CD39 positive regulatory T cell frequency as a biomarker of treatment response to methotrexate in rheumatoid arthritis

Gupta, Vikas; Katiyar, Shobhita; Singh, Avadhesh Pratap; Misra, Ramnath; Aggarwal, Amita

doi:10.1111/1756-185x.13333

Cited by 31 publications

(28 citation statements)

References 40 publications

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“…However, in this study, the authors suggest the direct production of Ado by Treg expressing both CD39 and CD73 which is in contradiction with observations we and others have reported [12,41]. However, high CD39 + Treg frequency at baseline could correlate with good MTX response, and CD39 is therefore suggested as a biomarker of the MTX response in RA [40,42]. Our analysis of untreated and MTX-treated paired samples of RA and PsA patients demonstrated a CD73 frequency in Th subsets closer to HD in MTX-treated patients.…”

Section: Discussioncontrasting

confidence: 93%

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production

Bossennec

Rodriguez

Hubert

et al. 2019

JCM

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Objectives: Th1.17 are highly polyfunctional, potentially harmful CD4+ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. Methods: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. Results: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73+ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. Conclusion: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.

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Section: Discussioncontrasting

confidence: 93%

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production

Bossennec

Rodriguez

Hubert

et al. 2019

JCM

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“…There is a large body of evidence that methotrexate mediates its anti-inflammatory effect through increasing ATP release (Morabito et al, 1998;Montesinos et al, 2007), which is subsequently degraded to adenosine through ectonucleotidases (Montesinos et al, 2007), which in turn suppresses inflammation (Montesinos et al, 2000). Recently, it was observed that methotrexate nonresponsiveness in RA patients was associated with low expression of CD39 on T regs (Peres et al, 2015;Gupta et al, 2018). This suggests that CD39 expression on T regs could be a noninvasive biomarker for the early identification of patients who are unlikely to respond to methotrexate therapy.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Antonioli¹,

Blandizzi²,

Pacher³

et al. 2019

Pharmacol Rev

132

108

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Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.

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“…Of the currently available treatments, conventional disease modifying antirheumatic drugs (DMARDs) and biological DMARDs, also known as biologics or biological immunotherapies, are the most effective for long-term management of RA. However, the effectiveness of these treatments at managing disease progression varies among patients [1], and can be influenced by genetic factors [2,3] and the duration of symptoms prior to the first treatment [4][5][6]. For example, these factors play a role in why nearly one third of patients do not respond to methotrexate, one of the most common first lines of defense against RA [2,5].…”

Section: Introductionmentioning

confidence: 99%

“…However, the effectiveness of these treatments at managing disease progression varies among patients [1], and can be influenced by genetic factors [2,3] and the duration of symptoms prior to the first treatment [4][5][6]. For example, these factors play a role in why nearly one third of patients do not respond to methotrexate, one of the most common first lines of defense against RA [2,5]. Such interpatient variability in terms of response to medication can interfere with a patient's ability to achieve remission and/or the desired level of disease activity.…”

Section: Introductionmentioning

confidence: 99%

“…Multiple meta-analyses have used pharmacogenetic studies to summarize how the efficacy, toxicity, and other adverse reactions of conventional DMARDs, such as methotrexate [2,7,8], and biologics [3] such as adalimumab and etanercept can be influenced by genetics. These studies point to polymorphisms in a variety of genes associated with a particular medication's metabolism, transport, target, and/or mechanism of action as a reason to why response to medication varies among patients.…”

Section: Introductionmentioning

confidence: 99%

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Berberine delays onset of collagen induced arthritis through T cell suppression

Vita¹,

Lyons²,

Aljobaily³

et al. 2019

Preprint

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RUNNING TITLE (less than 50 characters): Berberine delays onset of collagen arthritis model KEY WORDS (5 words not in the title): CIA, berberine, RA, autoimmune, T cell ABSTRACT (250 words or less): Previous evidence suggests that berberine (BBR), a clinically relevant plant-derived alkaloid, alleviates symptoms of clinically apparent collagen induced arthritis (CIA), and may have a prophylactic role from in vitro studies. Thus, we used a CIA model to determine if BBR merits further exploration as a prophylactic treatment for rheumatoid arthritis. Mice were treated with either 1 mg/kg/day of BBR or a vehicle (PBS) control via IP injections from day 0 to day 28, were left untreated (CIA control), or were in a non-arthritic control group. Incidence of arthritis in BBR mice was 40%, compared to 90% in the CIA and 80% in the PBS controls. Populations of B cells and T cells from the spleens and draining lymph nodes were examined from mice across treatment groups on day 14 and from the remaining mice on day 28 when arthritic signs and symptoms were expected to be apparent. BBR-treated mice had significantly reduced populations of CD4 + T cells, CXCR5 + T fh cells, and an increased proportion of T reg at both day 14 and day 28 endpoints, as well as decreased CD28 + and CD154 + CD4 + T cells at day 14. BBR-treated mice also experienced a significant reduction of CD19 + B cells in LNs at day 28. Additionally, BBR treatment resulted in significantly lower anti-collagen type II-specific (anti-CII) IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement, and that its effect may be mediated through T cell suppression, which indirectly affects B cell activity. and PBS controls ( Fig. 2B). When comparing anti-CII IgG levels between arthritic and nonarthritic mice within the BBR group specifically, however, anti-CI IgG1, IgG2a and total IgG were all significantly reduced in the non-arthritic mice compared to those who developed arthritis (Fig. 2C). Additionally, there appeared to be a vehicle-specific effect on circulating anti-CII IgG in which the administration of PBS with 0.01% DMSO elicited elevated levels of anti-CII IgG1 and total IgG in vehicle control mice ( Fig. 2A-B).Key CD4 + T cell population characteristics in response to berberine treatment-On day 14, we observed a significant reduction in populations of both CD4 + T cells and CXCR5 + T fh cells in the LNs and spleen of BBR-treated mice (Fig. 3A-B), as well as a reduction in the percentage of CD28 + and CD154 + CD4 + T cells in the spleen and LNs of BBR-treated mice (Fig. 3A-B). By the day 28 experimental endpoint we continued to observe a significant reduction in CD4 + T cells and CXCR5 + T fh cells in the spleen and LNs of BBR-treated mice ( Fig. 3C-D), however, there was no significant difference in the percentage of CD28 + and CD154 + CD4 + T cells between treatment groups (Fig 3C-D). Berberine treatment leads to increased proportion of FOXP3 + CD25 + CD4 + T cells-To examineBBRs effect on ...

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CD39 positive regulatory T cell frequency as a biomarker of treatment response to methotrexate in rheumatoid arthritis

Abstract: Higher frequencies of CD39 Tregs and CD4 CD25 CD39 cells in the peripheral blood are associated with response to MTX in RA and hence, these could be considered as potential biomarkers for prediction of response to MTX treatment.

Cited by 31 publications

References 40 publications

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Berberine delays onset of collagen induced arthritis through T cell suppression

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