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

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Rosa dos Santos, Ana Paula ; Vaz, Camila de Oliveira ; Hounkpe, Bidossessi Wilfried ; Jacintho, Bruna Cardoso ; Oliveira, Jose Diogo ; Tripiquia Vechiatto Mesquita, Gabriela Lisiane ; dos Santos, Irene Pereira ; Annichino-Bizzacchi, Joyce ; Appenzeller, Simone ; Mazetto Fonseca, Bruna de Moraes ; Orsi, Fernanda Andrade

• Document type: Journal article
• Source: Lupus; v. N/A, p. 11-pg., 2022-05-25.

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-alpha 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-alpha 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. (AU)

• FAPESP's process: 16/14172-6 - Investigation of the pathophysiological aspects and novel therapeutic approaches for thromboembolic disorders
• Grantee: Joyce Maria Annichino-Bizzacchi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/20891-3 - Characterization of plasmacytoid dendritic cell activity and type 1 interferon signature in primary antiphospholipid syndrome with thrombosis
• Grantee: Ana Paula Rosa dos Santos
• Support Opportunities: Scholarships in Brazil - Master