Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 2/2014

Open Access 01-04-2014 | Research article

T-helper 17 cell cytokines and interferon type I: partners in crime in systemic lupus erythematosus?

Authors: Zana Brkic, Odilia BJ Corneth, Cornelia G van Helden-Meeuwsen, Radboud JEM Dolhain, Naomi I Maria, Sandra MJ Paulissen, Nadine Davelaar, Jan Piet van Hamburg, Paul L van Daele, Virgil A Dalm, P Martin van Hagen, Johanna MW Hazes, Marjan A Versnel, Erik Lubberts

Published in: Arthritis Research & Therapy | Issue 2/2014

Login to get access

Abstract

Introduction

A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T-helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21, and IL-22, has been implicated in SLE. As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6+ memory T-helper cells producing IL-17A, IL-17F, IL-21, and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature.

Methods

In total, 25 SLE patients and 15 healthy controls (HCs) were included. SLE patients were divided into IFN type I signature-positive (IFN+) (n = 16) and negative (IFN-) (n = 9) patients, as assessed by mRNA expression of IFN-inducible genes (IFIGs) in monocytes. Expression of IL-17A, IL-17F, IL-21, and IL-22 by CD4+CD45RO+CCR6+ T cells (CCR6+ cells) was measured with flow cytometry and compared between IFN+, IFN- patients and HCs.

Results

Increased percentages of IL-17A and IL-17A/IL-17F double-producing CCR6+ cells were observed in IFN+ patients compared with IFN- patients and HCs. IL-17A and IL-17F expression within CCR6+ cells correlated significantly with IFIG expression. In addition, we found significant correlation between B-cell activating factor of the tumor necrosis family (BAFF)–a factor strongly correlating with IFN type I - and IL-21 producing CCR6+ cells.

Conclusions

We show for the first time higher percentages of IL-17A and IL-17A/IL-17F double-producing CCR6+ memory T-helper cells in IFN+ SLE patients, supporting the hypothesis that IFN type I co-acts with Th17 cytokines in SLE pathogenesis.
Appendix
Available only for authorised users
Literature
1.
2.
Higgs BW, Liu Z, White B, Zhu W, White WI, Morehouse C, Brohawn P, Kiener PA, Richman L, Fiorentino D, Greenberg SA, Jallal B, Yao Y: Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis. 2011, 70: 2029-2036. 10.1136/ard.2011.150326.CrossRefPubMed
3.
Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003, 100: 2610-2615. 10.1073/pnas.0337679100.PubMedCentralCrossRefPubMed
4.
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V: Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003, 197: 711-723. 10.1084/jem.20021553.PubMedCentralCrossRefPubMed
5.
Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK: Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 2005, 52: 1491-1503. 10.1002/art.21031.CrossRefPubMed
6.
Chen XQ, Yu YC, Deng HH, Sun JZ, Dai Z, Wu YW, Yang M: Plasma IL-17A is increased in new-onset SLE patients and associated with disease activity. J Clin Immunol. 2010, 30: 221-225. 10.1007/s10875-009-9365-x.CrossRefPubMed
7.
Yang J, Chu Y, Yang X, Gao D, Zhu L, Wan L, Li M: Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009, 60: 1472-1483. 10.1002/art.24499.CrossRefPubMed
8.
Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, Kang I: Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther. 2010, 12: R53-10.1186/ar2964.PubMedCentralCrossRefPubMed
9.
Wang Y, Ito S, Chino Y, Goto D, Matsumoto I, Murata H, Tsutsumi A, Hayashi T, Uchida K, Usui J, Yamagata K, Sumida T: Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis. Clin Exp Immunol. 2010, 159: 1-10. 10.1111/j.1365-2249.2009.04031.x.PubMedCentralCrossRefPubMed
10.
Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, Melendez AJ, McInnes IB: Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol. 2010, 184: 3336-3340. 10.4049/jimmunol.0903566.CrossRefPubMed
11.
Cua DJ, Tato CM: Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010, 10: 479-489. 10.1038/nri2800.CrossRefPubMed
12.
McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ: TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007, 8: 1390-1397. 10.1038/ni1539.CrossRefPubMed
13.
Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005, 201: 233-240. 10.1084/jem.20041257.PubMedCentralCrossRefPubMed
14.
Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR: IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007, 8: 967-974. 10.1038/ni1488.CrossRefPubMed
15.
Kyttaris VC, Zhang Z, Kuchroo VK, Oukka M, Tsokos GC: Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice. J Immunol. 2010, 184: 4605-4609. 10.4049/jimmunol.0903595.PubMedCentralCrossRefPubMed
16.
Ambrosi A, Espinosa A, Wahren-Herlenius M: IL-17: a new actor in IFN-driven systemic autoimmune diseases. Eur J Immunol. 2012, 42: 2274-2284. 10.1002/eji.201242653.CrossRefPubMed
17.
Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, Naves R, Han M, Zhong F, Castellanos JG, Mair R, Christakos A, Kolkowitz I, Katz L, Killestein J, Polman CH, de Waal Malefyt R, Steinman L, Raman C: T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010, 16: 406-412. 10.1038/nm.2110.PubMedCentralCrossRefPubMed
18.
Higgs R, Ni Gabhann J, Ben Larbi N, Breen EP, Fitzgerald KA, Jefferies CA: The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol. 2008, 181: 1780-1786.PubMedCentralCrossRefPubMed
19.
Espinosa A, Dardalhon V, Brauner S, Ambrosi A, Higgs R, Quintana FJ, Sjostrand M, Eloranta ML, Ni Gabhann J, Winqvist O, Sundelin B, Jefferies CA, Rozell B, Kuchroo VK, Wahren-Herlenius M: Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med. 2009, 206: 1661-1671. 10.1084/jem.20090585.PubMedCentralCrossRefPubMed
20.
Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, Browning JL: Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999, 190: 1697-1710. 10.1084/jem.190.11.1697.PubMedCentralCrossRefPubMed
21.
Becker-Merok A, Nikolaisen C, Nossent HC: B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time. Lupus. 2006, 15: 570-576. 10.1177/0961203306071871.CrossRefPubMed
22.
Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, Recta V, Zhong J, Freimuth W: Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008, 58: 2453-2459. 10.1002/art.23678.CrossRefPubMed
23.
Stohl W, Metyas S, Tan SM, Cheema GS, Oamar B, Xu D, Roschke V, Wu Y, Baker KP, Hilbert DM: B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 2003, 48: 3475-3486. 10.1002/art.11354.CrossRefPubMed
24.
Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, Wildenberg ME, Beumer W, Drexhage HA, Versnel MA: Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren’s syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis. 2013, 72: 728-735. 10.1136/annrheumdis-2012-201381.PubMedCentralCrossRefPubMed
25.
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
26.
Zotos D, Coquet JM, Zhang Y, Light A, D’Costa K, Kallies A, Corcoran LM, Godfrey DI, Toellner KM, Smyth MJ, Nutt SL, Tarlinton DM: IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010, 207: 365-378. 10.1084/jem.20091777.PubMedCentralCrossRefPubMed
27.
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
28.
Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997, 40: 1725-CrossRefPubMed
29.
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH: Derivation of the SLEDAI: a disease activity index for lupus patients: The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992, 35: 630-640. 10.1002/art.1780350606.CrossRefPubMed
30.
Drexhage RC, van der Heul-Nieuwenhuijsen L, Padmos RC, van Beveren N, Cohen D, Versnel MA, Nolen WA, Drexhage HA: Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder: a study in naturalistically treated patients. Int J Neuropsychopharmacol. 2010, 13: 1369-1381. 10.1017/S1461145710000799.CrossRefPubMed
31.
Beillard E, Pallisgaard N, van der Velden VH, Bi W, Dee R, van der Schoot E, Delabesse E, Macintyre E, Gottardi E, Saglio G, Watzinger F, Lion T, van Dongen JJ, Hokland P, Gabert J: Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR): a Europe against cancer program. Leukemia. 2003, 17: 2474-2486. 10.1038/sj.leu.2403136.CrossRefPubMed
32.
van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, Dolhain RJ, Lubberts E: 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: 73-83. 10.1002/art.30093.CrossRefPubMed
33.
Nikpour M, Dempsey AA, Urowitz MB, Gladman DD, Barnes DA: Association of a gene expression profile from whole blood with disease activity in systemic lupus erythaematosus. Ann Rheum Dis. 2008, 67: 1069-1075. 10.1136/ard.2007.074765.CrossRefPubMed
34.
Lood C, Amisten S, Gullstrand B, Jonsen A, Allhorn M, Truedsson L, Sturfelt G, Erlinge D, Bengtsson AA: Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood. 2010, 116: 1951-1957. 10.1182/blood-2010-03-274605.CrossRefPubMed
35.
Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G: Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007, 8: 639-646. 10.1038/ni1467.CrossRefPubMed
36.
Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S: The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int Immunol. 2008, 20: 1361-1368. 10.1093/intimm/dxn106.CrossRefPubMed
37.
Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR: The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006, 126: 1121-1133. 10.1016/j.cell.2006.07.035.CrossRefPubMed
38.
Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T: Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005, 434: 243-249. 10.1038/nature03308.CrossRefPubMed
39.
Lazear HM, Lancaster A, Wilkins C, Suthar MS, Huang A, Vick SC, Clepper L, Thackray L, Brassil MM, Virgin HW, Nikolich-Zugich J, Moses AV, Gale M, Früh K, Diamond MS: IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling. PLoS Pathog. 2013, 9: e1003118-10.1371/journal.ppat.1003118.PubMedCentralCrossRefPubMed
40.
Yu CF, Peng WM, Oldenburg J, Hoch J, Bieber T, Limmer A, Hartmann G, Barchet W, Eis-Hubinger AM, Novak N: Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation. J Immunol. 2010, 184: 1159-1167. 10.4049/jimmunol.0901706.CrossRefPubMed
41.
Matikainen S, Sareneva T, Ronni T, Lehtonen A, Koskinen PJ, Julkunen I: Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. Blood. 1999, 93: 1980-1991.PubMed
42.
Yasuda K, Richez C, Maciaszek JW, Agrawal N, Akira S, Marshak-Rothstein A, Rifkin IR: Murine dendritic cell type I IFN production induced by human IgG-RNA immune complexes is IFN regulatory factor (IRF)5 and IRF7 dependent and is required for IL-6 production. J Immunol. 2007, 178: 6876-6885.CrossRefPubMed
43.
Santini SM, Lapenta C, Donati S, Spadaro F, Belardelli F, Ferrantini M: Interferon-alpha-conditioned human monocytes combine a Th1-orienting attitude with the induction of autologous Th17 responses: role of IL-23 and IL-12. PLoS One. 2011, 6: e17364-10.1371/journal.pone.0017364.PubMedCentralCrossRefPubMed
44.
Lai Kwan Lam Q, King Hung Ko O, Zheng BJ, Lu L: Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proc Natl Acad Sci U S A. 2008, 105: 14993-4998. 10.1073/pnas.0806044105.PubMedCentralCrossRefPubMed
45.
Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, Thompson P, Chen P, Fox DA, Pennathur S, Kaplan MJ: NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013, 5: 178ra140-CrossRef
Metadata
Title
T-helper 17 cell cytokines and interferon type I: partners in crime in systemic lupus erythematosus?
Authors
Zana Brkic
Odilia BJ Corneth
Cornelia G van Helden-Meeuwsen
Radboud JEM Dolhain
Naomi I Maria
Sandra MJ Paulissen
Nadine Davelaar
Jan Piet van Hamburg
Paul L van Daele
Virgil A Dalm
P Martin van Hagen
Johanna MW Hazes
Marjan A Versnel
Erik Lubberts
Publication date
01-04-2014
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 2/2014
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar4499

Other articles of this Issue 2/2014

Arthritis Research & Therapy 2/2014 Go to the issue

Research article

Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout

Letter

Response to ‘Serum level of adiponectin is a surrogate independent biomarker of radiographic disease progression in early rheumatoid arthritis: results from the ESPOIR cohort’ – authors’ reply

Research article

Roles of mast cells in the pathogenesis of inflammatory myopathy

Review

High-resolution measurements of the multilayer ultra-structure of articular cartilage and their translational potential

Review

Molecular imaging of rheumatoid arthritis: emerging markers, tools, and techniques

Letter

Development of anti-citrullinated protein antibody and rheumatoid factor isotypes prior to the onset of rheumatoid arthritis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits