Background: Thrombotic risk in antiphospholipid syndrome (APS) is conferred by the association of antiphospholipid (aPL) antibodies (first hit) with additional pro-coagulant stimulus (second hit), such as inflammation. Among inflammatory responses, the production of large amounts of interferon (IFN)-I by plasmacytoid dendritic cells (pDCs) is at the basis of the pathophysiology of systemic autoimmune disorders, which raises the hypothesis that this mechanism could also be associated with vascular manifestations of APS. Purpose: Here, we determined the association of pDCs and IFN-I production with thrombotic APS. Research design: Patients with thrombotic primary (t-PAPS) and secondary APS (t-SAPS), asymptomatic aPL carriers and individuals without thrombosis (controls) were included. Data collection and analysis: Circulating pDCs and IFN-α intracellular expression (in the presence or not of oligodeoxynucleotides (CP) stimulus) were quantified by flow cytometry. The expression of five IFN-I inducing genes: ISG15, OASL, Ly6E, MX1, and OAS1 in mononuclear cells was determined by qPCR. Between-group differences were evaluated using chi-square or Kruskal–Wallis tests. Results: A total of 50 patients with t-PAPS, 50 patients with t-SAPS, 20 aPL carriers, and 50 individuals without thrombosis (controls) were included. Intracellular expression of IFN-α was increased after CPG stimulation in both t-SAPS (1.56%; IQR 1.07–2.02) and t-PAPS (0.96%; IQR 0.55–1.24), when compared to aPL carriers (0.71%; IQR 0.42–0.93) and controls (0.48%; IQR 0.24–0.78; p < .0001). ISG15, OASL, Ly6E, MX1, and OAS1 mRNA expressions were higher in t-SAPS (but not in t-PAPS) than in aPL carriers and controls. The expression of proteins and mRNA related to IFN-I response was similar between the triple aPL-positive profile and other aPL profiles. Conclusion: Our results indicate an association of IFN-I response and t-APS. Since IFN-I expression was not increased in aPL carriers or associated with a higher-risk aPL profile, this mechanism does not appear to be related to the presence of aPL alone. IFN-I response could possibly constitute a complementary mechanism for triggering clinical manifestations in APS.
GardinerCHillsJMacHinSJ, et al.Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus [Internet]2013; 22(1): 18–25.
2.
MiyakisSLockshinMDAtsumiT, et al.International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost2006; 4(2): 295–306.
3.
PengoVTripodiAReberG, et al.Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost2009; 7(10): 1737–1740.
4.
PalliEKravvaritiETektonidouMG. Type I interferon signature in primary antiphospholipid syndrome: clinical and laboratory associations. Front Immunol2019; 10: 487. [Internet].
5.
MazettoBDeMLazariniMTobaldiniLQ, et al.Expression of tissue factor mRNA in thrombosis associated with antiphospholipid syndrome. J Thromb Thrombolysis2021; 51(2): 370–378.
6.
da Silva SaraivaSde Moraes MazettoBTobaldineLQ, et al.The impact of antibody profile in thrombosis associated with primary antiphospholipid syndrome. Am J Hematol2017; 92(11): 1163–1169.
7.
ChaturvediSMcCraeKR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev2017; 31: 406–417.
8.
MeroniPLMeroniPLBorghiMO, et al.Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol [Internet]2011; 330: 330–339.
9.
CerveraRPietteJCFontJ, et al.Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum2002; 46(4): 1019–1027.
10.
SantamariaJRMandelliFLde BarrosMF, et al. Síndrome antifosfolípide Antiphospholipid syndrome. Anais Brasileiros de Dermatologia2005; 80(3): 225–239.
11.
DanowskiARegoJKakehasiAM, et al.Diretrizes para o tratamento da síndrome do anticorpo antifosfolipídeo. Revista Brasileira de Reumatologia2013; 53(2): 184–192.
12.
BertinDCamoin‐JauLVeitV, et al.Single or triple positivity for antiphospholipid antibodies in “carriers” or symptomatic patients: untangling the knot. J Thromb Haemost2021; 19: 34–3030.
13.
GiannakopoulosBKrilisSA. The pathogenesis of the antiphospholipid syndrome. New Engl J Med2013; 368(11): 1033–1044.
14.
Ruiz-IrastorzaGCrowtherMBranchW, et al.Antiphospholipid syndrome. The Lancet[Internet]2010; 376(9751): 1498–1509.
15.
Da Silva SaravsaSSaraivaSFernandes CustódioI, et al.Recurrent thrombosis in antiphospholipid syndrome may be associated with cardiovascular risk factors and inflammatory response. Thromb Res2015; 136(6): 1174–1178.
16.
ArantesFTMazettoBMSaraivaSS, et al.Inflammatory markers in thrombosis associated with primary antiphospholipid syndrome. J Thromb Thrombolysis2020; 50(4): 772–781.
17.
SinescuCHostiucMBartosD. Idiopathic venous thromboembolism and thrombophilia. J Medicine Life2011; 4: 57–62.
18.
TuriniRBFChechiaTEFernandesTA, et al.Síndrome antifosfolípide e trombocitopenia na infância. Revista Paulista de Pediatria2012; 30(3): 443–449.
19.
KuwanaMMatsuuraEKobayashiK, et al.Binding of β2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells. Blood2005; 105(4): 1552–1557.
20.
SchmittgenTDLivakKJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc2008; 3(6): 1101–1108.
21.
DoniaDDiviziaMPana’A. Use of armored RNA as a standard to construct a calibration curve for real-time RT-PCR. J Virol Methods[Internet]2005; 126(1-2): 157–163.
22.
MuskardinTLWNiewoldTB. Type I interferon in rheumatic diseases HHS Public Access. Nat Rev Rheumatol2018; 14(4): 214–228.
23.
YeYGauglerBMohtyM, et al.Plasmacytoid dendritic cell biology and its role in immune-mediated diseases. Clin Translational Immunol2020; 9: e1139.
24.
TangKTChenHHChenTT, et al.Dendritic cells and antiphospholipid syndrome: an updated systematic review. Life2021; 11: 801).
25.
MaîtreBManginPHEcklyA, et al.Immature myeloid dendritic cells capture and remove activated platelets from preformed aggregates. J Thromb Haemost2010; 8(10): 2262–2272.
26.
Ugolini-LopesMRTorrezanGTGândaraAPR, et al.Enhanced type I interferon gene signature in primary antiphospholipid syndrome: association with earlier disease onset and preeclampsia. Autoimmun Rev2019; 18: 393–398.
27.
BaechlerECBatliwallaFMKarypisG, et al.Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA[Internet]2003; 100(5): 2610–2615.
28.
HanGMChenSLShenN, et al.Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray. Genes Immun2003; 4: 177–186.
29.
FengXWuHGrossmanJM, et al.Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum2006; 54(9): 2951–2962.
30.
GrennRCYalavarthiSGandhiAA, et al.Endothelial progenitor dysfunction associates with a type i interferon signature in primary antiphospholipid syndrome. Ann Rheum Dis[Internet]2017; 76(2): 450–457.
ViannaJLKhamashtaMAOrdi-RosJ, et al.Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am J Med1994; 96(1): 3–9.
33.
HarrisENPierangeliSS. Primary, secondary, catastrophic antiphospholipid syndrome: is there a difference?Thromb Res2004; 114(5-6): 357–361.
34.
BakerWFBickRL. The clinical spectrum of antiphospholipid syndrome. Hematol Oncol Clin North Am2008; 22(1): 33–52.
35.
GrossmanJM. Primary versus secondary antiphospholipid syndrome: is this Lupus or not?Curr Rheumatol Rep2004; 6: 445–450.
36.
ShoenfeldYMeroniPLToubiE. Antiphospholipid syndrome and systemic lupus erythematosus: are they separate entities or just clinical presentations on the same scale?Curr Opin Rheumatol2009; 21(5): 495–500.
37.
CerveraRSerranoRPons-EstelGJ, et al.Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis2015; 74(6): 1011–1018.
38.
TaraborelliMReggiaRDall’AraF, et al.Longterm outcome of patients with primary antiphospholipid syndrome: a retrospective multicenter study. J Rheumatol2017; 44(8): 1165–1172.
39.
TarrTLakosGBhattoaHP, et al.Primary antiphospholipid syndrome as the forerunner of systemic lupus erythematosus. Lupus2007; 16(5): 324–328.
40.
Álvarez-RodríguezLMartínez-TaboadaVCalvo-AlénJ, et al.Altered Th17/treg ratio in peripheral blood of systemic lupus erythematosus but not primary antiphospholipid syndrome. Front Immunol2019; 10: 391.
41.
AmesPRJAntinolfiICiampaA, et al.Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease?Rheumatology2008; 47(12): 1832–1837.
42.
BeliznaCStojanovichLCohen-TervaertJW, et al.Primary antiphospholipid syndrome and antiphospholipid syndrome associated to systemic lupus: are they different entities?Autoimmun Rev2018; 17(8): 739–745.
43.
Perez-SanchezCBarbarrojaNMessineoS, et al.Gene profiling reveals specific molecular pathways in the pathogenesis of atherosclerosis and cardiovascular disease in antiphospholipid syndrome, systemic lupus erythematosus and antiphospholipid syndrome with lupus. Ann Rheum Dis2015; 74(7): 1441–1449.
44.
SwadzbaJIwaniecTMusialJ. Increased level of tumor necrosis factor-α in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state. Rheumatol Int2011; 31(3): 307–313.
SevimEZisaDAndradeD, et al.Characteristics of antiphospholipid antibody positive patients in antiphospholipid syndrome alliance for clinical trials and international networking. Arthritis Care Res2020; 74(2): 324–335.
47.
GebhartJPoschFKoderS, et al.High risk of adverse pregnancy outcomes in women with a persistent lupus anticoagulant. Blood Adv2019; 3(5): 769–776.
48.
LockshinMDKimMLaskinCA, et al.Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum2012; 64(7): 2311–2318.
49.
GalliMLucianiDBertoliniG, et al.Anti-β2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood2003; 1022717–2723.
50.
BertinDCamoin‐JauLVeitV, et al.Single or triple positivity for antiphospholipid antibodies in “carriers” or symptomatic patients: untangling the knot. J Thromb Haemost2021; 19: 3018–3030.
51.
GrantCRHolderBSLiberalR, et al.Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis. Clin Exp Immunol2017; 189(1): 71–82.
52.
IvashkivLBDonlinLT. Regulation of type i interferon responses. Nat Rev Immunol2014; 14(1): 36–49.
53.
WongSHGaoQTsoiKKF, et al.Effect of immunosuppressive therapy on interferon γ release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax2016; 71(1): 64–72.
54.
ElenkovIJ. Glucocorticoids and the Th1/Th2 balance. Ann NY Acad Sci2004; 1024: 138–146.
55.
SacreKCriswellLAMcCuneJM. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther2012; 14(3): R155.
56.
HanJLiXLuoX, et al.The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: inhibition of dendritic cell functions via Toll like receptor 9 signaling. Biomed Pharmacother2020; 132: 110848.
57.
RichardSAKampoSHechavarriaME, et al.Elucidating the pivotal immunomodulatory and anti-inflammatory potentials of chloroquine and hydroxychloroquine. J Immunol Res2020: 2020: 4582612.
