The Significance of Antibodies against Domain I of Beta-2 Glycoprotein I in Antiphospholipid Syndrome

Abstract

The antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Progress is being made in understanding the pathogenesis of the syndrome, but difficulties persist in the identification of patients at risk for thrombosis and/or pregnancy morbidity. Beta-2 glycoprotein I (βGPI), a plasma protein consisting of five sushi domains, is thought to be the main antigenic target of aPLs. Antibodies recognizing domain I of βGPI are predominantly present in patients with an elevated risk of thrombosis, whereas antidomain IV/V antibodies are found in nonthrombotic autoimmune diseases. Indeed, domain I antibodies proved to be pathogenic in multiple studies. Retrospective studies have provided evidence for an added clinical value of antidomain I antibodies in the risk stratification of patients with APS. Still, wide ranges of odds ratio exist between studies, probably due to differences in the study and control population, and detection methods used. Despite the proven pathogenicity of antidomain I antibodies and their correlations with clinical manifestations of APS, heterogeneity of the current studies has prohibited their acceptance in the official diagnostic criteria. Well-designed large longitudinal prospective studies with available and new, preferentially functional, assays for the risk stratification of patients with APS are required.

The association between antiphospholipid syndrome and atrial fibrillation: a single center retrospective case-control study

“…The effect of aCL and anti- β 2 GPI is evident in myocardial ischemia, myocarditis and valvular disease, which is related to the types and titers of antibodies ( Djokovic et al, 2022 ). According to existing literature, the mechanism is not only associated with thrombosis but also includes inflammation, complement pathways, platelet activation, etc ( Kelchtermans, Chayouâ & Laat, 2018 ; Pengo et al, 2010 ; Stojanovich et al, 2013 ). As previously mentioned, the deposition of anti- β 2GPI and complement in heart valves can cause inflammation, immune responses ( Zuily et al, 2013 ).…”

Evolution of Antiphospholipid Syndrome

“…Antibodies against all five domains of β2GPI may develop, but in APS the pathogenic groups of anti-β2GPI are thought to primarily recognize the first domain (domain I, DI), which becomes exposed upon closed-to-open conformational change. [54][55][56] In contrast, domain V (DV) is exposed in both conformations and contains regions that interact with cell surface molecules such as phospholipid and receptors. 51,55,56 Antibodies to domain V are considered nonpathogenic 57 and may be more common in people with transient aPL positivity following infection and clearance, 58,59 whereas anti-DI antibodies cause thrombosis 60,61 and pregnancy loss in mouse models of APS.…”

“…[54][55][56] In contrast, domain V (DV) is exposed in both conformations and contains regions that interact with cell surface molecules such as phospholipid and receptors. 51,55,56 Antibodies to domain V are considered nonpathogenic 57 and may be more common in people with transient aPL positivity following infection and clearance, 58,59 whereas anti-DI antibodies cause thrombosis 60,61 and pregnancy loss in mouse models of APS. 60 Studies of anti-DI in patient sera show definitive associations with the syndrome 62 and predominantly vascular complications in primary and SLE-associated APS.…”

The protective effect of apolipoprotein H in paediatric sepsis

“…It is primarily synthesized by liver cells and comprises five domains (I–V) [ 5 ]. APOH is a complement regulator across diverse biological processes and conditions, including antiphospholipid syndrome (APS), the procoagulant state, diabetes, and immune disorders [ 6 – 8 ]. Furthermore, studies have indicated APOH’s involvement in innate immunity by binding to viruses and bacteria [ 9 , 10 ].…”

“…It is primarily synthesized by liver cells and comprises five domains (I-V) [5]. APOH is a complement regulator across diverse biological processes and conditions, including antiphospholipid syndrome (APS), the procoagulant state, diabetes, and immune disorders [6][7][8].…”