Dipeptidyl peptidase-IV in synovial fluid and in synovial fluid mononuclear cells of patients with rheumatoid arthritis

Sromova, Lucie; Marecková, H; Šedová, Liliana; Balážiová, Eva; Šedo, Aleksi

doi:10.1016/j.cca.2010.03.034

Cited by 16 publications

(11 citation statements)

References 23 publications

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“…Molecular biomarkers for earlier diagnosis of rheumatoid arthritis (RA), (achieving remission of the disease is possible if diagnosed in the early stages)[ 1 , 2 ], and predictors of response to therapies or follow up markers of disease progression or remission are in demand [ 3 ]. Diminished dipeptidyl peptidase IV (DPP-IV, soluble CD26) activity in both serum and synovial fluid of RA patients has been previously reported [ 4 , 5 ] and we have also found a relationship between serum sCD26 levels and RA activity [ 6 ] (not all DPP-IV activity is ascribed to sCD26 [ 7 ]). Other groups reported similar or contradictory results in RA and other rheumatic diseases including systemic lupus erythematosus (SLE) [ 8 – 10 ].…”

Section: Introductionsupporting

confidence: 61%

CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis

et al. 2015

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We studied dipeptidyl peptidase IV (DPP-IV, CD26) expression in different T helper cells and serum soluble DPP-IV/sCD26 levels in rheumatoid arthritis (RA) patients, correlated these with disease activity score (DAS), and examined how they were affected by different therapies, conventional or biological (anti-TNF, anti-CD20 and anti-IL6R or Ig-CTLA4). The percentage of CD4+CD45R0+CD26- cells was greatly reduced in patients (up to 50%) when compared with healthy subjects. Three other subsets of CD4 cells, including a CD26high Th1-associated population, changed variably with therapies. Data from these subsets (frequency and staining density) significantly correlated with DAS28 or DAS28 components but different in each group of patients undergoing the different therapies. Th17 and Th22 subsets were implicated in RA as independent CCR4+ and CCR4- populations each, with distinct CD26 expression, and were targeted with varying efficiency by each therapy. Serum DPP-IV activity rather than sCD26 levels was lower in RA patients compared to healthy donors. DPP-IV and sCD26 serum levels were found related to specific T cell subsets but not to disease activity. We conclude that, according to their CD26 expression, different cell subsets could serve to monitor RA course, and an uncharacterized T helper CD26- subset, not targeted by therapies, should be monitored for early diagnosis.

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Section: Introductionsupporting

confidence: 61%

CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis

et al. 2015

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“…A number of studies show decreased levels of DPP4 activity in subjects suffering from this disease . Furthermore, the expression of CD26/DPP4 on joint‐infiltrating T cells has also been shown to be decreased . Lower serum DPP4 activity in rheumatoid arthritis is caused by hypersialylation and DPP4 autoantibodies, as illustrated in Fig.…”

Section: Involvement Of Cd26/dpp4 In Pathologymentioning

confidence: 99%

Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system

Klemann

Wagner

Stephan

et al. 2016

Clinical and Experimental Immunology

363

437

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SummaryCD26/DPP4 (dipeptidyl peptidase 4/DP4/DPPIV) is a surface T cell activation antigen and has been shown to have DPP4 enzymatic activity, cleaving-off amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. It plays a major role in glucose metabolism by Nterminal truncation and inactivation of the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). In 2006, DPP4 inhibitors have been introduced to clinics and have been demonstrated to efficiently enhance the endogenous insulin secretion via prolongation of the half-life of GLP-1 and GIP in patients. However, a large number of studies demonstrate clearly that CD26/DPP4 also plays an integral role in the immune system, particularly in T cell activation. Therefore, inhibition of DPP4 might represent a double-edged sword. Apart from the metabolic benefit, the associated immunological effects of long term DPP4 inhibition on regulatory processes such as T cell homeostasis, maturation and activation are not understood fully at this stage. The current data point to an important role for CD26/DPP4 in maintaining lymphocyte composition and function, T cell activation and co-stimulation, memory T cell generation and thymic emigration patterns during immune-senescence. In rodents, critical immune changes occur at baseline levels as well as after in-vitro and in-vivo challenge. In patients receiving DPP4 inhibitors, evidence of immunological side effects also became apparent. The scope of this review is to recapitulate the role of CD26/DPP4 in the immune system regarding its pharmacological inhibition and T cell-dependent immune regulation.Keywords: autoimmunity, B cell, cell activation, chemokines, T cells Structure and characterization of CD26Originally described 50 years ago [1], the lymphocyte cell surface protein CD26 possess a dipeptidyl peptidase-4 (DPP4) activity. It cleaves dipeptides from the N-termini of oligopeptides and smaller peptides with proline or alanine at the penultimate position, as illustrated in Fig. 1b [International Union of Biochemistry and Molecular Biology (IUBMB) Enzyme Nomenclature EC 3.4.14.5].CD26/DPP4 is a homodimer and an integral type II glycoprotein anchored to the membrane by its signal peptide. The primary structure consists of a short six amino acid cytoplasmic tail, a 22 amino acid transmembrane, a 738 amino acid extracellular portion comprised of a flexible stalk, glycosylation-rich region, cysteine-rich region and catalytic region with the catalytic triad Ser 630 , Asp 708 and His 740 (Fig. 1e). Recent studies have revealed that the transmembrane region contributes to enzyme activity and quaternary structure by dimerization [2]. The crystal structure of human CD26/DPP4 has been elucidated to reveal two domains: an eight-bladed propeller and an a/b-hydrolase domain. The propeller is open and consists of two subdomains made up of blades II-V and VI-VIII for the glycosylation-rich and cysteine-rich regions, respectively (Fig. 1d). Most monoclonal anti-CD26/DPP4 antibodies,...

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“…DPP‐4 is a ubiquitous protease with many substrates, and its function is not restricted to incretin regulation. In clinical settings, altered levels of DPP‐4 expression and DPP‐4 enzyme activity have been reported in several immune‐mediated diseases, including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), multiple sclerosis (MS) and systemic lupus erythematosus (SLE) . These results indicate that DPP‐4 mediates immune function and disease pathogenesis via the development, maturation and migration of T cells, cytokine secretion, T cell‐dependent antibody production, and immunoglobulin isotype switching of B cells .…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl peptidase‐4 inhibitors lower the risk of autoimmune disease in patients with type 2 diabetes mellitus: A nationwide population‐based cohort study

Seong

Yee

Gwak

2019

Brit J Clinical Pharma

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Aims: To evaluate the real-world effect of dipeptidyl peptidase-4 inhibitor (DPP4i) on the incidence of autoimmune diseases (AD), including rheumatoid arthritis (RA), inflammatory bowel diseases, multiple sclerosis and systemic lupus erythematosus. Methods: We identified new users of DPP4i (n = 497 619) or non-DPP4i (n = 643 165) oral combination therapy between 1 January 2011 and 30 June 2015 among patients with type 2 diabetes mellitus in the Korean national health insurance claims database. Patients were followed from the date of initiation of combination therapy until AD outcome, censoring for treatment discontinuation or switching, death or end of study (31 August 2016). Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for RA, inflammatory bowel diseases, other AD (multiple sclerosis and systemic lupus erythematosus), and the composite of all outcomes were estimated using propensity score (PS)-adjusted Cox model. Results: In the PS-weighted and PS-matched analysis, the risk of incident RA was decreased for DPP4i initiators compared with non-DPP4i initiators (aHR 0.67 [95% CI 0.49-0.92] and aHR 0.72 [95% CI 0.51-1.01], respectively). In both analyses, the risk of incident composite AD was also decreased for DPP4i initiators compared with non-DPP4i initiators (aHR 0.82 [95% CI 0.68-0.99] and aHR 0.76 [95% CI 0.62-0.93], respectively). Conclusions:In this large population-based cohort study, upfront DPP4i combination therapy was associated with a lower risk of composite AD compared with initial non-DPP4i combination therapy.

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Dipeptidyl peptidase-IV in synovial fluid and in synovial fluid mononuclear cells of patients with rheumatoid arthritis

Cited by 16 publications

References 23 publications

CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis

CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis

Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system

Dipeptidyl peptidase‐4 inhibitors lower the risk of autoimmune disease in patients with type 2 diabetes mellitus: A nationwide population‐based cohort study

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