Iranian Journal of Allergy, Asthma and Immunology 2017. 16(5):425-432.

Frequency of Circulatory Regulatory Immune Cells in Iranian Patients with Type 1 Diabetes
Tahereh Khamehchian, Eqlim Nemati, Marziyeh Jazayeri, shirin Azimi, Hassan Nikoueinejad, Hossein Akbari, Behnaz Irandoust

Abstract


Type 1 diabetes (T1D) is the result of the autoimmune destruction of insulin-producing beta cells. Regulatory T cells (Tregs) and plasmacytoid dendritic cells (PDCs) act as mediators of peripheral tolerance. We investigated the possible alterations of such cells in peripheral blood of patients with T1D compared to normal individuals. This comparison may lead to a better understanding of the immunopathogenesis processes involved in T1D. 92 participants, including 49 patients with T1D and 43 healthy controls were studied. 3 mL of blood was taken from all participants. After isolating peripheral blood mononuclear cells (PBMCs), PDCs as well as 2 subtypes of Tregs, CD4+CD25+FoxP3+ and CD8+CD28cells were counted by 3-colorflow cytometry. The association between such enumeration and T1D was studied by multivariate regression and discriminate function models. The frequency of CD4+CD25+FoxP3+Tregs (p=0.038) and PDCs (p=0.039) in the peripheral blood of diabetic patients was less than that in healthy subjects. Having compared some models consisting different cells as well as their combinations, we did not find any profound explanation of each subset or their combinations to identify T1D. The decrease of CD4+CD25+FoxP3+cells and PDCs in diabetic patients may suggest their role in the onset or development of the disease. Therefore, it is likely that their pharmacologic stimulation may direct immune responses towards tolerance and prevent the development or even the onset of diabetes in susceptible individuals.

Keywords


CD4+CD25+FoxP3+regulatory T cells; CD8+CD28-regulatory T cells; Diabetes mellitus; Plasmacytoid dendritic cells

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References


1. Rönnblom L, Pascual V. Thomas, Cells of the synovium in rheumatoid arthritis. Dendritic cells. Arthritis Res Ther 2007; 9(4):219.

2. Rönnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 2008; 17(5):394-9.

3. Vogelsang P, Brun JG, Oijordsbakken G, Skarstein K, Jonsson R, Appel S. Levels of plasmacytoid dendritic cells and type-2 myeloid dendritic cells are reduced in peripheral blood of patients with primary Sjogren's syndrome. Ann Rheum Dis 2010; 69(6):1235-8.

4. I. Pujol-Autonell et al., Immunotherapy with Tolerogenic Dendritic Cells Alone or in Combination with Rapamycin Does Not Reverse Diabetes in NOD Mice. ISRN endocrinology 2013, 346987 (2013).

5. A. Wilkinson et al., Type 1 Diabetic Children and siblings share a decrease in dendritic cell and monocyte numbers but are differentiated by expansion of CD4+ T cells expressing IL-17. J Clin Cell Immunol S 2, (2011).

6. Nieminen JK, Vakkila J, Salo HM, Ekström N, Härkönen T, Ilonen J, et al. Altered phenotype of peripheral blood dendritic cells in pediatric type 1 diabetes. Diabetes care 2012; 35(11):2303-10.

7. Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol 2011; 29:163-83.

8. de Heer HJ, Hammad H, Soullié T, Hijdra D, Vos N, Willart MA, et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 2004; 200(1):89-98.

9. Smit JJ, Bol-Schoenmakers M, Hassing I, Fiechter D, Boon L, Bleumink R, et al. The role of intestinal dendritic cells subsets in the establishment of food allergy. Clin Exp Allergy 2011; 41(6):890-8.

10. Kavousanaki M, Makrigiannakis A, Boumpas D, Verginis P. Novel role of plasmacytoid dendritic cells in humans: induction of interleukin-10-producing Treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy. Arthritis Rheum 2010; 62(1):53-63.

11. Haeryfar SM. The importance of being a pDC in antiviral immunity: the IFN mission versus Ag presentation? Trends Immunol 2005; 26(6):311-7.

12. Tisch R, Wang B. Role of plasmacytoid dendritic cells in type 1 diabetes: friend or foe? Diabetes 2009; 58(1):12-3.

13. Chen X, Makala LH, Jin Y, Hopkins D, Muir A, Garge N, et al., Type 1 diabetes patients have significantly lower frequency of plasmacytoid dendritic cells in the peripheral blood. Clin Immunol 2008; 129(3):413-8.

14. Saxena V, Ondr JK, Magnusen AF, Munn DH, Katz JD. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol 2007; 179, 5041-5053 (2007).

15. Montane J, Bischoff L, Soukhatcheva G, Dai DL, Hardenberg G, Levings MK, et al. Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets. J Clin Invest 2011; 121(8):3024-8.

16. Kouchaki E, Salehi M, Reza Sharif M, Nikoueinejad H, Akbari H. Numerical status of CD4(+)CD25(+)FoxP3(+) and CD8(+)CD28(-) regulatory T cells in multiple sclerosis. Iran J Basic Med Sci 2014; 17(4):250-5.

17. Lee JH, Wang LC, Lin YT, Yang YH, Lin DT, Chiang BL. Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 2006; 117(2):280-6.

18. Furuno K, Yuge T, Kusuhara K, Takada H, Nishio H, Khajoee V, et al. CD25+CD4+ regulatory T cells in patients with Kawasaki disease. J Pediatr 2004; 145(3):385-90.

19. Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 2004; 173(5):3119-30.

20. Lawson CA, Brown AK, Bejarano V, Douglas SH, Burgoyne CH, Greenstein AS, et al., Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology 2006; 45(10):1210-7.

21. Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 2005; 54(5):1407-14.

22. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005; 54(1):92-9.

23. Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 2005; 24(1):55-62.

24. Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D'hooghe MB, et al. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 2006; 83(8):1432-46.

25. Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004; 41(1):31-7.

26. Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med 2005; 202(10):1387-97.

27. Szypowska A, Stelmaszczyk-Emmel A, Demkow U, Luczyński W. Low frequency of regulatory T cells in the peripheral blood of children with type 1 diabetes diagnosed under the age of five. Arch Immunol Ther Exp (Warsz) 2012; 60(4):307-13.

28. Luczyński W, Stasiak-Barmuta A, Urban R, Urban M, Florys B, Hryszko M. Lower percentages of T regulatory cells in children with type 1 diabetes - preliminary report. Pediatr Endocrinol Diabetes Metab 2009; 15(1):34-8.

29. Ryba-Stanisławowska M, Rybarczyk-Kapturska K, Myśliwiec M, Myśliwska J. Elevated levels of serum IL-12 and IL-18 are associated with lower frequencies of CD4(+)CD25 (high)FOXP3 (+) regulatory t cells in young patients with type 1 diabetes. Inflammation 2014; 37(5):1513-20.

30. Tsai S, Shameli A, Yamanouchi J, Clemente-Casares X, Wang J, Serra P, et al. Reversal of autoimmunity by boosting memory-like autoregulatory T cells. Immunity 2010; 32(4):568-80.

31. Hubert P, Jacobs N, Caberg JH, Boniver J, Delvenne P. The cross-talk between dendritic and regulatory T cells: good or evil? J Leukoc Biol 2007; 82(4):781-94.

32. Welzen-Coppens JM, van Helden-Meeuwsen CG, Leenen PJ, Drexhage HA, Versnel MA. The kinetics of plasmacytoid dendritic cell accumulation in the pancreas of the NOD mouse during the early phases of insulitis. PloS one 2013; 8(1):e55071.

33. Lee MH, Lee WH, Todorov I, Liu CP. CD4+ CD25+ regulatory T cells prevent type 1 diabetes preceded by dendritic cell-dominant invasive insulitis by affecting chemotaxis and local invasiveness of dendritic cells. J Immunol 2010; 185(4):2493-501.

34. Ott PA, Anderson MR, Tary-Lehmann M, Lehmann PV. CD4+CD25+ regulatory T cells control the progression from periinsulitis to destructive insulitis in murine autoimmune diabetes. Cell Immunol 2005; 235(1):1-11.

35. Kayserova J, Vcelakova J, Stechova K, Dudkova E, Hromadkova H, Sumnik Z, et al. Decreased dendritic cell numbers but increased TLR9-mediated interferon-alpha production in first degree relatives of type 1 diabetes patients. Clin Immunol 2014; 153(1):49-55.

36. Steptoe RJ, Ritchie JM, Harrison LC. Increased generation of dendritic cells from myeloid progenitors in autoimmune-prone nonobese diabetic mice. J Immunol 2002; 168(10):5032-41.

37. Vrabelova Z Hrotekova Z, Hladikova Z, Bohmova K, Stechova K, Michalek J. CD 127- and FoxP3+ expression on CD25+CD4+ T regulatory cells upon specific diabetogeneic stimulation in high-risk relatives of type 1 diabetes mellitus patients. Scand J Immunol 2008; 67(4):404-10.


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