1,25-dihydroxyvitamin D3 regulates t helper and b lymphocyte responses substantially in drug-naive primary Sjögren’s syndrome patients’ mononuclear cells
1,25-dihydroxyvitamin D3 regulates t helper and b lymphocyte responses substantially in drug-naive primary Sjögren’s syndrome patients’ mononuclear cells
Background/aim: A correlation between vitamin D deficiency and primary Sjögren’s syndrome (pSS) has already been described. The limited data has been reported regarding the pathological relevance of vitamin D in primary Sjögren’s syndrome. In this study, the peripheral blood mononuclear cells were cocultured with 1,25-dihydroxyvitamin D3 to determine the modulatory effect of vitamin D3 on T and B lymphocyte phenotypes in pSS. Materials and methods: Venous blood samples were collected from 11 patients in the treatment phase and 9 drug-naive pSS patients. Peripheral blood mononuclear cells (PBMC) were isolated and separately cultured in the presence and absence of 1,25- dihydroxyvitamin D3 (10 mM) for 5 days of culture period. Lymphocyte proliferation was analyzed for CFSE signaling via flow cytometry. CD3+CD4+ cells were analyzed for intracellular IFN- and IL-17 expressions. CD19+IgD cells were analyzed for CD38 and CD27 expressions to evaluate naive and total memory B cell subsets. Culture supernatants were analyzed for the IFN-, IL-17, and IL10 cytokine secretions via flow cytometry. Results: 1,25-dihydroxyvitamin D3 significantly decreased Th lymphocyte proliferative responses in drug-naive (p < 0.005) and treated pSS patients (p < 0.05), and B lymphocyte proliferation in drug-naive pSS PBMC cultures (p < 0.01) compared to mononuclear cell cultures alone. 1,25-dihydroxyvitamin D3 significantly decreased IFN- and IL-17 secreting Th cells in both drug naive (p < 0.005 and p < 0.01, respectively) and treated subjects (p < 0.05 and p < 0.05, respectively) by increasing FoxP3 expressing CD4+CD25+ Treg cell frequency. Plasma B lymphocytes significantly reduced in the presence of 1,25-dihydroxyvitamin D3 in drug naive pSS (p < 0.001) and treated patients (p < 0.05) mononuclear cell cultures compared to PBMC cultures alone. Total memory B cell subsets significantly increased with 1,25-dihydroxyvitamin D3 in drug naive pSS when compared with PBMC cultures alone (p < 0.005). IFN- and IL-17 cytokine levels in culture supernatants significantly reduced (p < 0.05 and p < 0.01, respectively) in drug naive pSS patients’ PBMC cultures with 1,25-dihydroxyvitamin D3, and IL-10 levels significantly enhanced in both drug-naive (p < 0.01) and treated pSS patients’ PBMC cultures (p < 0.01) in the presence of 1,25-dihydroxyvitamin D3. Conclusion: In conclusion, 1,25-dihydroxyvitamin D3 regulated immune responses in both treated and drug-naive pSS patients, but have a more pronounced modulatory effect on mononuclear cell responses in drug-naive pSS patients.Key words: Primary Sjögren’s syndrome, 1,25-dihydroxyvitamin D3, immunomodulation
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- 1. Baldini C, Delle Sedie A, Luciano N, Pepe P, Ferro F et al. Vitamin D in "early" primary Sjögren's syndrome: does it play a role in influencing disease phenotypes? Rheumatology International 2014; 34 (8): 1159-1164. doi: 10.1007/s00296-013-2872-3
- 2. Baldini C, Pepe P, Luciano N, Ferro F, Talarico R et al. A clinical prediction rule for lymphoma development in primary Sjogren’s syndrome. The Journal of Rheumatology 2012; 39 (4): 804-808. doi: 10.3899/jrheum.110754
- 3. Maciel G, Crowson CS, Matteson EL, Cornec D. Incidence and mortality of physician-diagnosed primary sjögren syndrome: time trends over a 40-year period in a population-based US cohort. Mayo Clinic Proceedings 2017; 92 (5): 734-743. doi: 10.1016/j.mayocp.2017.01.020
- 4. Kurtul BE, Özer PA, Aydinli MS. The association of vitamin D deficiency with tear break-up time and Schirmer testing in non-Sjögren dry eye. Eye (London) 2015; 29 (8): 1081-1084. doi: 10.1038/eye.2015.96
- 5. Yin K, Agrawal DK. Vitamin D and inflammatory diseases. Journal of Inflammation Research 2014; 7: 69-87. doi: 10.2147/JIR.S63898
- 6. Logan VF, Gray AR, Peddie MC, Harper MJ, Houghton LA. Longterm vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months. British Journal of Nutrition 2013; 109 (6): 1082-1088. doi: 10.1017/S0007114512002851
- 7. Rosen CJ. Clinical practice. Vitamin D insufficiency. The New England Journal of Medicine 2011; 364 (3): 248-254. doi: 10.1056/NEJMcp1009570
- 8. Liu LC, Voors AA, Van Veldhuisen DJ, Van der Veer E, Belonje AM et al. Vitamin D status and outcomes in heart failure patients. European Journal of Heart Failure 2011; 13 (6): 619- 625. doi: 10.1093/eurjhf/hfr032
- 9. Hopkins MH, Owen J, Ahearn T, Fedirko V, Flanders WD et al. Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial. Cancer Prevention Research (Philadelphia) 2011; 4 (10): 1645-1654. doi: 10.1158/1940- 6207.CAPR-11-0105
- 10. Helming L, Böse J, Ehrchen J, Schiebe S, Frahm T et al. 1alpha,25-dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood 2005; 106 (13): 4351-4358. doi: 10.1182/blood-2005-03- 1029
- 11. Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS et al. 1,25- Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. Journal of Immunology 2009; 183 (9): 5458-5467. doi: 10.4049/jimmunol.0803217
- 12. Agmon-Levin N, Kivity S, Tzioufas AG, López Hoyos M, Rozman B et al. Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjögren's syndrome. Journal of Autoimmunity 2012; 39 (3): 234-239. doi: 10.1016/j.jaut.2012.05.018
- 13. Mackay IR, Rose NR. Autoimmunity and lymphoma: tribulations of B cells. Nature Immunology 2001; 2 (9): 793- 795. doi: 10.1038/ni0901-793. PMID: 11526388
- 14. Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. Autoimmunity Reviews 2012; 12 (2): 127-136. doi: 10.1016/j.autrev.2012.07.007
- 15. Ranganathan P, Pramesh CS, Buyse M. Common pitfalls in statistical analysis: clinical versus statistical significance. Perspectives in Clinical Research 2015; 6 (3): 169-170. doi: 10.4103/2229-3485.159943
- 16. Hoe E, Nathanielsz J, Toh ZQ, Spry L, Marimla R et al. Antiinflammatory effects of vitamin D on human immune cells in the context of bacterial infection. Nutrients 2016; 8 (12): 806. doi: 10.3390/nu8120806
- 17. Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflammation Research 2014; 63 (10): 803-819. doi: 10.1007/s00011-014-0755-z
- 18. Fisher SA, Rahimzadeh M, Brierley C, Gration B, Doree C et al. The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: a systematic review. PLoS One 2019; 14 (9): e0222313. doi: 10.1371/journal.pone.0222313
- 19. Prietl B, Pilz S, Wolf M, Tomaschitz A, Obermayer-Pietsch B et al. Vitamin D supplementation and regulatory T cells in apparently healthy subjects: vitamin D treatment for autoimmune diseases? The Israel Medical Association Journal 2010; 12 (3): 136-139.
- 20. Lin R, White JH. The pleiotropic actions of vitamin D. Bioassays 2004; 26 (1): 21-28. doi: 10.1002/bies.10368
- 21. van Etten E, Mathieu C. Immunoregulation by 1,25- dihydroxyvitamin D3: basic concepts. The Journal of Steroid Biochemistry and Molecular Biology 2005; 97 (1-2): 93-101. doi: 10.1016/j.jsbmb.2005.06.002
- 22. Verstappen GM, Corneth OBJ, Bootsma H, Kroese FGM. Th17 cells in primary Sjögren's syndrome: pathogenicity and plasticity. Journal of Autoimmunity 2018; 87: 16-25. doi: 10.1016/j.jaut.2017.11.003
- 23. Tang J, Zhou R, Luger D, Zhu W, Silver PB et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. Journal of Immunology 2009; 182 (8): 4624-4632. doi: 10.4049/jimmunol.0801543
- 24. Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. Journal of Biological Chemistry 2010; 285 (50): 38751-38755. doi: 10.1074/jbc.C110.185777
- 25. Colin EM, Asmawidjaja PS, Van Hamburg JP, Mus AM, Van Driel M et al. 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis. Arthritis & Rheumatology 2010; 62 (1): 132-142. doi: 10.1002/art.25043
- 26. Verstappen GM, Kroese FGM, Bootsma H. T cells in primary Sjögren's syndrome: targets for early intervention. Rheumatology (Oxford) 2019; kez004. doi: 10.1093/rheumatology/kez004
- 27. Ríos-Ríos WJ, Sosa-Luis SA, Torres-Aguilar H. T Cells subsets in the immunopathology and treatment of Sjogren's syndrome. Biomolecules 2020; 10 (11): 1539. doi: 10.3390/biom10111539
- 28. Sheikh V, Kasapoglu P, Zamani A, Basiri Z, Tahamoli-Roudsari A et al. Vitamin D3 inhibits the proliferation of T helper cells, downregulate CD4+ T cell cytokines and upregulate inhibitory markers. Human Immunology 2018; 79 (6): 439-445. doi: 10.1016/j.humimm.2018.03.001
- 29. Ragab D, Soliman D, Samaha D, Yassin A. Vitamin D status and its modulatory effect on interferon gamma and interleukin-10 production by peripheral blood mononuclear cells in culture. Cytokine 2016; 85: 5-10. doi: 10.1016/j.cyto.2016.05.024
- 30. Švajger U, Rožman PJ. Synergistic effects of interferon-γ and vitamin D3 signaling in Induction of ILT-3 high PDL-1 high tolerogenic dendritic cells. Frontiers in Immunology 2019; 10: 2627. doi: 10.3389/fimmu.2019.02627
- 31. Ibrahem HM. B cell dysregulation in primary Sjögren's syndrome: a review. Japanese Dental Science Review 2019; 55 (1): 139-144. doi: 10.1016/j.jdsr.2019.09.006
- 32. Ambrus JL, Suresh L, Peck A. Multiple roles for B-lymphocytes in Sjogren's syndrome. Journal of Clinical Medicine 2016; 5 (10): 87. doi: 10.3390/jcm5100087
- 33. Rolf L, Muris AH, Hupperts R, Damoiseaux J. Illuminating vitamin D effects on B cells-the multiple sclerosis perspective. Immunology 2016; 147 (3): 275-284. doi: 10.1111/imm.12572
- 34. Rolf L, Muris AH, Hupperts R, Damoiseaux J. Vitamin D effects on B cell function in autoimmunity. Annals of the New York Academy of Sciences 2014; 1317: 84-91. doi: 10.1111/nyas.12440
- 35. Rausch-Fan X, Leutmezer F, Willheim M, Spittler A, Bohle B et al. Regulation of cytokine production in human peripheral blood mononuclear cells and allergen-specific th cell clones by 1alpha,25-dihydroxyvitamin D3. International Archives of Allergy and Immunology 2002; 128 (1): 33-41. doi: 10.1159/000058001
- 36. Müller K, Haahr PM, Diamant M, Rieneck K, Kharazmi A et al. 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level. Cytokine 1992; 4 (6): 506-512. doi: 10.1016/1043- 4666(92)90012-g