Increased Circulating T Follicular Helper Cells in Iranian Children with Type I Diabetes
-
Mansour Arab
,
Maryam Razzaghy-Azar
,
Zahra Salehi
,
Maryam Keshavarz
,
Ensieh Nasli- Esfahani
,
Mahdi Shekarabi
,
Maryam Izad
Abstract
Type 1 diabetes (T1D) is an autoimmune disease resulting from the damage of pancreatic B-cells mediated by autoreactive CD4+ and CD8+ T cells. In recent years, follicular T helper (Tfh) cells have been recognized as a subpopulation of CD4+ T cells providing help for B cells differentiation and antibody production. In this study, we examined the frequency of circulating CD4+CXCR5+ and CD4+CXCR5+ICOS+ (representing Tfh) cells as well as serum levels of anti-glutamic acid decarboxylase 65 (GAD65) and islet cell autoantibodies (ICA) in children with type I diabetes. We analyzed the percentage of Tfh cells within peripheral blood mononuclear cells in 20 children with T1D (≤300 days from disease onset; Mean age 6.8±4.6 years) and 18 healthy individuals (Mean age 8.8±2.2 years) using flow cytometry. Anti-glutamic acid decarboxylase (GAD) and islet-cell cytoplasmic autoantibodies (ICA) levels were determined by ELISA and indirect immunofluorescence respectively. We found that the frequency of CD4+CXCR5+ and CD4+CXCR5+ICOS+ (Tfh) cells were significantly increased in the peripheral blood of patients compared with healthy controls (p<0.001). Furthermore, elevated levels of anti-GAD and ICA antibodies were detected in children with T1D (p=0.001 and p=0.02 respectively). There was no correlation between Tfh cells frequency and the autoantibody levels. The results of our study indicate an increased frequency of Tfh cells in children With T1D that could suggest a possible role of these cells in the disease pathogenesis.
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2. Herold KC, Vignali DA, Cooke A, Bluestone JA. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 2013; 13(4):243-56.
3. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011; 34(1):108-21.
4. Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon) 2014; 42(12):698-702.
5. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am 2010; 39(3):481-97.
6. Kendall PL, Moore DJ, Hulbert C, Hoek KL, Khan WN, Thomas JW. Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J Immunol 2009; 183(10):6403-12.
7. Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, et al. B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care 2014; 37(2):453-9.
8. Winter WE, Schatz DA. Autoimmune markers in diabetes. Clin Chem 2011; 57(2):168-75.
9. Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity 2009; 30(3):324-35.
10. Zhang X, Ing S, Fraser A, Chen M, Khan O, Zakem J. Follicular helper T cells: new insights into mechanisms of autoimmune diseases. Ochsner J 2013; 13(1):131-9.
11. Deenick EK, Ma CS. The regulation and role of T follicular helper cells in immunity. Immunology 2011; 134(4):361-7.
12. Ma CS, Deenick EK, Batten M, Tangye SG. The origins, function, and regulation of T follicular helper cells. J Exp Med 2012; 209(7):1241-53.
13. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Müller G. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent
of CD57 expression. Eur J Immunol 2006; 36(7):1892-903.
14. Jin L, Yu D, Li X, Yu N, Li X, Wang Y, et al. CD4+CXCR5+ follicular helper T cells in salivary gland promote B cells maturation in patients with primary Sjogren's syndrome. Int J Clin Exp Pathol 2014; 7(5):1988-96.
15. Le Coz C, Joublin A, Pasquali JL, Korganow AS, Dumortier H, Monneaux F. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease. PLoS One 2013; 8(9):e75319.
16. Arroyo-Villa I, Bautista-Caro MB, Balsa A, Aguado-Acín P, Bonilla-Hernán MG, Plasencia C, et al. Constitutively altered frequencies of circulating follicullar helper T cell counterparts and their subsets in rheumatoid arthritis. Arthritis Res Ther 2014; 16(6):500.
17. Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol 2012; 2012:827480.
18. Wu S, Yang T, Pan F, Xia G, Hu Y, Liu L, et al. Increased frequency of circulating follicular helper T cells in patients with ankylosing spondylitis. Mod Rheumatol 2015; 25(1):110-5.
19. Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J, et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2012; 97(3):943-50.
20. Xie J, Cui D, Liu Y, Jin J, Tong H, Wang L, et al. Changes in follicular helper T cells in idiopathic thrombocytopenic purpura patients. Int J Biol Sci 2015; 11(2):220-9.
21. Schmitt N. Role of T Follicular Helper cells in Multiple Sclerosis. J Nat Sci 2015; 1(7):e139.
22. Xu X, Shi Y, Cai Y, Zhang Q, Yang F, Chen H, et al. Inhibition of increased circulating Tfh cell by anti-CD20 monoclonal antibody in patients with type 1 diabetes. PLoS One 2013; 8(11):e79858.
23. Kenefeck R, Wang CJ, Kapadi T, Wardzinski L, Attridge K, Clough LE, et al. Follicular helper T cell signature in type 1 diabetes. J Clin Invest 2015; 125(1):292-303.
24. Ferreira RC, Simons HZ, Thompson WS, Cutler AJ, Dopico XC, Smyth DJ, et al. IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients. Diabetologia 2015; 58(4):781-90.
25. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 199; 15(7):539-53.
26. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; (26 Suppl 1):S5-20.
27. Viisanen T, Ihantola EL, Näntö-Salonen K, Hyöty H, Nurminen N, Selvenius J, et al. Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies. Diabetes 2017; 66(2):437-47.
28. Hennerici T, Pollmann R, Schmidt T, Seipelt M, Tackenberg B, Möbs C, et al. Increased Frequency of T Follicular Helper Cells and Elevated Interleukin-27 Plasma Levels in Patients with Pemphigus. PLoS One 2016; 11(2):e0148919.
29. Kong YH, Kim MS, Lee DY. Comparison of the prevalence of islet autoantibodies according to age and disease duration in patients with type 1 diabetes mellitus. Ann Pediatr Endocrinol Metab 2013; 18(2):65-70.
30. Ziegler AG, Nepom GT. Nepom, Prediction and pathogenesis in type 1 diabetes. Immunity 2010; 32(4):468-78.
2. Herold KC, Vignali DA, Cooke A, Bluestone JA. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 2013; 13(4):243-56.
3. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011; 34(1):108-21.
4. Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon) 2014; 42(12):698-702.
5. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am 2010; 39(3):481-97.
6. Kendall PL, Moore DJ, Hulbert C, Hoek KL, Khan WN, Thomas JW. Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J Immunol 2009; 183(10):6403-12.
7. Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, et al. B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care 2014; 37(2):453-9.
8. Winter WE, Schatz DA. Autoimmune markers in diabetes. Clin Chem 2011; 57(2):168-75.
9. Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity 2009; 30(3):324-35.
10. Zhang X, Ing S, Fraser A, Chen M, Khan O, Zakem J. Follicular helper T cells: new insights into mechanisms of autoimmune diseases. Ochsner J 2013; 13(1):131-9.
11. Deenick EK, Ma CS. The regulation and role of T follicular helper cells in immunity. Immunology 2011; 134(4):361-7.
12. Ma CS, Deenick EK, Batten M, Tangye SG. The origins, function, and regulation of T follicular helper cells. J Exp Med 2012; 209(7):1241-53.
13. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Müller G. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent
of CD57 expression. Eur J Immunol 2006; 36(7):1892-903.
14. Jin L, Yu D, Li X, Yu N, Li X, Wang Y, et al. CD4+CXCR5+ follicular helper T cells in salivary gland promote B cells maturation in patients with primary Sjogren's syndrome. Int J Clin Exp Pathol 2014; 7(5):1988-96.
15. Le Coz C, Joublin A, Pasquali JL, Korganow AS, Dumortier H, Monneaux F. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease. PLoS One 2013; 8(9):e75319.
16. Arroyo-Villa I, Bautista-Caro MB, Balsa A, Aguado-Acín P, Bonilla-Hernán MG, Plasencia C, et al. Constitutively altered frequencies of circulating follicullar helper T cell counterparts and their subsets in rheumatoid arthritis. Arthritis Res Ther 2014; 16(6):500.
17. Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol 2012; 2012:827480.
18. Wu S, Yang T, Pan F, Xia G, Hu Y, Liu L, et al. Increased frequency of circulating follicular helper T cells in patients with ankylosing spondylitis. Mod Rheumatol 2015; 25(1):110-5.
19. Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J, et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 2012; 97(3):943-50.
20. Xie J, Cui D, Liu Y, Jin J, Tong H, Wang L, et al. Changes in follicular helper T cells in idiopathic thrombocytopenic purpura patients. Int J Biol Sci 2015; 11(2):220-9.
21. Schmitt N. Role of T Follicular Helper cells in Multiple Sclerosis. J Nat Sci 2015; 1(7):e139.
22. Xu X, Shi Y, Cai Y, Zhang Q, Yang F, Chen H, et al. Inhibition of increased circulating Tfh cell by anti-CD20 monoclonal antibody in patients with type 1 diabetes. PLoS One 2013; 8(11):e79858.
23. Kenefeck R, Wang CJ, Kapadi T, Wardzinski L, Attridge K, Clough LE, et al. Follicular helper T cell signature in type 1 diabetes. J Clin Invest 2015; 125(1):292-303.
24. Ferreira RC, Simons HZ, Thompson WS, Cutler AJ, Dopico XC, Smyth DJ, et al. IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients. Diabetologia 2015; 58(4):781-90.
25. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 199; 15(7):539-53.
26. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; (26 Suppl 1):S5-20.
27. Viisanen T, Ihantola EL, Näntö-Salonen K, Hyöty H, Nurminen N, Selvenius J, et al. Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies. Diabetes 2017; 66(2):437-47.
28. Hennerici T, Pollmann R, Schmidt T, Seipelt M, Tackenberg B, Möbs C, et al. Increased Frequency of T Follicular Helper Cells and Elevated Interleukin-27 Plasma Levels in Patients with Pemphigus. PLoS One 2016; 11(2):e0148919.
29. Kong YH, Kim MS, Lee DY. Comparison of the prevalence of islet autoantibodies according to age and disease duration in patients with type 1 diabetes mellitus. Ann Pediatr Endocrinol Metab 2013; 18(2):65-70.
30. Ziegler AG, Nepom GT. Nepom, Prediction and pathogenesis in type 1 diabetes. Immunity 2010; 32(4):468-78.
| Files | ||
| Issue | Vol 17, No 6 (2018) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v17i6.620 | |
| Keywords | ||
| Anti-glutamic acid decarboxylase antibody Islet-cell antibodies Type 1 diabetes T follicular helper cell | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Arab M, Razzaghy-Azar M, Salehi Z, Keshavarz M, Nasli- Esfahani E, Shekarabi M, Izad M. Increased Circulating T Follicular Helper Cells in Iranian Children with Type I Diabetes. Iran J Allergy Asthma Immunol. 2018;17(6):557-563.
