Increased gene expression of CCR6 and RORγt in peripheral blood cells of rheumatoid arthritis patients and their correlation with anti-cyclic citrullinated peptide and disease activity.
CCR6
DAS-28
RORγt
anti-CCP
rheumatoid arthritis
Journal
Immunity, inflammation and disease
ISSN: 2050-4527
Titre abrégé: Immun Inflamm Dis
Pays: England
ID NLM: 101635460
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
revised:
13
11
2023
received:
22
06
2023
accepted:
18
11
2023
medline:
29
12
2023
pubmed:
29
12
2023
entrez:
29
12
2023
Statut:
ppublish
Résumé
The significance of T helper 17 (Th17) cells in the pathogenesis of rheumatoid arthritis (RA) has recently been demonstrated in many studies. Retinoic acid receptor-related orphan receptor γt (RORγt) is a transcription factor that is specifically involved in the generation of Th17 cells. Besides, the chemokine receptor CCR6, the receptor for CCL20, is characteristically expressed by these cells. Considering the pivotal roles of Th17 cells in RA pathogenesis, in this study, we assessed the gene expression of CCR6 and RORγt in the peripheral blood leukocytes of new case RA patients. Also, we evaluated their association with anticyclic citrullinated peptide (anti-CCP) antibodies and disease activity. Forty-five new case RA patients and 45 healthy persons have been recruited in this investigation. The gene expression of CCR6 and RORγt was evaluated by quantitative real-time PCR (qRT-PCR), and anti-CCP antibodies plasma levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. Disease activity was measured according to the disease activity score-28 (DAS-28) formula. The gene expression of CCR6 and RORγt increased remarkably in new case RA patients compared to healthy controls (p < .05 and p < .01, respectively). Moreover, there was a positive correlation between RORγt gene expression and parameters, including gene expression of CCR6 (p = .001, r = .461), plasma levels of CCL20 (p = .0009, r = .477), ESR (p = .004, r = .419), DAS-28 (p = .006, r = .402), anti-CCP (p = .019, r = .346), and RF (p = .001, r = .451). Also, CCR6 gene expression was positively associated with the DAS-28 (p = .037, r = .310), plasma levels of anti-CCP (p = .037, r = .312), and ESR (p = .029, r = .327). Increased gene expression of CCR6 and RORγt in peripheral blood leukocytes of new case RA patients may contribute to the exacerbation and pathogenesis of RA.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1112Subventions
Organisme : Deputy for Research and Technology, Kermanshah University of Medical Sciences
ID : 3010723
Informations de copyright
© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.
Références
Müller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1(2):102-110. doi:10.1038/ncprheum0047
Buch MH, Eyre S, McGonagle D. Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis. Nat Rev Rheumatol. 2021;17(1):17-33. doi:10.1038/s41584-020-00541-7
Newton J, Harney S, Wordsworth B, Brown M. A review of the MHC genetics of rheumatoid arthritis. Genes Immun. 2004;5(3):151-157. doi:10.1038/sj.gene.6364045
McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-442. doi:10.1038/nri2094
Szekanecz Z, Kim J, Koch AE. Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol. 2003;15(1):15-21. doi:10.1016/s1044-5323(02)00124-0
van Boekel MA, Vossenaar ER, van den Hoogen FH, van Venrooij WJ. Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res. 2002;4(2):87-93. doi:10.1186/ar395
Szekanecz Z, Koch AE. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat Rev Rheumatol. 2016;12(1):5-13. doi:10.1038/nrrheum.2015.157
Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J. 2018;285(16):2944-2971. doi:10.1111/febs.14466
Elemam NM, Hannawi S, Maghazachi AA. Role of chemokines and chemokine receptors in rheumatoid arthritis. Immunotargets Ther. 2020;9:43-56. doi:10.2147/itt.s243636
Pournazari M, Feizollahi P, Roghani SA, et al. Increased plasma levels of CCL20 in peripheral blood of rheumatoid arthritis patients and its association with clinical and laboratory parameters. Clin Rheumatol. 2022;41(1):265-270. doi:10.1007/s10067-021-05899-x
Paulissen SMJ, van Hamburg JP, Dankers W, Lubberts E. The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis. Cytokine. 2015;74(1):43-53. doi:10.1016/j.cyto.2015.02.002
Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485-517. doi:10.1146/annurev.immunol.021908.132710
Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev. 2008;223:87-113. doi:10.1111/j.1600-065X.2008.00628.x
Lee AY, Körner H. CCR6 and CCL20: emerging players in the pathogenesis of rheumatoid arthritis. Immunol Cell Biol. 2014;92(4):354-358. doi:10.1038/icb.2013.97
Kochi Y, Okada Y, Suzuki A, et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat Genet. 2010;42(6):515-519. doi:10.1038/ng.583
Tan J, Liu H, Huang M, et al. Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation. Cell Death Dis. 2020;11(8):697. doi:10.1038/s41419-020-02891-2
Chi X, Jin W, Zhao X, et al. RORγt expression in mature T(H)17 cells safeguards their lineage specification by inhibiting conversion to T(H)2 cells. Sci Adv. 2022;8(34):eabn7774. doi:10.1126/sciadv.abn7774
Bukhari M, Thomson W, Naseem H, et al. The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of radiologic damage in inflammatory polyarthritis: results from the Norfolk Arthritis Register. Arthritis Rheum. 2007;56(9):2929-2935. doi:10.1002/art.22868
Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology. 2012;51(suppl 6):vi5-vi9. doi:10.1093/rheumatology/kes279
Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. doi:10.1093/nar/29.9.e45
Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N. Comparison of Disease Activity Score (DAS)28-erythrocyte sedimentation rate and DAS28-C-reactive protein threshold values. Ann Rheum Dis. 2007;66(3):407-409. doi:10.1136/ard.2006.054205
van Hamburg JP, Asmawidjaja PS, Davelaar N, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 2011;63(1):73-83. doi:10.1002/art.30093
Jimeno R, Gomariz RP, Garín M, et al. The pathogenic Th profile of human activated memory Th cells in early rheumatoid arthritis can be modulated by VIP. J Mol Med. 2015;93(4):457-467. doi:10.1007/s00109-014-1232-4
Takatori H, Kanno Y, Chen Z, O'Shea JJ. New complexities in helper T cell fate determination and the implications for autoimmune diseases. Mod Rheumatol. 2008;18(6):533-541. doi:10.1007/s10165-008-0099-z
Arroyo-Villa I, Bautista-Caro MB, Balsa A, et al. Frequency of Th17 CD4+ T cells in early rheumatoid arthritis: a marker of anti-CCP seropositivity. PLoS One. 2012;7(8):e42189. doi:10.1371/journal.pone.0042189
Murphy PM, Baggiolini M, Charo IF, et al. International union of pharmacology. XXII. nomenclature for chemokine receptors. Pharmacol Rev. 2000;52(1):145-176.
Wasilko DJ, Johnson ZL, Ammirati M, et al. Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20. Nat Commun. 2020;11(1):3031. doi:10.1038/s41467-020-16820-6
Onuora S. Targeting the CCR6-CCL20 axis improves experimental PsA. Nat Rev Rheumatol. 2021;17(8):441. doi:10.1038/s41584-021-00663-6
Cheng P, Zhang Y, Huang H, et al. Association between CCR6 and rheumatoid arthritis: a meta-analysis. Int J Clin Exp Med. 2015;8(4):5388-5396.
Hirota K, Yoshitomi H, Hashimoto M, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204(12):2803-2812. doi:10.1084/jem.20071397
Razawy W, Asmawidjaja PS, Mus AM, et al. CD4(+) CCR6(+) T cells, but not γδ T cells, are important for the IL-23R-dependent progression of antigen-induced inflammatory arthritis in mice. Eur J Immunol. 2020;50(2):245-255. doi:10.1002/eji.201948112
Takeuchi T, Miyasaka N, Inui T, et al. High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study. Arthritis Res Ther. 2017;19(1):194. doi:10.1186/s13075-017-1401-2
Kaneko S, Kondo Y, Yokosawa M, et al. The RORγt-CCR6-CCL20 axis augments Th17 cells invasion into the synovia of rheumatoid arthritis patients. Mod Rheumatol. 2018;28(5):814-825. doi:10.1080/14397595.2017.1416923
Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev. 2021;20(7):102846. doi:10.1016/j.autrev.2021.102846
Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83(6):841-850. doi:10.1016/0092-8674(95)90200-7
Huh JR, Littman DR. Small molecule inhibitors of RORγt: targeting Th17 cells and other applications. Eur J Immunol. 2012;42(9):2232-2237. doi:10.1002/eji.201242740
Kondo Y, Yao Z, Tahara M, et al. Involvement of RORγt-overexpressing T cells in the development of autoimmune arthritis in mice. Arthritis Res Ther. 2015;17(1):105. doi:10.1186/s13075-015-0606-5