested cytokine levels in plasma by ELISA. Results: The disease activity of RA patients notably decreased after TAC treatment. At baseline, the percentages of CD4+ T cells and T regulatory cells (CD4+CD25+CD127low) expressing Gal-9 were higher in the group with severe disease than in mild or moderate groups. After TAC treatment in RA patients, the Gal-9 expression in CD3+, CD4+, CD8+ and CD4-CD8- cell subsets decreased, as well as Gal-9 mean fluorescence intensity in CD3+, CD4+ and CD8+ T cells. Similarly, plasma Gal-9 levels were lower at week 12 than at baseline. Good responders showed significantly lower Gal-9 expression on CD3+ and CD4+ T cell subsets as well as lower plasma Gal-9 levels than poor responders. Gal-9 expression positively correlates with disease activity in RA patients.Conclusion: Gal-9 can be regarded as a new biomarker for evaluating RA activity and efficacy of TAC.

Increased Levels of Interleukin 33 in Sera and Synovial Fluid from Patients with Active Rheumatoid Arthritis

2009 ◽  
Vol 37 (1) ◽  
pp. 18-25 ◽  
Author(s):  
YASUSHI MATSUYAMA ◽  
HITOAKI OKAZAKI ◽  
HIROYUKI TAMEMOTO ◽  
HIROTAKA KIMURA ◽  
YASUYUKI KAMATA ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Disease Activity ◽  
Mononuclear Cells ◽  
Sandwich Elisa ◽  
Protein A ◽  
Peripheral Blood Mononuclear ◽  
Interleukin 33 ◽  
Activity Group ◽  
Culture Supernatants

Objective.To determine levels of interleukin 33 (IL-33) in serum and synovial fluid (SF) and their clinical associations in patients with rheumatoid arthritis (RA). To evaluate the ability of activated peripheral blood mononuclear cells (PBMC) and fibroblast-like synoviocytes (FLS) from RA patients to release IL-33.Methods.Sera were obtained from 59 patients with RA, 10 patients with infectious diseases, and 42 healthy volunteers. SF samples were obtained from 15 patients with RA and 13 with osteoarthritis. IL-33 levels were measured using a sandwich ELISA after removal of rheumatoid factor with protein A-Sepharose beads. FLS were stimulated with IL-1ß and tumor necrosis factor, and treated with or without chemical damage. PBMC were stimulated with anti-CD3/CD28 antibodies. The levels of IL-33 were measured in the culture supernatants and cell lysates by ELISA or immunoblotting.Results.Serum IL-33 levels were significantly higher in RA patients, especially in the high disease activity group compared to the moderate or low activity group. IL-33 levels in SF were elevated in all 15 RA patients measured. IL-33 levels were higher in SF samples than in sera in 7 RA patients measured simultaneously. The 30-kDa IL-33 precursor was detected in the culture supernatants of damaged FLS but was not detected in those of activated PBMC and non-damaged FLS.Conclusion.IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA.

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