BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) is suggested to contribute to the pathogenesis of several autoimmune diseases. The aim of this study was to evaluate the association of DPP-IV presence in blood plasma and mononuclear cells with the disease activity in rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 27) were examined at the study enrolment and a follow-up examination was performed after the regression of the joint effusions and at least 6 months after the first investigation. The control group comprised patients with a noninflammatory joint disease, i.e. osteoarthritis (OA; n = 15). The DPP-IV-like enzymatic activity was measured by a kinetic fluorimetric method, the concentration of DPP-IV in the blood plasma was determined using ELISA and the expression of DPP-IV in leukocytes was assayed by flow cytometry. RESULTS: Blood plasma DPP-IV-like enzymatic activity (median ± SD 220.15 ± 83.6 pkat/mL in RA vs. 376.9 ± 144.9 pkat/mL in OA, p < 0.001) and concentrations (median ± SD 465.1 ± 215.6 ng/mL in RA vs. 953.3 ± 368.4 ng/mL in OA, p < 0.001) were lower in patients with active RA compared to OA. In RA patients, the blood plasma DPP-IV-like enzymatic activity negatively correlated with the CRP concentration (r = -0.39, p = 0.044). No significant differences were observed in the DPP-IV-like enzymatic activity and DPP-IV expression in blood mononuclear cells between the RA and OA groups. At follow-up, 18 RA patients had a less active disease as demonstrated by an improved DAS28 score. In this group, comparison of the entry and the follow-up values in individual patients revealed an increase of the blood plasma DPP-IV-like enzymatic activity (median ± SD 141 ± 46% of the patient's entry values, p = 0.011) and DPP-IV concentration (median ± SD 168 ± 25%, of the patient's entry values, p = 0.033). In contrast to the blood plasma, the DPP-IV expression in blood mononuclear cells was reduced in these patients as evidenced by a decrease in the cell surface DPP-IV-like enzymatic activity as well as the median fluorescence intensity of DPP-IV staining in lymphocytes (median ± SD 66 ± 56%, p = 0.018 and 63 ± 31 % of the patient's entry values, p = 0.005, respectively). CONCLUSIONS: The association between RA activity and the changes in blood plasma and blood mononuclear cell DPP-IV in individual patients supports the possible relationship of DPP-IV to RA pathophysiology.

Institute of Rheumatology Na Slupi 4 128 50 Prague Czech Republic

Laboratory of Cancer Cell Biology Institute of Biochemistry and Experimental Oncology of the 1st Faculty of Medicine Charles University Prague U Nemocnice 5 128 53 Prague 2 Czech Republic

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Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003;40(3):209–94. doi: 10.1080/713609354. PubMed DOI

Morimoto C, Torimoto Y, Levinson G, Rudd CE, Schrieber M, Dang NH, Letvin NL, Schlossman SF. 1F7, a novel cell surface molecule, involved in helper function of CD4 cells. J Immunol. 1989;143(11):3430–9. PubMed

Krakauer M, Sorensen PS, Sellebjerg F. CD4(+) memory T cells with high CD26 surface expression are enriched for Th1 markers and correlate with clinical severity of multiple sclerosis. J Neuroimmunol. 2006;181(1–2):157–64. doi: 10.1016/j.jneuroim.2006.09.006. PubMed DOI

Ohnuma K, Hosono O, Dang NH, Morimoto C. Dipeptidyl peptidase in autoimmune pathophysiology. Adv Clin Chem. 2011;53:51–84. doi: 10.1016/B978-0-12-385855-9.00003-5. PubMed DOI

Sedo A, Duke-Cohan JS, Balaziova E, Sedova LR. Dipeptidyl peptidase IV activity and/or structure homologs: contributing factors in the pathogenesis of rheumatoid arthritis? Arthritis Res Ther. 2005;7(6):253–69. doi: 10.1186/ar1852. PubMed DOI PMC

Dang NH, Morimoto C. CD26: an expanding role in immune regulation and cancer. Histol Histopathol. 2002;17(4):1213–26. PubMed

von Bonin A, Huhn J, Fleischer B. Dipeptidyl-peptidase IV/CD26 on T cells: analysis of an alternative T-cell activation pathway. Immunol Rev. 1998;161:43–53. doi: 10.1111/j.1600-065X.1998.tb01570.x. PubMed DOI

Ohnuma K, Dang NH, Morimoto C. Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol. 2008;29(6):295–301. doi: 10.1016/j.it.2008.02.010. PubMed DOI

McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19. doi: 10.1056/NEJMra1004965. PubMed DOI

Fleischer B. CD26: a surface protease involved in T-cell activation. Immunol Today. 1994;15(4):180–4. doi: 10.1016/0167-5699(94)90316-6. PubMed DOI

Sromova L, Mareckova H, Sedova L, Balaziova E, Sedo A. Dipeptidyl peptidase-IV in synovial fluid and in synovial fluid mononuclear cells of patients with rheumatoid arthritis. Clin Chim Acta. 2010;411(15–16):1046–50. doi: 10.1016/j.cca.2010.03.034. PubMed DOI

Balaziova E, Sedova L, Mares V, Vlasicova K, Sevcik J, Sedo A. Dipeptidyl peptidase-IV activity and/or structure homologs (DASH): contributing factors in the pathogenesis of rheumatic diseases? Adv Exp Med Biol. 2006;575:169–74. doi: 10.1007/0-387-32824-6_18. PubMed DOI

Ulusoy H, Kamanli A, Ilhan N, Kuru O, Arslan S, Alkan G, Ozgocmen S. Serum levels of soluble CD26 and CD30 and their clinical significance in patients with rheumatoid arthritis. Rheumatol Int. 2012;32(12):3857–62. doi: 10.1007/s00296-011-2302-3. PubMed DOI

Hagihara M, Ohhashi M, Nagatsu T. Activities of dipeptidyl peptidase II and dipeptidyl peptidase IV in mice with lupus erythematosus-like syndrome and in patients with lupus erythematosus and rheumatoid arthritis. Clin Chem. 1987;33(8):1463–5. PubMed

Muscat C, Bertotto A, Agea E, Bistoni O, Ercolani R, Tognellini R, Spinozzi F, Cesarotti M, Gerli R. Expression and functional role of 1F7 (CD26) antigen on peripheral blood and synovial fluid T cells in rheumatoid arthritis patients. Clin Exp Immunol. 1994;98(2):252–6. doi: 10.1111/j.1365-2249.1994.tb06134.x. PubMed DOI PMC

Ellingsen THN, Møller BK, Hjelm-Poulsen J, Stengaard-Pedersen K. In active chronic rheumatoid arthritis, dipeptidyl peptidase IV density is increased on monocytes and CD4(+) T lymphocytes. Scand J Immunol. 2007;66(4):451–7. doi: 10.1111/j.1365-3083.2007.01966.x. PubMed DOI

Gerli R, Muscat C, Bertotto A, Bistoni O, Agea E, Tognellini R, Fiorucci G, Cesarotti M, Bombardieri S. CD26 surface molecule involvement in T cell activation and lymphokine synthesis in rheumatoid and other inflammatory synovitis. Clin Immunol Immunopathol. 1996;80(1):31–7. doi: 10.1006/clin.1996.0091. PubMed DOI

Nakao H, Eguchi K, Kawakami A, Migita K, Otsubo T, Ueki Y, Shimomura C, Tezuka H, Matsunaga M, Maeda K. Increment of Tal positive cells in peripheral blood from patients with rheumatoid arthritis. J Rheumatol. 1989;16(7):904–10. PubMed

Cordero OJ, Salgado FJ, Mera-Varela A, Nogueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int. 2001;21(2):69–74. doi: 10.1007/s002960100134. PubMed DOI

Busso N, Wagtmann N, Herling C, Chobaz-Peclat V, Bischof-Delaloye A, So A, Grouzmann E. Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am J Pathol. 2005;166(2):433–42. doi: 10.1016/S0002-9440(10)62266-3. PubMed DOI PMC

Gotoh H, Hagihara M, Nagatsu T, Iwata H, Miura T. Activities of dipeptidyl peptidase II and dipeptidyl peptidase IV in synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Clin Chem. 1989;35(6):1016–8. PubMed

Kobayashi H, Hosono O, Mimori T, Kawasaki H, Dang NH, Tanaka H, Morimoto C. Reduction of serum soluble CD26/dipeptidyl peptidase IV enzyme activity and its correlation with disease activity in systemic lupus erythematosus. J Rheumatol. 2002;29(9):1858–66. PubMed

Hildebrandt M, Rose M, Ruter J, Salama A, Monnikes H, Klapp BF. Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease. Scand J Gastroenterol. 2001;36(10):1067–72. doi: 10.1080/003655201750422675. PubMed DOI

Stancikova M, Lojda Z, Lukac J, Ruzickova M. Dipeptidyl peptidase IV in patients with systemic lupus erythematosus. Clin Exp Rheumatol. 1992;10(4):381–5. PubMed

Hafler DA, Fox DA, Manning ME, Schlossman SF, Reinherz EL, Weiner HL. In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. N Engl J Med. 1985;312(22):1405–11. doi: 10.1056/NEJM198505303122201. PubMed DOI

Tejera-Alhambra M, Casrouge A, de Andres C, Ramos-Medina R, Alonso B, Vega J, Albert ML, Sanchez-Ramon S. Low DPP4 expression and activity in multiple sclerosis. Clin Immunol. 2014;150(2):170–83. doi: 10.1016/j.clim.2013.11.011. PubMed DOI

Kullertz G, Boigk J. Dipeptidyl peptidase IV activity in the serum and synovia of patients with rheumatoid arthritis. Z Rheumatol. 1986;45(2):52–6. PubMed

Fujita K, Hirano M, Ochiai J, Funabashi M, Nagatsu I, Nagatsu T, Sakakibara S. Serum glycylproline p-nitroanilidase activity in rheumatoid arthritis and systemic lupus erythematosus. Clin Chim Acta. 1978;88(1):15–20. doi: 10.1016/0009-8981(78)90142-0. PubMed DOI

Cuchacovich M, Gatica H, Pizzo SV, Gonzalez-Gronow M. Characterization of human serum dipeptidyl peptidase IV (CD26) and analysis of its autoantibodies in patients with rheumatoid arthritis and other autoimmune diseases. Clin Exp Rheumatol. 2001;19(6):673–80. PubMed

Ellingsen T, Hansen I, Thorsen J, Kuno Moller B, Tarp U, Jacobsen S, Lund Hetland M, Vestergaard A, Horslev-Petersen K, Stengaard-Pedersen K. Up-regulated dipeptidyl-peptidase IV (CD26) on monocytes was unaffected by effective DMARD treatment in early steroid and DMARD-naive rheumatoid arthritis. Clin Exp Rheumatol. 2012;30(1):58–63. PubMed

Mavropoulos JC, Cuchacovich M, Llanos C, Aguillon JC, Gatica H, Pizzo SV, Gonzalez-Gronow M. Anti-tumor necrosis factor-alpha therapy augments dipeptidyl peptidase IV activity and decreases autoantibodies to GRP78/BIP and phosphoglucose isomerase in patients with rheumatoid arthritis. J Rheumatol. 2005;32(11):2116–24. PubMed