Mechanism of action of β2-glycoprotein I-dependent lupus anticoagulants

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 23-28 ◽  
Author(s):  
J Amout ◽  
J Vermylen
Keyword(s):  
Mechanism Of Action ◽  
Molecular Basis ◽  
Current Knowledge ◽  
Indirect Evidence ◽  
Integrated Model ◽  
Anticardiolipin Antibodies ◽  
Pathogenic Role ◽  
Lupus Anticoagulants ◽  
Glycoprotein I

There is accumulating evidence showing that lupus anticoagulants (LA) are more strongly associated with thrombosis than anticardiolipin antibodies. In addition, indirect evidence has been presented indicating that β2GPI-dependent LA are more strongly associated with thrombosis than prothrombin-dependent LA. From this, one may assume that anti-β2GPl antibodies with LA activity are more pathogenic than anti-β2GPI antibodies without LA activity. Therefore, it is of the utmost importance to understand the molecular basis on which some anti-β2GPI antibodies behave as LA. In this presentation, the current knowledge on the interaction of β2GPI with phospholipids and with anti-β2GPI antibodies is reviewed and an integrated model for the anti-β2GPI - dependent LA activity is proposed with implications for a pathogenic role of these particular antibodies.

Antiphospholipid Syndrome: Diagnostic Aspects of Lupus Anticoagulants

2001 ◽  
Vol 86 (07) ◽  
pp. 83-91 ◽  
Author(s):  
J. Arnout
Keyword(s):  
Monoclonal Antibodies ◽  
Antiphospholipid Syndrome ◽  
Autoimmune Disorder ◽  
Coagulation Factors ◽  
Laboratory Diagnosis ◽  
Anticardiolipin Antibodies ◽  
Lupus Anticoagulants ◽  
Glycoprotein I ◽  
Antigen Antibody

SummaryAntiphospholipid syndrome (APS) is an autoimmune disorder in which antiphospholipid antibodies (aPL) are thought to be involved in the development of venous and/or arterial thrombosis. APL found in this syndrome are antibodies directed against a variety of phospholipid (PL) binding-proteins of which β2-glycoprotein I (β2GPI) and prothrombin are considered to be the major antigens. Some of these antibodies prolong PL-dependent clotting reactions and are termed lupus anticoagulants (LA). Autoimmune aPL which bind through β2GPI to cardiolipin are called anticardiolipin antibodies (aCL). Clinical studies indicate that LA is a stronger risk factor for thrombosis than aCL. The production of monoclonal antibodies against β2GPI and prothrombin has enabled us to understand the mechanism by which LA prolong coagulation in vitro. LA form bivalent antigen-antibody complexes with increased affinity for PL which compete with coagulation factors for the same catalytic surface. These LA positive monoclonal antibodies may be helpful in further improving the laboratory diagnosis of LA.

Pathophysiology of β2-glycoprotein I in antiphospholipid syndrome

Lupus ◽  
2010 ◽  
Vol 19 (4) ◽  
pp. 379-384 ◽  
Author(s):  
E. Matsuura ◽  
L. Shen ◽  
Y. Matsunami ◽  
N. Quan ◽  
M. Makarova ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Antiphospholipid Syndrome ◽  
Mechanism Of Action ◽  
Antiphospholipid Antibodies ◽  
Physiological Role ◽  
Therapeutic Strategies ◽  
Physiological Functions ◽  
Glycoprotein I ◽  
The Impact

Since β2-glycoprotein I (β2GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of β2GPI and anti-β2GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of β2GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. β2GPI’s epitopes for anti-β2GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-β2GPI antibodies are pathogenic. The pathophysiologic role of β2GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of β2GPI, its metabolites and autoantibodies to β2GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease. Lupus (2010) 19, 379—384.

scholarly journals Pathogenic role of anti-β2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin

2006 ◽  
Vol 13 (2) ◽  
pp. 189-196 ◽  
Author(s):  
N. Di Simone ◽  
P.L. Meroni ◽  
M. D’Asta ◽  
F. Di Nicuolo ◽  
M.C. D’Alessio ◽  
...  
Keyword(s):  
Human Placenta ◽  
Pathogenic Role ◽  
Glycoprotein I

scholarly journals Glyoxalases in Urological Malignancies

2017 ◽  
Author(s):  
Cinzia Antognelli ◽  
Vincenzo Nicola Talesa
Keyword(s):  
Molecular Basis ◽  
Current Knowledge ◽  
Critical Role ◽  
Cellular Damage ◽  
Survival Strategy ◽  
Urological Cancers ◽  
Urological Malignancies ◽  
Incidence And Mortality ◽  
Research Challenge

Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide and although advances have been made toward understanding the molecular basis of these diseases, a complete insight of the pathogenic mechanisms is still a research challenge for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these neoplasms for which no effective therapies exist. Glyoxalases are enzymes that catalyzes the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggest that glyoxalases, especially Glo1, would act as oncogenes in urological malignancies and be central to their initiation, growth and progression. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-PCa therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis.

scholarly journals Induction of retinopathy by fibrillar oxalate assemblies

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Dor Zaguri ◽  
Shira Shaham-Niv ◽  
Efrat Naaman ◽  
Michael Mimouni ◽  
Daniella Magen ◽  
...  
Keyword(s):  
Paradigm Shift ◽  
Molecular Basis ◽  
Metabolic Disorders ◽  
Cultured Cells ◽  
Primary Hyperoxaluria ◽  
Clinical Indication ◽  
Retinal Damage ◽  
Calcium Oxalate Crystals ◽  
Pathogenic Role

AbstractThe formation of metabolite fibrillar assemblies represents a paradigm shift in the study of human metabolic disorders. Yet, direct clinical relevance has been attributed only to metabolite crystals. A notable example for metabolite crystallization is calcium oxalate crystals observed in various diseases, including primary hyperoxaluria. We unexpectedly observed retinal damage among young hyperoxaluria patients in the absence of crystals. Exploring the possible formation of alternative supramolecular organizations and their biological role, here we show that oxalate can form ordered fibrils with no associated calcium. These fibrils inflict intense retinal cytotoxicity in cultured cells. A rat model injected with oxalate fibrils recaptures patterns of retinal dysfunction observed in patients. Antibodies purified from hyperoxaluria patient sera recognize oxalate fibrils regardless of the presence of calcium. These findings highlight a new molecular basis for oxalate-associated disease, and to our knowledge provide the first direct clinical indication for the pathogenic role of metabolite fibrillar assemblies.

scholarly journals New insights into the role of the GABAA–benzodiazepine receptor in psychiatric disorder

2001 ◽  
Vol 179 (5) ◽  
pp. 390-396 ◽  
Author(s):  
David J. Nutt ◽  
Andrea L. Malizia
Keyword(s):  
Molecular Biology ◽  
Molecular Basis ◽  
Current Knowledge ◽  
Molecular Genetic ◽  
Benzodiazepine Receptor ◽  
Receptor Complex ◽  
Genetic Studies ◽  
Substantial Growth ◽  
Disease States

BackgroundIn the 40 years since the first benzodiazepine was brought into clinical use there has been a substantial growth in understanding the molecular basis of action of these drugs and the role of their receptors in disease states.AimsTo present current knowledge about the role of the GABAA–benzodiazepine receptor in anxiety disorders, new insights into the molecular biology of the receptor complex and neuroimaging studies suggesting involvement of these receptors in disease states.MethodAn overview of published literature, including some recent data.ResultsThe molecular biology of this receptor is detailed. Molecular genetic studies suggesting involvement of the GABAA–benzodiazepine receptor in animal behaviour and learning are outlined; possible parallels with human psychopathology are discussed.ConclusionsCurrent insights into the role of the GABAA–benzodiazepine receptor in the action of benzodiazepines and as a factor in disease states, in both animals and humans, may lead to new, more sophisticated interventions at this receptor complex and potentially significant therapeutic gains.

scholarly journals The Role of Genetics in Sporadic GEP-NETs: A Comprehensive Review of the Literature

2017 ◽  
Vol 8 (1) ◽  
pp. 1-5
Author(s):  
George Fotopoulos ◽  
Ioannis Vathiotis ◽  
George C. Nikou ◽  
Konstantinos Syrigos
Keyword(s):  
Nervous System ◽  
Targeted Therapy ◽  
Personalized Medicine ◽  
Molecular Basis ◽  
Current Knowledge ◽  
Review Of The Literature ◽  
Comprehensive Review ◽  
Cell Compartments ◽  
Genomic Landscape

AbstractNeuroendocrine tumors (NETs) are composed of a heterogeneous group of malignancies from neuroendocrine cell compartments, with roles in both the endocrine and the nervous system. The majority of NETs are gastroenteropancreatic (GEP) in origin, arising in the foregut, midgut, or hindgut. The genomic landscape of GEP-NETs has been scarcely studied in terms of genomic profiling.The following algorithm was followed using the keywords neuroendocrine, genomics, targeted therapy, personalized medicine, gastroenteropancreatic and NET. The search was performed in PubMed and ScienceDirect database. Our current knowledge of sporadic GEP-NETs genetics must be further advanced to elucidate the molecular basis and pathogenesis of the disease, improve the accuracy of diagnosis, and guide tailor-made therapies.

scholarly journals Molecular Basis of Inflammation in the Pathogenesis of Cardiomyopathies

2020 ◽  
Vol 21 (18) ◽  
pp. 6462
Author(s):  
Emanuele Monda ◽  
Giuseppe Palmiero ◽  
Marta Rubino ◽  
Federica Verrillo ◽  
Federica Amodio ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Molecular Targets ◽  
Diverse Group ◽  
Myocardial Diseases ◽  
Immune System Activation ◽  
System Activation ◽  
Sarcomeric Genes

Cardiomyopathies (CMPs) represent a diverse group of heart muscle diseases, grouped into specific morphological and functional phenotypes. CMPs are associated with mutations in sarcomeric and non-sarcomeric genes, with several suspected epigenetic and environmental mechanisms involved in determining penetrance and expressivity. The understanding of the underlying molecular mechanisms of myocardial diseases is fundamental to achieving a proper management and treatment of these disorders. Among these, inflammation seems to play an important role in the pathogenesis of CMPs. The aim of the present study is to review the current knowledge on the role of inflammation and the immune system activation in the pathogenesis of CMPs and to identify potential molecular targets for a tailored anti-inflammatory treatment.

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