he role of TNF-α in rheumatoid arthritis: a focus on regulatory T cells
The autoimmune disorder rheumatoid arthritis (RA) causes chronic inflammation and destruction of joints. T-cells are a predominant component of the synovial environment in RA, however the functional role of these cells is not yet fully understood. This is in part due to the fact that the balance and importance of the relation of Tregs with T-effector cells in RA is still under investigation.The current treatment regimen for this debilitating disease focuses on controlling symptoms and preventing further joint damage through the use of therapies which affect different areas of the immune system at the synovium. One of the main therapies involves Tumour Necrosis Factor alpha (TNF-α) inhibitors. In the RA immune-environment, TNF-α has been shown to have an influential and extensive but as yet poorly understood effect on Treg function in vivo, and undoubtably an important role in the treatment of RA. Interestingly, the high levels of TNF-α found in RA patients appear to interfere with the mechanisms controlling the suppressive function of Tregs. This review focuses on the conflicting literature available regarding the role played by Tregs in RA and the impact of TNF-α and anti-TNF-α therapies on Tregs in this scenario.
[1] Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham III CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MC, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. Rheumatoid arthritis class ification criteria: An American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569-2581.
[2] McInnes IB, Schett G. The Pathogenesis of Rheumatoid Ar thritis. N Engl J Med 2011; 365: 2205-2219.
[3] Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid ar thritis. Am J Pathol 1998; 152: 943-951.
[4] Cimmino MA, Zampogna A, Murroni S, Baruffi S, Alessio G, Maio T, Mela GS. Methodology of an epidemiologic preva lence study in rheumatology: the Chiavari study. Reumatismo 2002; 54: 40-47.
[5] Aho K, Kaipaiainen-Seppanen O, Helovaara M, Klaukka T. Epidemiology of rheumatoid arthritis in Finland. Semin Ar thritis Rheum 1998; 27: 325-334.
[6] Mallia C. Treating Rheumatoid Arthritis Yesterday and Today. MMJ 2004; 16: 18-21.
[7] Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Practice Res Clin Rheumatol 2010; 24: 733-745.
[8] Carbonell J, Cobo T, Balsa A, Descalzo MA, Carmona L. The incidence of rheumatoid arthritis in Spain: results from a na tionwide primary care registry. Rheumatology 2008; 47: 1088-1092.
[9] Pedersen JK, Kjaer NK, Svendsen AJ, Horslev-Petersen K. In cidence of rheumatoid arthritis from 1995 to 2001: impact of ascertainment from multiple sources. Rheumatol Int 2009; 29: 411-415.
[10] Kumar P and Banik S. Pharmacotherapy Options in Rheuma toid Arthritis. Clin Med Insights Arthritis Musculoskelet Dis ord 2013; 6: 35-43.
[11] Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chok kalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT. A missense single-nucleotide poly morphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75:330-337.
[12] Plenge RM, Cotsapas C, Davies L, Price AL, De Bakker PI, Maller J, Pe'er I, Burtt NP, Blumenstiel B, DeFelice M, Parkin M. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007; 39: 1477-1482.
[13] Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Beh rens TW, De Bakker PI, Le JM, Lee HS, Batliwalla F, Li W. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357: 977-986.
[14] Szekanecz Z, Pakozdi A, Szentpetery A, Besenyei T, Koch AE. Chemokines and angiogenesis in rheumatoid arthritis. Front Biosci (Elite Ed) 2009; 1: 44-51.
[15] Liew FY, McInnes IB. The role of innate mediators in inflam matory response. Mol Immunol 2002; 38: 887-890.
[16] Cascão R, Rosário HS, Souto-Carneiro MM, Fonseca JE. Neutrophils in rheumatoid arthritis: more than simple final ef fectors. Autoimmun Rev 2010; 9: 531-535.
[17] Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell 1996; 85: 307-310.
[18] Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Ser geeva M, Saake M, Garcia M, Kollias G, Straub RH. Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci USA 2011; 108: 3731-3736.
[19] Perez C, Albert I, DeFay K, Zachariades N, Gooding L, Mi chael K. A non secretable cell surface mutant of tumor necro-sis factor (TNF) kills by cell-to cell contact. Cell 1990; 63: 251-258.
[20] Amiot F, Fitting C, Tracey KJ, Cavaillon JM, Dautry F. Lipo polysaccharide-induced cytokine cascade and lethality in LT alpha/TNF alpha-deficient mice. Mol Med 1997; 3: 864-875.
[21] Firestein GS. Evolving concepts of rheumatoid arthritis. Na ture 2003; 423: 356-361.
[22] Isler P, Vey E, Zhang JH, Dayer JM. Cell surface glycopro teins expressed on activated human T cells induce production of interleukin-1 beta by monocytic cells: a possible role of CD69. Eur Cytokine Netw 1993; 4: 15-23.
[23] Burbano C, Rojas M, Vásquez G, Castaño D (2015). Micro particles That Form Immune Complexes as Modulatory Structures in Autoimmune Responses. Mediators Inflamm 2015; Article ID 26759.
[24] Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T. Activated T cells regulate bone loss and joint destruction in adjuvant ar thritis through osteoprotegerin ligand. Nature 1999; 402: 304- 309.
[25] Chabaud M, Fossiez F, Taupin JL, Miossec P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regu lation by Th2 cytokines. J Immunol 1998; 161: 409-414.
[26] Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009; 361: 888-898.
[27] Zheng SG. Regulatory T cells vs Th17: differentiation of Th17 versus Treg, are the mutually exclusive? Am J Clin Exp Im munol 2013; 2: 94-106.
[28] Behrens F, Himsel A, Rehart S, Stanczyk J, Beutel B, Zim mermann SY, Koehl U, Möller B, Gay S, Kaltwasser JP, Pfeilschifter JM. Imbalance in distribution of functional au tologous regulatory T cells in rheumatoid arthritis. Ann Rheum Dis 2007; 66: 1151-1156.
[29] van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 2004; 50: 2775-2785.
[30] Liu MF, Wang CR, Fung LL, Lin LH, Tsai CN. The presence of cytokine-suppressive CD4+ CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol 2005; 62: 312-317.
[31] Möttönen M, Heikkinen J, Mustonen L, Isomäki P, Luukkainen R, Lassila O. CD4+ CD25+ T cells with the phe notypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid ar thritis. Clin Exp Immunol 2005; 140: 360-367.
[32] Cao D, Malmström V, Baecher‐Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of reg ulatory CD25brightCD4+T cells from the target organ of pa tients with rheumatoid arthritis. Eur J Immunol 2003; 33: 215-223.
[33] de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, de Jager W, Pugayung G, Giannoni F, Rijkers G, Al bani S. CD4+CD25(bright) regulatory T cells actively regu- late inflammation in the joints of patients with the remittingform of juvenile idiopathic arthritis. J Immunol 2004; 172: 6435-6443.
[34] Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Is enberg DA, Mauri C. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF alpha therapy. J Exp Med 2004; 200: 277-285.
[35] Lawson CA, Brown AK, Bejarano V, Douglas SH, Burgoyne CH, Greenstein AS, Boylston AW, Emery P, Ponchel F, Isaacs JD. Early rheumatoid arthritis is associated with a deficit in the CD4 + CD25 high regulatory T cell population in peripheral blood. Rheumatology 2006; 45: 1210-1217.
[36] Xiao H, Wang S, Miao R, Kan W. TRAIL is associated with impaired regulation of CD4 + CD25- T cells by regulatory T cells in patients with rheumatoid arthritis. J Clin Immunol 2011; 31: 1112-1119.
[37] Walter GJ, Fleskens V, Frederiksen KS, Rajasekhar M, Menon B, Gerwien JG, Evans HG, Taams LS. Phenotypic, Functional, and Gene Expression Profiling of Peripheral CD45RA+ and CD45RO+ CD4+ CD25+ CD127low Treg Cells in Patients with Chronic Rheumatoid Arthritis. Arthritis Rheumatol 2016; 68: 103-116.
[38] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133: 775-787.
[39] Farrugia M, Baron B. Role of Regulatory T-cells in Oral Tol erance and Immunotherapy. Biochem Physiol 2016; 5: 2.
[40] van Amelsfort JM, van Roon JA, Noordegraaf M, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. Proinflammatory media tor-induced reversal of CD4+, CD25+ regulatory T cell-med iated suppression in rheumatoid arthritis. Arthritis Rheum 2007; 56: 732-742.
[41] Tetta C, Camussi G, Modena V, Di Vittorio C, Baglioni C. Tumour necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann Rheum Dis 1990; 49: 665-667.
[42] Nadkarni S, Mauri C, Ehrenstein MR. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 2007; 204: 33-39.
[43] Biton J, Semerano L, Delavallée L, Lemeiter D, Laborie M, Grouard-Vogel G, Boissier MC, Bessis N. Interplay between TNF and regulatory T cells in a TNF-driven murine model of arthritis. J Immunol 2011; 186: 3899-3910.
[44] Chandrasekharan UM, Siemionow M, Unsal M, Yang L, Pop tic E, Bohn J, Ozer K, Zhou Z, Howe PH, Penn M, DiCorleto PE. Tumor necrosis factor α (TNF-α) receptor-II is required for TNF-α-induced leukocyte-endothelial interaction in vivo. Blood 2007; 109: 1938-1944.
[45] Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4 + CD25hi T-regulatory cells. Blood 2006; 108: 253-261.
[46] Nagar M, Jacob-Hirsch J, Vernitsky H, Berkun Y, Ben-Horin S, Amariglio N, Bank I, Kloog Y, Rechavi G, Goldstein I. TNF activates a NFkappaB-regulated cellular program in human CD45RA-regulatory T cells that modulates their suppressive function. J Immunol 2010; 184: 3570-3581.
[47] Zanin-Zhorov A, Ding Y, Kumari S, Attur M, Hippen KL, Brown M, Blazar BR, Abramson SB, Lafaille JJ, Dustin ML. Protein kinase C-theta mediates negative feedback on regula tory T cell function. Science 2010; 328: 372-376.
[48] Zanin-Zhorov A, Lin J, Scher J, Kumari S, Blair D, Hippen KL, Blazar BR, Abramson SB, Lafaille JJ, Dustin ML. Scaf fold protein Disc large homolog 1 is required for T-cell recep tor-induced activation of regulatory T-cell function. Proc Natl Acad Sci U S A 2012; 109: 1625-1630.
[49] Cooles FAH, Isaacs JD and Anderson AE. Treg Cells in Rheumatoid Arthritis: An Update. Curr Rheumatol Rep 2013; 15:1-9.
[50] Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, Chin YE. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheu matoid arthritis. Nat Med 2013; 19, 322-328.
[51] Chen X, Bäumel M, Männel DN, Howard OZ, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expan sion and function of mouse CD4+CD25+ T regulatory cells. J Immunol 2007; 179: 154-161.
[52] Zaragoza B, Chen X, Oppenheim JJ, Baeyens A, Gregoire S, Chader D, Gorochov G, Miyara M, Salomon BL. Suppressive activity of human regulatory T cells is maintained in the pres ence of TNF. Nat Med 2016; 22: 16-17.
[53] van Mierlo GJ, Scherer HU, Hameetman M, Morgan ME, Flierman R, Huizinga TW, Toes RE. Cutting edge: TNFR- shedding by CD4+CD25+ regulatory T cells inhibits the in duction of inflammatory mediators. J Immunol 2008; 180: 2747-2751.
[54] Black, R. A., C. T. Rauch, C. J. Kozlosky, J. J. Peschon, J. L. Slack, M. F. Wolfson, B. J. Castner, K. L. Stocking, P. Reddy, S. Srinivasan, Nelson N. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997; 385: 729-733.
[55] MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal 2002; 14: 477-492
[56] Huang Z, Yang B, Shi Y, Cai B, Li Y, Feng W, Fu Y, Luo L, Wang L. Anti-TNF-α therapy improves Treg and suppresses Teff in patients with rheumatoid arthritis. Cell Immunol 2012; 279: 25-29.
[57] Nguyen DX, Ehrenstein MR. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF- TNF-RII binding in rheumatoid arthritis. J Exp Med 2016; 213: 1241-1253.
[58] Kodama S, Davis M, Faustman DL. The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanis tically based hypothesis. Cell Mol Life Sci 2005; 62: 1850- 1862.
[59] Bloom BJ. Development of diabetes mellitus during etanercept therapy in a child with systemic-onset juvenile rheumatoid ar thritis. Arthritis Rheum 2000; 43: 2606-2608.
[60] Tack CJ, Kleijwegt FS, Van Riel PL, Roep BO. Development of type 1 diabetes in a patient treated with anti-TNF-alpha therapy for active rheumatoid arthritis. Diabetologia 2009; 52: 1442-1444.