T Helper 22 Pathway Evaluation in Type 1 Diabetes and Its Complications
Abstract
A subset of CD4+ T cells named T helper (Th)22 cells play some pathogenic roles in some autoimmune disorders such as type 1 diabetes (T1D). We aimed to study the correlation between the circulatory number of these cells and serum levels of its related cytokines with T1D as well as diabetic complications including metabolic control, atherosclerosis, and nephropathy. Fortynine patients with T1D and 43 healthy controls underwent the assessment of circulatory number of Th22 cells (by flow cytometry), serum level of Th22 related cytokines including Interleukin-22 (IL-22), Interleukin-10 (IL-10), Transforming growth factor-β (TGF-β), Tumor necrosis factor-α (TNF-α) (by ELISA) and carotid intima-media thickness (cIMT) measurement (by doppler ultrasonography). In addition, fasting blood and urine samples were taken to measure levels of hemoglobin A1C, lipid profile, cell blood count (CBC), serum and urine creatinine and urine protein in all participants. Th22 frequency and serum levels of IL-22 and TNF-α in patients were significantly higher than those in controls (p<0.001). Serum levels of IL-10 and TGF-β in healthy individuals were higher than those in patients (p<0.001). None of the Th22 related markers had a significant correlation with diabetic complications. There was only a significant effect of IL-22 on HbA1C variations. Th22 pathway has a significant correlation with T1D but not with its complications of cIMT and Urine Albumin/Creatinine Ratio (UACR). We report that Th22 pathway is not a good prognostic as well as diagnostic marker of early macrovascular complications in T1D.
1. Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; 311(17):1778-86.
2. Vaseghi H, Jadali Z. Th1/Th2 cytokines in Type 1 diabetes: Relation to duration of disease and gender. Indian J Endocrinol Metab 2016; 20(3):312-6.
3. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nat Immunol 2009; 10(8):864-71.
4. Goudy KS, Burkhardt BR, Wasserfall C, Song S, Campbell-Thompson ML, Brusko T, et al. Systemic overexpression of IL-10 induces CD4+ CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. J Immunol 2003; 171(5):2270-8.
5. Bazzaz JT, Amoli MM, Taheri Z, Larijani B, Pravica V, Hutchinson IV. TGF-β1 and IGF-I gene variations in type 1 diabetes microangiopathic complications. J Diabetes Metab Disord 2014; 13(1):45.
6. Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R. Single cell analysis shows decreasing FoxP3 and TGFβ1 coexpressing CD4+ CD25+ regulatory T cells
during autoimmune diabetes. J Exp Med 2005; 201(8):1333-46.
7. 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.
8. Kaas A, Pfleger C, Kharagjitsingh A, Schloot N, Hansen L, Buschard K, et al. Association between age, IL‐10, IFNγ, stimulated C‐peptide and disease progression in children with newly diagnosed Type 1 diabetes. Diabet Med 2012; 29(6):734-41.
9. Nguyen DV, Shaw L, Grant M. Inflammation in the pathogenesis of microvascular complications in diabetes. Front Endocrinol (Lausanne) 2012; 3:170.
10. Gerstl EM, Rabl W, Rosenbauer J, Gröbe H, Hofer SE, Krause U, et al. Metabolic control as reflectet by HbA1c in children, adolescents and young adults with type-1 diabetes mellitus: combined longitudinal analysis including 27,035 patients from 207 centers in Germany and Austria during the last decade. Eur J Pediatr 2008; 167(4):447-53.
11. Zhao R-x, Li W-j, Lu Y-r, Qin J, Wu C-l, Tian M, et al. Increased peripheral proinflammatory T helper subsets contribute to cardiovascular complications in diabetic patients. Mediators Inflamm 2014; 2014.
12. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness. Circulation 2007; 115(4):459-67.
13. Atabek ME, Kurtoglu S, Pirgon O, Baykara M. Arterial wall thickening and stiffening in children and adolescents with type 1 diabetes. Diabetes Res Clin Pract 2006; 74(1):33-40.
14. Gerstl EM, Rabl W, Rosenbauer J, Gröbe H, Hofer SE, Krause U, et al. Metabolic control as reflectet by HbA1c in children, adolescents and young adults with type-1 diabetes mellitus: combined longitudinal analysis including 27,035 patients from 207 centers in Germany and Austria during the last decade. Eur J Pediatr 2008; 167(4):447-53.
15. Nilsson J, Bengtsson E, Fredrikson GN, Björkbacka H. Inflammation and immunity in diabetic vascular complications. Curr Opin Lipidol 2008; 19(5):519-24.
16. Graves DT, Kayal RA. Diabetic complications and dysregulated innate immunity. Front Biosci 2008; 13:1227-39.
17. Røndbjerg AK, Omerovic E, Vestergaard H. YKL-40 levels are independently associated with albuminuria in type 2 diabetes. Cardiovasc Diabetol 2011; 10(1):54.
18. Tooley JE, Vudattu N, Choi J, Cotsapas C, Devine L, Raddassi K, et al. Changes in T‐cell subsets identify responders to FcR‐nonbinding anti‐CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol 2016; 46(1):230-41.
19. Viisanen T, Ihantola E-L, 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.
20. Li H, Rostami A. IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity. J Neuroimmune Pharmacol 2010; 5(2):198-209.
21. Zhao R, Tang D, Yi S, Li W, Wu C, Lu Y, et al. Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PloS one 2014; 9(1):e85770.
22. Xu X, Zheng S, Yang F, Shi Y, Gu Y, Chen H, et al. Increased Th22 cells are independently associated with Th17 cells in type 1 diabetes. Endocrine 2014; 46(1):90-8.
23. Rutz S, Eidenschenk C, Ouyang W. IL‐22, not simply a Th17 cytokine. Immunol Rev 2013; 252(1):116-32.
24. van der Torren CR, Stuart AAV, Lee D, Meerding J, van de Velde U, Pipeleers D, et al. Serum cytokines as biomarkers in islet cell transplantation for type 1 diabetes. PloS one 2016; 11(1):e0146649.
25. Bellemore S, Nikoopour E, Krougly O, Lee‐Chan E, Fouser L, Singh B. Pathogenic T helper type 17 cells contribute to type 1 diabetes independently of interleukin‐22. Clin Exp Immunol 2016; 183(3):380-8.
26. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 2007; 27(4):647-59.
27. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 2008; 118(2):534-44.
28. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 2008; 29(6):947-57.
29. Couturier M, Lamarthee B, Arbez J, Renauld J, Bossard C, Malard F, et al. IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect. Leukemia 2013; 27(7):1527-37.
30. Boniface K, Bernard F-X, Garcia M, Gurney AL, Lecron J-C, Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 2005; 174(6):3695-702.
31. Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, et al. Expression of interleukin‐22 in rheumatoid arthritis: Potential role as a proinflammatory cytokine. Arthritis Rheum 2005; 52(4):1037-46.
32. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 2011; 12(5):383-90.
33. Ryba-Stanisławowska M, Werner P, Brandt A, Myśliwiec M, Myśliwska J. Th9 and Th22 immune response in young patients with type 1 diabetes. Immunol Res 2016; 64(3):730-5.
| Files | ||
| Issue | Vol 17, No 3 (2018) | |
| Section | Original Article(s) | |
| Keywords | ||
| Diabetic nephropathy Diabetes type 1 Intima media thickness Interleukin-10 Interleukin-22 T helper 22 Transforming growth factor-β Tumor necrosis factor-α | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
