Soluble LILRA3 is aberrantly expressed in antiphospholipid syndrome (APS) and is a potential marker of thrombotic APS

Abstract

Objective Leucocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of leucocyte receptors. Our previous study reported LILRA3 transcripts were markedly upregulated in neutrophils from patients with antiphospholipid syndrome (APS). We undertook this study to investigate clinical implications of LILRA3 in APS and its potential role in APS-associated thrombosis. Methods Two independent cohorts were studied. The first consisted of 294 APS patients, 48 asymptomatic antiphospholipid antibody (aPL) carriers, and 150 healthy controls (HCs) from Peking University People’s Hospital. The second included 99 APS patients, 25 aPL carriers, and 40 HCs from United States APS centers. Serum or plasma concentrations of LILRA3 and MPO-DNA complexes were measured. Additionally, 35 patients with thrombotic APS (tAPS) were evaluated to determine potential effects of immunosuppressive therapy on serum concentrations of LILRA3 and MPO-DNA complexes. Results Both positivity and serum concentration of LILRA3 were significantly increased in APS patients, especially in those with tAPS. LILRA3-positive tAPS patients displayed more severe thrombotic manifestations. Serum LILRA3 was positively correlated with MPO-DNA complexes in LILRA3-positive tAPS. After immunosuppressive treatment, LILRA3 and MPO-DNA complexes were consistently decreased in tAPS patients. Key findings from the Peking cohort were confirmed in the United States cohort. Conclusion Our study provides first evidence that LILRA3 is aberrantly expressed in APS, especially in patients with tAPS. Serum LILRA3 correlated with MPO-DNA complexes, and the two indices were consistently decreased in tAPS patients after treatment. LILRA3 may play a role in thrombosis of APS and may serve as a biomarker and/or therapeutic target in tAPS.

An update on inflammation in antiphospholipid syndrome

“…By evaluating the expression of pro-NETosis genes ( PADI4 , ELANE , and MPO ), as well as circulating NET remnants (citrullinated histone H3 and myeloperoxidase-DNA complexes), the authors found a pronounced association between thrombotic APS (particularly those patients with triple aPL positivity or recurrent thrombosis) and increased NET formation [68 ▪ ]. An additional 2022 study also found that leukocyte immunoglobulin receptor A3 (LILRA3) was significantly increased in patients with thrombotic APS [69 ▪▪ ]. Furthermore, it was shown that LILRA3 was positively correlated with myeloperoxidase–DNA complexes (NET remnants) in patients with LILRA3-positive thrombotic APS [69 ▪▪ ].…”

“…Furthermore, it was shown that LILRA3 was positively correlated with myeloperoxidase–DNA complexes (NET remnants) in patients with LILRA3-positive thrombotic APS [69 ▪▪ ]. After treatment, the levels of LILRA3 and myeloperoxidase-DNA complexes were consistently decreased amongst these patients, suggesting that LILRA3 might eventually be leveraged as a biomarker or therapeutic target in thrombotic APS [69 ▪▪ ].…”

The role of NETosis in the pathogenesis of immunoinflammatory rheumatic diseases

“…По данным других авторов, наблюдается выраженная ассоциация между «тромботическим» подтипом АФС (тройная позитивность по аФЛ и рецидивирующий тромбоз) и увеличением образования компонентов NETs (цитруллинированный гистон Н3 и МПО-ДНК комплексы) [144]. Увеличение экспрессии LILRA3 (leukocyte immunoglobulin like receptor A3), участвующего в регуляции иммунного ответа, положительно коррелирует с формированием комплексов МПО-ДНК и развитием тромботического субтипа АФС [145].…”