Characterization of plasmocytoid dendritic cell activity and type 1 interferon signature in thrombotic antiphospholipid syndrome

Author(s)

Ana Paula Rosa dos Santos

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2022-02-21

Examining board members

Fernanda Loureiro de Andrade Orsi; Eder de Carvalho Pincinato; Suely Meireles Rezende

• Advisor: Bruna de Moraes Mazetto Fonseca; Fernanda Loureiro de Andrade Orsi

Abstract

Thrombotic risk in antiphospholipid syndrome (APS) is conferred by the association of antiphospholipids (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)-1 by plasmacytoid dendritic cells (pDCs) is at the basis of systemic autoimmune disorders pathophysiology, which raises the hypothesis that this mechanism could also be associated with vascular manifestations of APS. Here, we determined the association of pDCs and IFN-1 production with thrombotic APS. Patients with thrombotic primary (t-PAPS) and secondary APS (t-SAPS), asymptomatic aPL carriers and individuals without thrombosis (controls) were included. Circulating pDCs and IFN-? intracellular expression (in the presence or not of oligodeoxynucleotides [CPG] 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. 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-? 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 the aPL carriers (0.71%; IQR 0.42-0.93) and controls (0.48%; IQR 0.24-0.78; P<0.0001). 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-1 response was similar between triple aPL-positive profile and other aPL profiles. Our results point towards an association of IFN-1 response and t-APS. Since IFN-1 expression was not increased in aPL carriers or associated with higher-risk aPL profile, such mechanism seems not to be related to the presence of aPL alone. It is possible that IFN-1 response constitutes a complementary mechanism for triggering clinical manifestations in APS (AU)

• 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