Restricted accessResearch articleFirst published online 2022-06
Elevated Level of Serum Interleukin-21 and Its Influence on Disease Activity in Anti-Neutrophil Cytoplasmic Antibodies Against Myeloperoxidase-Associated Vasculitis
Interleukin-21 (IL-21) has been shown to play an important role in the immune system. This study aimed to investigate the changes in the level of IL-21 in patients with anti-neutrophil cytoplasmic antibodies against myeloperoxidase (MPO-ANCA)-associated vasculitis (MPO-AAV), as well as explore its influence on disease activity and the potential mechanism. Flow cytometry was performed to detect the percentage of follicular helper T cells (Tfh) among CD4+T cells (Tfh%); the percentage of Tfh-expressing inducible costimulator (ICOS) among Tfh cells (ICOS+Tfh%); the percentage of Tfh-expressing programmed cell death protein 1 (PD-1) among Tfh cells (PD-1+Tfh%); and mean fluorescence intensity of Tfh-expressing ICOS or PD-1 in the peripheral blood. An enzyme-linked immunosorbent assay was used to measure the levels of serum IL-21 and MPO-ANCA. The Birmingham Vasculitis Activity Score was used to evaluate disease activity. Our results revealed that the level of IL-21 in the patient group was significantly higher than that in the healthy control group (1324.0 ± 812.4 pg/mL vs. 704.2 ± 266.3 pg/mL, P < 0.001), and it was an independent factor affecting the disease activity (P = 0.022). Thus, blocking the activity of IL-21 may represent a potential novel target for the future treatment of MPO-AAV.
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References
1.
AbdulahadWH, LepseN, StegemanCA, HuitemaMG, Doornbos-van der MeerB, TademaH, RutgersA, LimburgPC, KallenbergCGM, HeeringaP. 2013. Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA). Arthritis Res Ther, 15(3):12.
2.
Al-HussainT, HusseinMH, ConcaW, Al ManaH, AkhtarM. 2017. Pathophysiology of ANCA-associated Vasculitis. Adv Anat Pathol, 24(4):226–234.
3.
AlmaaniS, FussnerLA, BrodskyS, MearaAS, JayneD. 2021. ANCA-associated vasculitis: an update. J Clin Med 10(7):. 1446.
4.
BansalPJ, TobinMC. 2004. Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement. Ann Allergy Asthma Immunol, 93(4):398–401.
5.
BryantVL, MaCS, AveryDT, LiY, GoodKL, CorcoranLM, MalefytRD, TangyeSG. 2007. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5(+) T follicular helper cells. J Immunol, 179(12):8180–8190.
6.
Cartin-CebaR, Diaz-CaballeroL, Al-QadiMO, TryfonS, FervenzaFC, YtterbergSR, SpecksU. 2016. Diffuse alveolar hemorrhage secondary to antineutrophil cytoplasmic antibody-associated vasculitis: predictors of respiratory failure and clinical outcomes. Arthritis Rheumatol, 68(6):1467–1476.
7.
ChangDY, LiZY, ChenM, ZhaoMH. 2019. Myeloperoxidase-ANCA-positive granulomatosis with polyangiitis is a distinct subset of ANCA-associated vasculitis: a retrospective analysis of 455 patients from a single center in China. Semin Arthritis Rheum, 48(4):701–706.
8.
CharlesLA, CaldasML, FalkRJ, TerrellRS, JennetteJC. 1991. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol, 50(6):539–546.
9.
CornecD, GallEC, FervenzaFC, SpecksU. 2016. ANCA-associated vasculitis—clinical utility of using ANCA specificity to classify patients. Nat Rev Rheumatol, 12(10):570–579.
10.
EttingerR, SimsGP, RobbinsR, WithersD, FischerRT, GrammerAC, KuchenS, LipskyPE. 2007. IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells. J Immunol, 178(5):2872–2882.
11.
FalkRJ, TerrellRS, CharlesLA, JennetteJC. 1990. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A, 87(11):4115–4119.
12.
GoodKL, BryantVL, TangyeSG. 2006. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J Immunol, 177(8):5236–5247.
13.
HaoJ, MengLQ, XuPC, ChenM, ZhaoMH. 2012. p38MAPK, ERK and PI3K signaling pathways are involved in C5a-primed neutrophils for ANCA-mediated activation. PLoS One, 7(5):e38317.
14.
JarrotPA, KaplanskiG. 2016. Pathogenesis of ANCA-associated vasculitis: an update. Autoimmunity reviews, 15(7):704–713.
KornT, BettelliE, GaoW, AwasthiA, JagerA, StromTB, OukkaM, KuchrooVK. 2007. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature, 448(7152):484–487.
19.
KroenkeMA, EtoD, LocciM, ChoM, DavidsonT, HaddadEK, CrottyS. 2012. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol, 188(8):3734–3744.
20.
LeavittRY, FauciAS, BlochDA, MichelBA, HunderGG, ArendWP, CalabreseLH, FriesJF, LieJT, LightfootRWJr., MasiAT, McshaneDJ, MillsJA, StevensMB, WallaceSL, ZvaiflerNJ.1990. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum, 33(8):1101–1107.
21.
LepseN, LandJ, RutgersA, KallenbergCGM, StegemanCA, AbdulahadWH, HeeringaP. 2016. Toll-like receptor 9 activation enhances B cell activating factor and interleukin-21 induced anti-proteinase 3 autoantibody production in vitro. Rheumatology, 55(1):162–172.
22.
LittleMA, NightingaleP, VerburghCA, HauserT, De GrootK, SavageC, JayneD, HarperL, European Vasculitis StudyG. 2010. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis, 69(6):1036–1043.
McKinneyEF, WillcocksLC, BroeckerV, SmithKG. 2014. The immunopathology of ANCA-associated vasculitis. Semin Immunopathol, 36(4):461–478.
29.
MehtaDS, WursterAL, WhittersMJ, YoungDA, CollinsM, GrusbyMJ. 2003. IL-21 induces the apoptosis of resting and activated primary B cells. J Immunol, 170(8):4111–4118.
30.
MunCH, YooJ, JungSM, SongJJ, ParkYB, LeeSW. 2018. The initial predictors of death in 153 patients with ANCA-associated vasculitis in a single Korean centre. Clin Exp Rheumatol, 36 (Suppl 111):65–72.
31.
NurievaR, YangXO, MartinezG, ZhangY, PanopoulosAD, MaL, SchlunsK, TianQ, WatowichSS, JettenAM, DongC. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature, 448(7152):480–483.
32.
ParkJS, KimSM, ChoiJ, JungKA, HwangSH, YangS, KwokSK, ChoML, ParkSH. 2020. Interleukin-21-mediated suppression of the Pax3-Id3 pathway exacerbates the development of Sjogren's syndrome via follicular helper T cells. Cytokine, 125:154834.
33.
PearceFA, CravenA, MerkelPA, LuqmaniRA, WattsRA. 2017. Global ethnic and geographic differences in the clinical presentations of anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford), 56(11):1962–1969.
34.
PefanisA, WilliamsDS, SkrzypekH, FungA, PaizisK. 2020. A case of ANCA-associated vasculitis presenting de novo in pregnancy, successfully treated with rituximab. Obstet Med, 13(1):41–44.
35.
PhillipR, LuqmaniR. 2008. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol, 26(5 Suppl 51):S94–S104.
36.
RiellaLV, PatersonAM, SharpeAH, ChandrakerA. 2012. Role of the PD-1 Pathway in the Immune Response. Am J Transplant, 12(10):2575–2587.
SchliebenDJ, KorbetSM, KimuraRE, SchwartzMM, LewisEJ. 2005. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis, 45(4):758–761.
39.
SpolskiR, LeonardWJ. 2010. IL-21 and T follicular helper cells. Int Immunol, 22(1):7–12.
40.
VerstappenGM, MeinersPM, CornethOBJ, VisserA, ArendsS, AbdulahadWH, HendriksRW, VissinkA, KroeseFGM, BootsmaH. 2017. Attenuation of Follicular Helper T Cell-Dependent B Cell Hyperactivity by Abatacept Treatment in Primary Sjogren's Syndrome. Arthritis Rheumatol, 69(9):1850–1861.
XiaoH, HeeringaP, HuP, LiuZ, ZhaoM, ArataniY, MaedaN, FalkRJ, JennetteJC. 2002. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest, 110(7):955–963.
43.
XieG, RoshandelD, ShervaR, MonachPA, LuEY, KungT, CarringtonK, ZhangSS, PulitSL, RipkeS, CaretteS, DellaripaPF, EdbergJC, HoffmanGS, KhalidiN, LangfordCA, MahrAD, St ClairEW, SeoP, SpecksU, SpieraRF, StoneJH, YtterbergSR, RaychaudhuriS, de BakkerPIW, FarrerLA, AmosCI, MerkelPA, SiminovitchKA. 2013. Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum, 65(9):2457–2468.
44.
ZhouP, MaJ, WangG. 2021. Impact of interstitial lung disease on mortality in ANCA-associated vasculitis: A systematic literature review and meta-analysis. Chron Respir Dis, 18:1479973121994562.
