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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 3/2013

Open Access 01-06-2013 | Research article

Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA)

Authors: Wayel H Abdulahad, Nikola Lepse, Coen A Stegeman, Minke G Huitema, Berber Doornbos-van der Meer, Henko Tadema, Abraham Rutgers, Pieter C Limburg, Cees GM Kallenberg, Peter Heeringa

Published in: Arthritis Research & Therapy | Issue 3/2013

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Abstract

Introduction

The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA).

Methods

Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (TFH), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed.

Results

Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs.

Conclusion

The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA.
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Literature
1.
Fauci AS, Haynes BF, Katz P, Wolff SM: Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983, 98: 76-85. 10.7326/0003-4819-98-1-76.CrossRefPubMed
2.
van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, van der GM, van der Hem GK, The TH: Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985, 1: 425-429.CrossRefPubMed
3.
Niles JL, McCluskey RT, Ahmad MF, Arnaout MA: Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood. 1989, 74: 1888-1893.PubMed
4.
Brouwer E, Tervaert JW, Horst G, Huitema MG, van der GM, Limburg PC, Kallenberg CG: Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener's granulomatosis and clinically related disorders. Clin Exp Immunol. 1991, 83: 379-386.PubMedCentralCrossRefPubMed
5.
Komocsi A, Lamprecht P, Csernok E, Mueller A, Holl-Ulrich K, Seitzer U, Moosig F, Schnabel A, Gross WL: Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis. Am J Pathol. 2002, 160: 1717-1724. 10.1016/S0002-9440(10)61118-2.PubMedCentralCrossRefPubMed
6.
Lamprecht P, Moosig F, Csernok E, Seitzer U, Schnabel A, Mueller A, Gross WL: CD28 negative T cells are enriched in granulomatous lesions of the respiratory tract in Wegener's granulomatosis. Thorax. 2001, 56: 751-757. 10.1136/thorax.56.10.751.PubMedCentralCrossRefPubMed
7.
Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der MB, Limburg PC, Kallenberg CG: Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission. Arthritis Rheum. 2007, 56: 2080-2091. 10.1002/art.22692.CrossRefPubMed
8.
Morgan MD, Day CJ, Piper KP, Khan N, Harper L, Moss PA, Savage CO: Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells. Immunology. 2010, 130: 64-73. 10.1111/j.1365-2567.2009.03213.x.PubMedCentralCrossRefPubMed
9.
Abdulahad WH, van der Geld YM, Stegeman CA, Kallenberg CG: Persistent expansion of CD4+ effector memory T cells in Wegener's granulomatosis. Kidney Int. 2006, 70: 938-947. 10.1038/sj.ki.5001670.CrossRefPubMed
10.
Abdulahad WH, Stegeman CA, Limburg PC, Kallenberg CG: Skewed distribution of Th17 lymphocytes in patients with Wegener's granulomatosis in remission. Arthritis Rheum. 2008, 58: 2196-2205. 10.1002/art.23557.CrossRefPubMed
11.
Nogueira E, Hamour S, Sawant D, Henderson S, Mansfield N, Chavele KM, Pusey CD, Salama AD: Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol Dial Transplant. 2010, 25: 2209-2217. 10.1093/ndt/gfp783.CrossRefPubMed
12.
Ettinger R, Sims GP, Robbins R, Withers D, Fischer RT, Grammer AC, Kuchen S, Lipsky PE: IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells. J Immunol. 2007, 178: 2872-2882.CrossRefPubMed
13.
14.
Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, Senices M, Wu PW, Sibley B, Leathurby Y, Brown TP, Nickerson-Nutter C, Keith JC, Collins M: Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 2007, 56: 1152-1163. 10.1002/art.22452.CrossRefPubMed
15.
Herber D, Brown TP, Liang S, Young DA, Collins M, Dunussi-Joannopoulos K: IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J Immunol. 2007, 178: 3822-3830.CrossRefPubMed
16.
Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F, Stolfi C, Cardolini I, Dottori M, Boirivant M, Pallone F, Macdonald TT, Monteleone G: Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008, 134: 1038-1048. 10.1053/j.gastro.2008.01.041.CrossRefPubMed
17.
Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ: IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci USA. 2008, 105: 14028-14033. 10.1073/pnas.0804358105.PubMedCentralCrossRefPubMed
18.
Sawalha AH, Kaufman KM, Kelly JA, Adler AJ, Aberle T, Kilpatrick J, Wakeland EK, Li QZ, Wandstrat AE, Karp DR, James JA, Merrill JT, Lipsky P, Harley JB: Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis. 2008, 67: 458-461.CrossRefPubMed
19.
Festen EA, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, Lefebvre C, Brant SR, Cho JH, Silverberg MS, Taylor KD, de Jong DJ, Stokkers PC, Mcgovern D, Palmieri O, Achkar JP, Xavier RJ, Daly MJ, Duerr RH, Wijmenga C, Weersma RK, Rioux JD: Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut. 2009, 58: 799-804. 10.1136/gut.2008.166918.PubMedCentralCrossRefPubMed
20.
Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, Wise C, Miner A, Malloy MJ, Pullinger CR, Kane JP, Saccone S, Worthington J, Bruce I, Kwok PY, Menter A, Krueger J, Barton A, Saccone NL, Bowcock AM: A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008, 4: e1000041-10.1371/journal.pgen.1000041.PubMedCentralCrossRefPubMed
21.
22.
Dolff S, Abdulahad WH, Westra J, Doornbos-van der MB, Limburg PC, Kallenberg CG, Bijl M: Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther. 2011, 13: R157-10.1186/ar3474.PubMedCentralCrossRefPubMed
23.
Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG, Manku H, Vyse TJ, Roncador G, Huttley GA, Goodnow CC, Vinuesa CG, Cook MC: Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010, 62: 234-244. 10.1002/art.25032.CrossRefPubMed
24.
Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, Wu W, Chen J, Tong J, Yang M, Jiao Z, Xu H, Lu L, Wang S: Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol. 2012, 2012: 827480-PubMedCentralPubMed
25.
Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG, Mccluskey RT, Sinico RA, Rees AJ, Van Es LA, Waldherr R, Wiik A: Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994, 37: 187-192. 10.1002/art.1780370206.CrossRefPubMed
26.
Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, Calabrese LH, Fries JF, Lie JT, Lightfoot RW, Masi AT, McShane DJ, Mills JA, Stevens MB, Wallace SL, Zvaifler NJ: The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990, 33: 1101-1107.CrossRefPubMed
27.
Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D: Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994, 87: 671-678.PubMed
28.
Tervaert JW, Mulder L, Stegeman C, Elema J, Huitema M, The H, Kallenberg C: Occurrence of autoantibodies to human leucocyte elastase in Wegener's granulomatosis and other inflammatory disorders. Ann Rheum Dis. 1993, 52: 115-120. 10.1136/ard.52.2.115.PubMedCentralCrossRefPubMed
29.
Tervaert JW, Goldschmeding R, Elema JD, van der GM, Huitema MG, van der Hem GK, The TH, von dem Borne AE, Kallenberg CG: Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int. 1990, 37: 799-806. 10.1038/ki.1990.48.CrossRefPubMed
30.
Savige J, Dimech W, Fritzler M, Goeken J, Hagen EC, Jennette JC, McEvoy R, Pusey C, Pollock W, Trevisin M, Wiik A, Wong R: Addendum to the International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies. Quality control guidelines, comments, and recommendations for testing in other autoimmune diseases. Am J Clin Pathol. 2003, 120: 312-318. 10.1309/WAEPADW0K4LPUHFN.CrossRefPubMed
31.
Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallenberg CG, Heeringa P: Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology (Oxford). 2011, 50: 689-696. 10.1093/rheumatology/keq375.CrossRef
32.
Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK: IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007, 448: 484-487. 10.1038/nature05970.PubMedCentralCrossRefPubMed
33.
Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C: Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007, 448: 480-483. 10.1038/nature05969.CrossRefPubMed
34.
Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma CS, Li QJ, Parish CR, Mackay CR, Vinuesa CG: The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009, 31: 457-468. 10.1016/j.immuni.2009.07.002.CrossRefPubMed
35.
Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C: Bcl6 mediates the development of T follicular helper cells. Science. 2009, 325: 1001-1005. 10.1126/science.1176676.PubMedCentralCrossRefPubMed
36.
Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C: Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011, 17: 983-988. 10.1038/nm.2426.PubMedCentralCrossRefPubMed
37.
Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KG, Vinuesa CG: Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011, 17: 975-982. 10.1038/nm.2425.PubMedCentralCrossRefPubMed
38.
Pene J, Gauchat JF, Lecart S, Drouet E, Guglielmi P, Boulay V, Delwail A, Foster D, Lecron JC, Yssel H: Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J Immunol. 2004, 172: 5154-5157.CrossRefPubMed
39.
Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, Leonard WJ, Lipsky PE: IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol. 2005, 175: 7867-7879.CrossRefPubMed
40.
Kuchen S, Robbins R, Sims GP, Sheng C, Phillips TM, Lipsky PE, Ettinger R: Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration. J Immunol. 2007, 179: 5886-5896.CrossRefPubMed
41.
42.
Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL, Le TV, Lorenz RG, Xu H, Kolls JK, Carter RH, Chaplin DD, Williams RW, Mountz JD: Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol. 2008, 9: 166-175. 10.1038/ni1552.CrossRefPubMed
43.
Chen Q, Yang W, Gupta S, Biswas P, Smith P, Bhagat G, Pernis AB: IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity. 2008, 29: 899-911. 10.1016/j.immuni.2008.10.011.PubMedCentralCrossRefPubMed
44.
Caruso R, Fina D, Peluso I, Stolfi C, Fantini MC, Gioia V, Caprioli F, Del Vecchio BG, Paoluzi OA, Macdonald TT, Pallone F, Monteleone G: A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. Gastroenterology. 2007, 132: 166-175. 10.1053/j.gastro.2006.09.053.CrossRefPubMed
45.
Liu Y, Yang B, Ma J, Wang H, Huang F, Zhang J, Chen H, Wu C: Interleukin-21 induces the differentiation of human Tc22 cells via phosphorylation of signal transducers and activators of transcription. Immunology. 2011, 132: 540-548. 10.1111/j.1365-2567.2010.03399.x.PubMedCentralCrossRefPubMed
46.
Ebert EC: Interleukin 21 up-regulates perforin-mediated cytotoxic activity of human intra-epithelial lymphocytes. Immunology. 2009, 127: 206-215. 10.1111/j.1365-2567.2008.02941.x.PubMedCentralCrossRefPubMed
47.
Liu Z, Yang L, Cui Y, Wang X, Guo C, Huang Z, Kan Q, Liu Z, Liu Y: Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm Bowel Dis. 2009, 15: 1133-1144. 10.1002/ibd.20923.CrossRefPubMed
48.
Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, Morse HC, Lipsky PE, Leonard WJ: Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol. 2004, 173: 5361-5371.CrossRefPubMed
49.
Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, Hogan JJ, Verma NK, Smyth MJ, Rigby RJ, Vinuesa CG: IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010, 207: 353-363. 10.1084/jem.20091738.PubMedCentralCrossRefPubMed
50.
Slot MC, Tervaert JW, Boomsma MM, Stegeman CA: Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis. Arthritis Rheum. 2004, 51: 269-273. 10.1002/art.20234.CrossRefPubMed
51.
Pierrot-Deseilligny DC, Pouchot J, Pagnoux C, Coste J, Guillevin L: Predictors at diagnosis of a first Wegener's granulomatosis relapse after obtaining complete remission. Rheumatology (Oxford). 2010, 49: 2181-2190. 10.1093/rheumatology/keq244.CrossRef
52.
Abdulahad WH, Kallenberg CG, Limburg PC, Stegeman CA: Urinary CD4+ effector memory T cells reflect renal disease activity in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009, 60: 2830-2838. 10.1002/art.24747.CrossRefPubMed
Metadata
Title
Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA)
Authors
Wayel H Abdulahad
Nikola Lepse
Coen A Stegeman
Minke G Huitema
Berber Doornbos-van der Meer
Henko Tadema
Abraham Rutgers
Pieter C Limburg
Cees GM Kallenberg
Peter Heeringa
Publication date
01-06-2013
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 3/2013
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar4247

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