Association between interferon-I producing plasmacytoid dendritic cells and thrombotic antiphospholipid syndrome

Abstract

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.

Evaluation of a gene signature related to thrombotic manifestations in antiphospholipid syndrome

“…PAPS and SAPS share the expression of genes involved in the type 1 interferon signature, inflammation and atherosclerosis ( 10 ), whereas PAPS differs from systemic lupus erythematosus (SLE) by the expression of genes related to mitochondrial function, oxidative stress and antioxidant capacity ( 10 , 18 , 19 ). We recently observed that genes related to the type 1 interferon signature were overexpressed in t-SAPS, but not in t-PAPS, compared to controls ( 20 ), suggesting that the inflammatory profile is different between these two presentations of APS. A recent meta-analysis identified 16 genes differentially expressed in t-PAPS compared to controls that were expressed in 32 different tissues, which may explain the fact that thrombosis in APS occurs in any vascular site ( 18 ).…”