Utilizing type I interferon expression in the identification of antiphospholipid syndrome subsets

Abstract

Introduction: Antiphospholipid Syndrome (APS) is a systemic autoimmune disease with a complex multifactorial pathogenesis, combining genetic background, traditional cardiovascular risk factors, disease-specific features such as the presence of antiphospholipid antibodies (aPL), and an imbalance of various immune system functions. Recent data support the role of interferons (IFNs), especially type IIFN (IFN-I), in the onset and development of APS clinical manifestations, including thrombotic events and obstetric complications.

Areas covered: In this review, the authors aimed to discuss the growing body of evidence on the relevance of IFN-I pathways in APS, both from a basic mechanistic perspective, focusing on its possible use in disease/patients stratification. The IFN-I signature has shown promising, although preliminary, results in segregating aPL-positive subjects by aPL profile, association with other autoimmune conditions, such as lupus, age at onset, and current treatment, among others.

Expert opinion: To date, the scarce available data as well as methodological and technical heterogeneity among studies limit the comparability of the results, thus requiring further validation to translate these findings to routine clinical practice. Therefore, further research is required in pursuit of more nuanced patient profiling and the development of new immunomodulatory therapeutic strategies for APS beyond anti-coagulant and antiplatelet agents.

Keywords: Antiphospholipid Antibodies; antiphospholipid Syndrome; interferon; interferon Signature; type I Interferon.

Figure 1.. Main sources and effects of type I interferon in antiphospholipid syndrome.

pDCs are recognized as the main source of IFN-I. Although not completely elucidated, it is known that a number of complex processes causes an increased production of IFN-I in APS setting, leading to endothelial dysfunction, accelerated atherosclerosis, and higher levels of BAFF which are responsible for an increased production of autoantibodies. APL, especially aβ2GPI, are thought to induce IFN-I production through the hyperactivation of TLR. Moreover, IFN-I production seems to be modulated by microRNA, which global expression have been reported to be downregulated in pDCs of APS patients, and by NETs. It is still debated whether the increase in NETs formation and LGDs number are directly responsible for higher IFN-I levels, as it has been reported in SLE pathogenesis. This figure also shows the main treatment agents with immunomodulant properties employed in APS, along with possible future therapeutic targets including those with direct anti-IFN-I effects. pDCs means plasmacytoid dendritic cells; IFN-I, type I interferon; BAFF, B-cell activating factor; aPL, antiphospholipid antibodies; aβ2GPI, anti-β2-glycoprotein I antibodies; LDGs, low-density granulocytes; NETs, neutrophil extracellular traps; TLR, toll like receptor; HCQ, hydroxychloroquine; APS, antiphospholipid syndrome. Created using BioRender.com.