Anti-CD26 autoantibodies are involved in rheumatoid arthritis and show potential clinical interest

Objectives Rheumatoid arthritis (RA) patients show low serum levels of the Ag dipeptidyl peptidase IV (DPP-IV/CD26), both soluble CD26 (sCD26) concentration and its DPP-IV activity. The aim of this study was to test if anti-DPP-IV/CD26 Abs (Anti-CD26) cleared sCD26. Design & methods Serum Anti-CD26 and Total titers (as comparison) of isotypes IgA, IgM and IgG as well as sCD26 concentration and DPP-IV activity were measured in a cohort of RA patients undergoing different biological and non-biological therapies (n = 105) and controls (n = 50). Results Anti-CD26 levels were increased approximately two-fold for each isotype in RA, were not related to the sCD26 clearance, showed several correlations with disease activity parameters, were significantly higher in smokers and they were not ACPA. Anti-CD26 Igs showed high diagnostic power (82% sensitivity and 96% specificity) and their levels differed amongst the different groups of patients stratified by the type of therapy. Conclusions As DPP-IV/CD26 is associated to factors triggering RA in the lung and periodontal tissue, these results suggest that Anti-CD26 isotypes may participate in pathogenesis and may be useful as biomarkers for earlier diagnosis and/or precision medicineThis work was supported by an unrestricted medical grant from Pfizer Spain (WS1541122). Dr. Pego has support from the European Union Seventh Framework Programme [FP7/REGPOT-2012-2013.1] under grant agreement no 316265, BIOCAPS. The funding organization (s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.S

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

Correction 28 Sep 2015: Cordero OJ, Varela-Calviño R, López-González T, Calviño-Sampedro C, Viñuela JE, et al. (2015) Correction: CD26 Expression on T Helper Populations and sCD26 Serum Levels in Patients with Rheumatoid Arthritis. PLOS ONE 10(9): e0139535, https://doi.org/10.1371/journal.pone.0139535We 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 diagnosisThis work was supported by an unrestricted medical grant from Pfizer Spain to OJC and JMP. European Union Seventh Framework Programme [FP7/REGPOT-2012-2013.1] under grant agreement n° 316265, BIOCAPS, supports to JMPS

Correlation between disease activity and CD26⁺ naïve T cells.

<p>DAS28 (Disease Activity Score 28) correlations with CD26 cell surface density of circulating CD4 CD45R0^<b>-</b> CD26^<b>+</b> naïve T lymphocytes in the whole cohort of patients (upper left panel), in the No BT group (patients without biological activity, upper right panel), and in two groups of patients with biological therapies (lower panels). Pearson’s coefficient (r) and significance (p) data are insert in the panels.</p

Total cell number of CD4 T cells subsets gated according to the effector/memory CD45RO and CD26 staining and CD26 cell surface level (MFI) in RA patients undergoing different therapies.

<p>n = number of samples; CI = confidence interval; SD = standard deviation; BT = biological therapy</p><p>*Values significantly different to No BT group at p < 0.05 (Student´s t-test)</p><p>** Values significantly different to anti-TNFα group at p < 0.05 (Student´s t-test)</p><p># Values significantly different to control group (No BT) at p < 0.05 (Dunnett´s t-test)</p><p>Total cell number of CD4 T cells subsets gated according to the effector/memory CD45RO and CD26 staining and CD26 cell surface level (MFI) in RA patients undergoing different therapies.</p

Major CD4⁺ T cell subsets defined by surface CD45R0 and CD26 expression.

<p>A) Representative flow cytometry dot-plot showing lymphocytes gated physically. B) Representative dot-plot of gated CD4^<b>+</b> T lymphocytes. C) and D) Dot-plots showing the differential expression of CD45R0 and CD26 in the whole lymphocyte region gated in A (C) or in the CD3^<b>+</b>CD4^<b>+</b> region gated in B (D). Naïve CD4 cells are mostly CD26^<b>+</b> in contrast to the CD8^<b>+</b> cells (compare C and D). From D) four major subsets were selected by their differential expression of CD45R0 and CD26: CD4^<b>+</b>CD45R0^{<b>low/−</b>} CD26^<b>+</b> (naïve T cells); and effector/memory CD4^<b>+</b>CD45R0^<b>+</b>CD26^<b>-</b> (CD26 negative), CD4^<b>+</b>CD45R0^<b>+</b>CD26^<b>+</b> (intermediate) and CD4^<b>+</b>CD45R0^<b>+</b>CD26^<b>++</b> (CD26high).</p

Percentages and total number of different CD4 T subsets gated according to the CCR6, CCR4 and CCR10 staining.

<p>n = number of samples; CI = confidence interval; SD = standard deviation; BT = biological therapy</p><p>* Values significantly different among groups (not specified) at p < 0.05 (Student´s t test)</p><p># Values significantly different among groups at p < 0.05 (Scheffé´s test)</p><p>¢ Values significantly different among groups at p < 0.05 (Dunnett´s C test)</p><p>Patients were grouped according to the kind of therapy.</p