Beta 2 glycoprotein I (β2GPI) is the major autoantigen in the antiphospholipid syndrome, an autoimmune disorder characterized by thrombotic and obstetric complications. The autoantibodies that target ...beta 2 glycoprotein I are pathogenic and contribute to disease pathogenesis. The β2GPI molecule is composed of 5 domains that are numbered 1 through to 5. Autoantibodies bind mainly to domain 1 whereas the majority of the biological functions of the β2GPI molecule in diverse processes such as apoptotic cell clearance, complement regulation, lipopolysaccharide clearance and anticoagulation have been localised to domain 5 and its unique biochemistry, reviewed in this article. The role of purified domain 5 peptide as a potential therapeutic agent in APS and ischemia reperfusion injury is discussed.
This article discusses how we approach medical decision making in the treatment of the various facets of the antiphospholipid syndrome (APS), including secondary prophylaxis in the setting of venous ...and arterial thrombosis, as well as treatment for the prevention of recurrent miscarriages and fetal death. The role of primary thromboprophylaxis is also discussed in depth. Great emphasis is given to incorporating the most up-to-date and relevant evidence base both from the APS literature, and from large, recent, randomized controlled trials (RCTs) of primary and secondary thrombotic prophylaxis in the general population setting (ie, the population that has not been specifically investigated for APS).
The antiphospholipid syndrome (APS) is an acquired thrombophilia, characterized by the occurrence of venous and arterial events. This article examines the laboratory and key clinical aspects of APS. ...Particular focus is given to anti–beta 2-glycoprotein I (β2GPI) antibodies in view of their recent inclusion in the APS classification criteria. The clinical utility of using the β2GPI enzyme-linked immunosorbent assay, in conjunction with the established lupus anticoagulant assays and cardiolipin enzyme-linked immunosorbent assay, for diagnosing and risk stratifying patients suspected of having APS is discussed. The relative importance of the various assays in diagnosing obstetric APS (early and late gestation miscarriages) is explored. The implications of recent epidemiologic findings for possibly understanding the underlying pathophysiologic mechanisms of obstetric APS are highlighted. Insights into which patients with obstetric APS may be at most risk of thrombotic complications are presented.
The anti-phospholipid syndrome (APS) is a prothrombotic autoimmune disorder characterized by either thrombosis or pregnancy complications in the setting of persistent anti-phospholipid antibodies ...(aPL). βeta 2-glycoprotein I (β2-GPI) is the major autoantigen in APS that binds anionic phospholipids as well as specific receptors on platelets and endothelial cells resulting in activation of prothrombotic pathways. β2-GPI consists of 5 Domains that exist in a circular or linear form, with the latter occurring after binding to anionic phospholipids. β2-GPI also undergoes dynamic posttranslational modification between oxidized and free thiol forms. The relationship between posttranslational modification and structural conformation is yet to be definitively clarified. Compared with controls, patients with the APS have higher levels of total β2-GPI and lower levels of free thiol β2-GPI. This raises the possibility of using quantification of β2-GPI posttranslational modification as a redox biomarker in the management and diagnosis of the APS.
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•βeta 2-glycoprotein I (β2-GPI) is the Antiphospholipid Syndrome major autoantigen.•β2-GPI exists in either a circular or “hockey stick-like” form.•β2-GPI undergoes posttranslational changes between oxidized and free thiol forms.•Antiphospholipid Syndrome patients have higher levels of total and oxidized β2-GPI.•Antiphospholipid Syndrome patients have lower levels of free thiol β2-GPI.
The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it ...can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (β2-GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in this disorder. Delineating the strengths and limitations of the experimental evidence accumulated thus far will hopefully stimulate further experimentation toward achieving the ultimate goal of precisely defining the dominant pathogenic mechanisms operational in APS. This may pave the way for the development of improved therapies.
Atherosclerotic coronary artery disease is well recognised as an inflammatory disorder that is also influenced by oxidative stress. β2-GPI (β-2-glycoprotein-I) is a circulating plasma protein that ...undergoes post-translational modification and exists in free thiol as well as oxidized forms. The aim of this study was to assess the association between these 2 post-translational redox forms of β2-GPI and atherosclerotic coronary artery disease. Approach and Results: Stable patients presenting for elective coronary angiography or CT coronary angiography were prospectively recruited. A separate group of patients after reperfused ST-segment-elevation myocardial infarction formed an acute coronary syndrome subgroup. All patients had collection of fasting serum and plasma for quantification of total and free thiol β2-GPI. Coronary artery disease extent was quantified by the Syntax and Gensini scores. A total of 552 patients with stable disease and 44 with acute coronary syndrome were recruited. While total β2-GPI was not associated with stable coronary artery disease, a higher free thiol β2-GPI was associated with its presence and extent. This finding remained significant after correcting for confounding variables, and free thiol β2-GPI was a better predictor of stable coronary artery disease than hs-CRP (high-sensitivity C-reactive protein). Paradoxically, there were lower levels of free thiol β2-GPI after ST-segment-elevation myocardial infarction.
Free thiol β2-GPI is a predictor of coronary artery disease presence and extent in stable patients. Free thiol β2-GPI was a better predictor than high-sensitivity C-reactive protein.
Complement Factor H (CFH) is an important inhibitor of the alternate complement pathway in Bruch's membrane (BM), located between the choriocapillaris and the retinal pigment epithelium. Furthermore ...dysfunction of its activity as occurs with certain polymorphisms is associated with an increased risk of age related macular degeneration (AMD).
The retina is a site of high generation of reactive oxygen species (ROS) and dysfunction of redox homeostasis in this milieu also contributes to AMD pathogenesis. In this study we wanted to explore if CFH exists in distinct redox forms and whether these species have unique protective biological functions. CFH can be reduced by the naturally occurring thioredoxin − 1 in CFH domains 1–4, 17–20. We found a duality of function between the oxidised and reduced forms of CFH. The oxidised form was more efficient in binding to C3b and lipid peroxidation by-products that are known to accumulate in the retinae and activate the alternate complement pathway.
Oxidised CFH enhances Factor I mediated cleavage of C3 and C3b whereas the reduced form loses this activity. In the setting of oxidative stress (hydrogen peroxide)-mediated death of human retinal pigment epithelial cells as can occur in AMD, the free thiol form of CFH offers a protective function compared to the oxidised form. We found for the first time using a novel ELISA system we have developed for free thiol CFH, that both redox forms of CFH are found in the human plasma. Furthermore there is a distinct ratio of these redox forms in plasma depending if an individual has early or late AMD, with individuals with early AMD having higher levels of the free thiol form compared to late AMD.
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•CFH exists in an oxidised and reduced (free thiol) form in human plasma.•The oxidised form of CFH is more efficient in binding C3b.•The oxidised form of CFH enhances Factor I cleavage of C3 and C3b.•The free thiol form of CFH protects against free radical cell injury.•Reduced and oxidised CFH protect against early and late AMD in a reciprocal manner.
Patients with inflammatory bowel disease (IBD) have increased numbers of human tryptase-β (hTryptase-β)-positive mast cells (MCs) in the gastrointestinal tract. The amino acid sequence of mouse mast ...cell protease (mMCP)-6 is most similar to that of hTryptase-β. We therefore hypothesized that this mMCP, or the related tryptase mMCP-7, might have a prominent proinflammatory role in experimental colitis. The dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid (TNBS) colitis models were used to evaluate the differences between C57BL/6 (B6) mouse lines that differ in their expression of mMCP-6 and mMCP-7 with regard to weight loss, colon histopathology, and endoscopy scores. Microarray analyses were performed, and confirmatory real-time PCR, ELISA, and/or immunohistochemical analyses were carried out on a number of differentially expressed cytokines, chemokines, and matrix metalloproteinases (MMPs). The mMCP-6-null mice that had been exposed to DSS had significantly less weight loss as well as significantly lower pathology and endoscopy scores than similarly treated mMCP-6-expressing mice. This difference in colitis severity was confirmed endoscopically in the TNBS-treated mice. Evaluation of the distal colon segments revealed that numerous proinflammatory cytokines, chemokines that preferentially attract neutrophils, and MMPs that participate in the remodeling of the ECM were all markedly increased in the colons of DSS-treated WT mice relative to untreated WT mice and DSS-treated mMCP-6-null mice. Collectively, our data show that mMCP-6 (but not mMCP-7) is an essential MC-restricted mediator in chemically induced colitis and that this tryptase acts upstream of many of the factors implicated in IBD.
Mast cells (MCs) are active participants in blood coagulation and innate and acquired immunity. This review focuses on the development of mouse and human MCs, as well as the involvement of their ...granule serine proteases in inflammation and the connective tissue remodeling that occurs during the different phases of the healing process of wounded skin and other organs. The accumulated data suggest that MCs, their tryptases, and their chymases play important roles in tissue repair. While MCs initially promote healing, they can be detrimental if they are chronically stimulated or if too many MCs become activated at the same time. The possibility that MCs and their granule serine proteases contribute to the formation of keloid and hypertrophic scars makes them potential targets for therapeutic intervention in the repair of damaged skin.
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