β2GP1, Anti-β2GP1 Antibodies and Platelets: Key Players in the Antiphospholipid Syndrome

Ho, Yik C; Ahuja, Kiran; Körner, Heinrich; Adams, Murray J.

doi:10.3390/antib5020012

Cited by 25 publications

(20 citation statements)

References 104 publications

(176 reference statements)

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“…The presence of reactive oxygen species assists in the transformation of a circulating, nonoxidized, circular‐shaped β 2 ‐glycoprotein 1 (β 2 GP1) into an oxidized J‐shape (Fig 1D, Step 2) 14 . This J‐shape of β2GP1 exposes its immunogenic domain I and is the antigen that binds to antiphospholipid (aPL) antibodies such as anticardiolipin, lupus anticoagulant, and anti‐β 2 GP1 antibodies 15 . Domain V of β 2 GP1 (+ charge) binds with the phospholipid layer (– charge) of platelets 15 or endothelial cells via Annexin 4 …”

Section: Plausible Mechanisms For Blood Clots In Covid‐19mentioning

confidence: 99%

“…This J‐shape of β2GP1 exposes its immunogenic domain I and is the antigen that binds to antiphospholipid (aPL) antibodies such as anticardiolipin, lupus anticoagulant, and anti‐β 2 GP1 antibodies 15 . Domain V of β 2 GP1 (+ charge) binds with the phospholipid layer (– charge) of platelets 15 or endothelial cells via Annexin 4 …”

Section: Plausible Mechanisms For Blood Clots In Covid‐19mentioning

confidence: 99%

“…First, the primary mechanisms by which endothelial cells prevent a platelet plug (eg, via nitric oxide, prostacyclins, and ADPase CD39) are overcome because of endothelial dysfunction 16 . Second, platelet adhesion begins at the site of endothelial dysfunction with von Willebrand factor (vWF) binding with subendothelial collagen and platelets (via GPIb) as the nonoxidized form of β 2 GP1 is no longer available to competitively bind vWF (Fig 1D, Step 3) 15 . Third, oxidized β 2 GP1 and aPL antibody complex is stabilized by platelet factor 4 (PF4) released from alpha (α) granules within platelets and promotes platelet activation (Fig 1D, Step 4) 15 .…”

Section: Plausible Mechanisms For Blood Clots In Covid‐19mentioning

confidence: 99%

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COVID‐19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy

Janardhan¹,

Janardhan²,

Kalousek

2020

Journal of Neuroimaging

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the name suggests was initially thought to only cause a respiratory illness. However, several reports have been published of patients with ischemic strokes in the setting of coronavirus disease 2019 (COVID-19). The mechanisms of how SARS-CoV-2 results in blood clots and large vessel strokes need to be defined as it has therapeutic implications. SARS-CoV-2 enters the blood stream by breaching the blood-air barrier via the lung capillary adjacent to the alveolus, and then attaches to the angiotensin-converting enzyme II receptors on the endothelial cells. Once SARS-CoV-2 enters the blood stream, a cascade of events (Steps 1-8) unfolds including accumulation of angiotensin II, reactive oxygen species, endothelial dysfunction, oxidation of beta 2 glycoprotein 1, formation of antiphospholipid antibody complexes promoting platelet aggregation, coagulation cascade, and formation of cross-linked fibrin blood clots, leading to pulmonary emboli (PE) and large vessel strokes seen on angiographic imaging studies. There is emerging evidence for COVID-19 being a blood clotting disorder and SARS-CoV-2 using the respiratory route to enter the blood stream. As the blood-air barrier is breached, varying degrees of collateral damage occur. Although antiviral and immune therapies are studied, the role of blood thinners in the prevention, and management of blood clots in Covid-19 need evaluation. In addition to ventilators and blood thinners, continuous aspiration and clot retrieval devices (approved in Europe, cleared in the United States) or cyclical aspiration devices (approved in Europe) need to be considered for the emergent management of life-threatening clots including PE and large vessel strokes.

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Section: Plausible Mechanisms For Blood Clots In Covid‐19mentioning

confidence: 99%

Section: Plausible Mechanisms For Blood Clots In Covid‐19mentioning

confidence: 99%

Section: Plausible Mechanisms For Blood Clots In Covid‐19mentioning

confidence: 99%

See 1 more Smart Citation

COVID‐19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy

Janardhan¹,

Janardhan²,

Kalousek

2020

Journal of Neuroimaging

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“…B2GP1 is composed of 5 short consensus repeat domains (“sushi” domains). There are several different conformations for B2GP1, the most important of which are the circular plasma conformation and an open conformation which resembles a fish-hook or “ hockey stick” (6, 7).…”

Section: Introductionmentioning

confidence: 99%

The IgA Isotype of Anti-β2 Glycoprotein I Antibodies Recognizes Epitopes in Domains 3, 4, and 5 That Are Located in a Lateral Zone of the Molecule (L-Shaped)

et al. 2019

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Background: Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with presence of anti-phospholipid antibodies (aPL). The APS classification criteria only consider the aPL of IgG/IgM isotype, however testing of aPL of IgA isotype is recommended when APS is suspected and consensus aPL are negative. IgA anti-βeta-2 glycoprotein-I (B2GP1) has been clearly related with occurrence of thrombotic events. Antibodies anti-B2GP1 of IgG/M isotypes recognize an epitope in Domain 1 (R39-G43), the epitopes that recognize IgA anti-B2GP1 antibodies are not well-identified. Aim: To determine the zones of B2GP1 recognized by antibodies of IgA isotype from patients with APS symptomatology and positive for IgA anti-B2GP1. Methods: IgA antibodies to Domain-1(D1) and Domain-4/5(D4/5) of B2GP1 (ELISA) and epitope mapping on oligopeptide arrays of B2GP1 were evaluated in sera from a group of 93 patients with at least one thrombotic and with isolated positivity for IgA anti-B2GP1 antibodies (negative for other aPL). Results: A total of 47 patients (50.5%) were positive for anti-D4/5 and 23(25%) were positive for anti-D1. When peptide arrays were analyzed, three zones of B2GP1 reactivity were identified for more than 50% of patients. The center of these zones corresponds to amino acids 140(D3), 204(D4), and 264(D5). The peptides recognized on D3 and D4 contain amino acid sequences sharing high homology with proteins of microorganism that were previously related with a possible APS infectious etiology. In the three-dimensional structure of B2GP1, the three peptides, as the R39-G43 epitope, are located on the right side of the molecule (L-shape). The left side (J-shape) does not bind the antibodies. Conclusions: Patients with thrombotic APS clinical-criteria, and isolated IgA anti-B2GP1 positivity appear to preferentially bind, not to the D1 or D4/5 domains of B2GP1, but rather to three sites in D3, D4, and D5. The sites on D3 and D4 were previously described as the target identified by human monoclonal antibodies derived from patients that were capable of inducing APS in animal models. The localization of these epitopes opens a new route to explore to increase understanding of the patholophysiology of the APS and to propose new alternatives and therapeutic targets.

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“…Beta2GPI is known to adopt different protein conformations. 17,18 A rather circular (closed) conformation, likely to be the inactive form circulating in blood, was visualized by Agar et al and is characterized by the interaction of DI and DV. 19 A linear and fishhook-like (open) conformation was revealed by X-ray crystal structure analysis.…”

Section: Introductionmentioning

confidence: 99%

Lysine residues control the conformational dynamics of beta 2-glycoprotein I

Buchholz

Nestler

Köppen

et al. 2018

Phys. Chem. Chem. Phys.

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One of the major problems in the study of the dynamics of proteins is the visualization of changing conformations that are important for processes ranging from enzyme catalysis to signaling. A protein exhibiting conformational dynamics is the soluble blood protein beta 2-glycoprotein I (beta2GPI), which exists in two conformations: the closed (circular) form and the open (linear) form. It is hypothesized that an increased proportion of the open conformation leads to the autoimmune disease antiphospholipid syndrome (APS). A characteristic feature of beta2GPI is the high content of lysine residues. However, the potential role of lysine in the conformational dynamics of beta2GPI has been poorly investigated. Here, we report on a strategy to permanently open up the closed protein conformation by chemical acetylation of lysine residues using acetic acid N-hydroxysuccinimide ester (NHS-Ac). Specific and complete acetylation was demonstrated by the quantification of primary amino groups with fluoraldehyde o-phthalaldehyde (OPA) reagent, as well as western blot analysis with an anti-acetylated lysine antibody. Our results demonstrate that acetylated beta2GPI preserves its secondary and tertiary structures, as shown by circular dichroism spectroscopy. We found that after lysine acetylation, the majority of proteins are in the open conformation as revealed by atomic force microscopy high-resolution images. Using this strategy, we proved that the electrostatic interaction of lysine residues plays a major role in stabilizing the beta2GPI closed conformation, as confirmed by lysine charge distribution calculations. We foresee that our approach will be applied to other lysine-rich proteins (e.g. histones) undergoing conformational transitions. For instance, conformational dynamics can be triggered by environmental conditions (e.g. pH, ion concentration, post-translational modifications, and binding of ligands). Therefore, our study may be relevant for investigating the equilibrium of protein conformations causing diseases.

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β2GP1, Anti-β2GP1 Antibodies and Platelets: Key Players in the Antiphospholipid Syndrome

Cited by 25 publications

References 104 publications

COVID‐19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy

COVID‐19 as a Blood Clotting Disorder Masquerading as a Respiratory Illness: A Cerebrovascular Perspective and Therapeutic Implications for Stroke Thrombectomy

The IgA Isotype of Anti-β2 Glycoprotein I Antibodies Recognizes Epitopes in Domains 3, 4, and 5 That Are Located in a Lateral Zone of the Molecule (L-Shaped)

Lysine residues control the conformational dynamics of beta 2-glycoprotein I

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