Dysfunction In Antiphospholipid Syndrome Research Articles

Pyroptosis-triggered pathogenesis: New insights on antiphospholipid syndrome.

APS (antiphospholipid syndrome) is a systematic autoimmune disease presenting with the high levels of aPLs (antiphospholipid antibodies). These autoantibodies are involved in various clinical manifestations, mainly including arterial or venous thrombosis formation, proinflammatory response, and recurrent pregnant loss. Pyroptosis is a form of lytic programmed cell death, and it aggravates autoimmune diseases progression via activating NOD-like receptors, especially the NLRP3 inflammasome and its downstream inflammatory factors IL (interleukin)-1β and IL-18. However, the underlying mechanisms of pyroptosis-induced APS progression remain to be elucidated. ECs (endothelial cells), monocytes, platelets, trophoblasts, and neutrophils are prominent participants in APS development. Of significance, pyroptosis of APS-related cells leads to the excessive release of proinflammatory and prothrombotic factors, which are the primary contributors to APOs (adverse pregnancy outcomes), thrombosis formation, and autoimmune dysfunction in APS. Furthermore, pyroptosis-associated medicines have made encouraging advancements in attenuating inflammation and thrombosis. Given the potential of pyroptosis in regulating APS development, this review would systematically expound the molecular mechanisms of pyroptosis, and elaborate the role of pyroptosis-mediated cellular effects in APS progression. Lastly, the prospective therapeutic approaches for APS would be proposed based on the regulation of pyroptosis.

Mechanisms of Endothelial Dysfunction in Antiphospholipid Syndrome: Association With Clinical Manifestations.

The endothelium is a monolayer of cells that covers the inner surface of blood vessels and its integrity is essential for the maintenance of vascular health. Endothelial dysfunction is a key pathological component of antiphospholipid syndrome (APS). Its systemic complications include thrombotic endocarditis, valvular dysfunction, cerebrovascular occlusions, proliferative nephritis, deep vein thrombosis, and pulmonary embolism. In women, APS is also associated with pregnancy complications (obstetric APS). The conventional treatment regimens for APS are ineffective when the clinical symptoms are severe. Therefore, a better understanding of alterations in the endothelium caused by antiphospholipid antibodies (aPL) may lead to more effective therapies in patients with elevated aPL titers and severe clinical symptoms. Currently, while in vivo analyses of endothelial dysfunction in patients with APS have been reported, most research has been performed using in vitro models with endothelial cells exposed to either patient serum/plasma, monoclonal aPL, or IgGs isolated from patients with APS. These studies have described a reduction in endothelial cell nitric oxide synthesis, the induction of inflammatory and procoagulant phenotypes, an increase in endothelial proliferation, and impairments in vascular remodeling and angiogenesis. Despite these lines of evidence, further research is required to better understand the pathophysiology of endothelial dysfunction in patients with APS. In this review, we have compared the current understanding about the mechanisms of endothelial dysfunction induced by patient-derived aPL under the two main clinical manifestations of APS: thrombosis and gestational complications, either alone or in combination. We also discuss gaps in our current knowledge regarding aPL-induced endothelial dysfunction.

Antiphospholipid Syndrome--Not a Noninflammatory Disease.

The autoimmune disease antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity in patients with persistent antiphospholipid antibodies (aPLs). Although inflammation is not a key feature of the clinical presentation of the syndrome, there are indications that the inflammatory response plays an important role in APS. The major antigen of aPLs, the plasma protein β2-glycoprotein I, is involved in clearance of microparticles and in the innate immune response. In light of these physiological functions, the formation of antibodies against the protein is easily understood, as antibodies might augment the clearance reaction. In addition, inflammatory mediators are thought to play a role in the activation of leukocytes and the induction of endothelial dysfunction in APS. Moreover, evidence for a role of complement activation in the pathogenesis of the syndrome is accumulating. This review will provide an overview of current knowledge on the physiological function of β2-glycoprotein I, the formation of autoantibodies against β2-glycoprotein I and will explore the contribution of inflammation to the clinical manifestations of APS.

Infliximab improves endothelial dysfunction in a mouse model of antiphospholipid syndrome: Role of reduced oxidative stress

Antiphospholipid syndrome (APS), induces endothelial dysfunction, oxidative stress and systemic inflammation that may be mediated by TNFα. Thus, we investigated the possible protective effect of the anti-TNFα antibody infliximab (5μg/g) on endothelial function in a mouse APS model (induced by injection of purified human anti-β2GP1-IgG).Seven days after anti-β2GPI-IgG injection, we observed an increase in plasma sVCAM-1 and sE-selectin levels and in aortic mRNA expression of VCAM-1 and E-selectin. This was associated with a decreased endothelium-dependent relaxation of isolated mesenteric arteries to acetylcholine, together with decreased mesenteric eNOS mRNA expression and increased eNOS uncoupling, accompanied by increased iNOS and gp91phox mRNA and increased left ventricular GSH/GSSH ratio. Infliximab significantly improved the NO-mediated relaxing responses to acetylcholine, and induced a decrease in iNOS and gp91phox mRNA expression. The õpro-adhesive and pro-coagulant phenotypes induced by the anti-β2GP1-IgG were also reversed.This study provides the first evidence that TNFα antagonism improves endothelial dysfunction in APS and suggests that endothelial dysfunction is mediated by TNFα and oxidative stress. Therefore, infliximab may be of special relevance in clinical practice.

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q10 treatment

AbstractThe exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q10 (CoQ10). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ10 preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ10 significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS–induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ10.

Autonomic dysfunction and primary antiphospholipid syndrome: a frequent and frightening correlation?

Introductionthe correlation between primary antiphospholipid syndrome (APS) and cardiovascular events is well known, but the correlation between APS and sudden death is not clear; it probably correlates with sympathetic alterations of the autonomic system.AimTo compare the autonomic nervous system (ANS) in a group of subjects suffering from APS against that of a control group with no cardiovascular risk factors, matched for age, sex, and body mass index.Subjects and methodsAn equal number (n = 31) of subjects with APS, and healthy controls, underwent autonomic evaluation: tilt test, deep breath, Valsalva maneuver, hand grip, lying-to-standing, Stroop, and sweat tests.ResultsCases in the APS group were positive for the tilt test, relating to changes in respiratory rate intervals, by comparison with controls. Results of other tests were also altered significantly in APS cases, by comparison with controls. (The sweat and Stroop tests were only performed in 14 cases). Autonomic disease did not correlate with age, sex, history of disease, arterial or venous thrombosis, or antibody positivity; only their coagulation parameters correlated with autonomic dysfunction.ConclusionAutonomic dysfunction in APS seems to correlate with coagulation parameters. APS patients should receive autonomic evaluation, to minimize the risks of fatal arrhythmias and sudden death.

The Pathogenesis of Neural Injury in Animal Models of the Antiphospholipid Syndrome

Circulating antiphospholipid antibodies (aPL) are associated with central nervous system dysfunction in antiphospholipid syndrome (APS) patients and in a mouse model of APS. We propose a logical pathway of how experimental APS (eAPS) causes brain dysfunction: binding of the antibodies to the brain endothelium evoking microthrombosis, endothelial dysfunction, and IgG leakage through the blood-brain barrier (BBB), then secondary inflammatory cell spread around blood vessels and production of cytokines by these inflammatory cells leading to further disruption of the BBB. The diffuse brain endothelial dysfunction would result in extravasation of serum proteins including APS IgG and activated thrombin, which may induce the behavioral changes observed in the APS mice. We have collected data from the mouse eAPS model which supports this hypothesis. Elucidating the mechanism of the pathogenicity of aPL in vitro and in vivo will serve as a much needed basis for developing new therapeutic modalities in this important disorder.

Cognitive Deficits in Patients With Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by arterial and venous thromboses, pregnancy morbidity, and various neuropsychiatric manifestations. Cognitive dysfunction in APS has been poorly recognized. We examined for the first time, to our knowledge, the presence of cognitive dysfunction in patients with APS and its association with clinical, laboratory, and cerebral magnetic resonance imaging characteristics. Sixty patients (39 with primary APS and 21 with systemic lupus erythematosus-related APS) and 60 healthy individuals matched for age, sex, and education were examined by means of a comprehensive 3-hour battery of neuropsychological tests. Twenty-three patients had a history of central nervous system involvement. Fifty-nine of 60 patients underwent brain magnetic resonance imaging at the time of neuropsychological assessment. A disease control group not fulfilling criteria for APS (15 patients with systemic lupus erythematosus and 10 with rheumatoid arthritis) was also included. The demographic, clinical, and laboratory characteristics of patients were recorded. Twenty-five (42%) of the 60 patients with APS had cognitive deficits compared with 11 (18%) healthy control subjects (P = .005). No patient was diagnosed as having dementia. The most commonly involved cognitive domains were complex attention and verbal fluency. No difference was found in cognitive performance between patients with primary APS and those with systemic lupus erythematosus-related APS. No relationship was detected between cognitive dysfunction and prior central nervous system disease. We noted a significant association between cognitive dysfunction and livedo reticularis (P = .004) as well as between cognitive dysfunction and the presence of white matter lesions on the findings of brain magnetic resonance imaging (P=.01). No difference was detected in cognitive performance between the disease control group and healthy individuals (P=.86). Cognitive deficits may often be found among patients with APS, independent of any history of central nervous system involvement. Livedo reticularis and the presence of white matter lesions on brain magnetic resonance imaging are associated with an increased risk for cognitive dysfunction in APS.

Valvular dysfunction in antiphospholipid syndrome: Prevalence, clinical features, and treatment

Valvular abnormalities develop in 36% and 35% of patients with primary antiphospholipid syndrome (PAPS) and with systemic lupus erythematosus (SLE) respectively, and in 48% of patients with SLE and antiphospholipid antibodies (aPL). Valvulopathy includes leaflet thickening, vegetations, regurgitation, and stenosis. A literature survey shows that significant morbidity from valvular dysfunction, mostly mitral regurgitation leading to congestive heart failure, occurs in 4% and 6% of SLE and PAPS patients, respectively. The pathogenesis of valvulopathy may involve interaction of aft with antigens on the valve surface, resulting in valvulitis. Current therapy includes symptomatic measures and valve replacement. A novel approach for symptomatic antiphospholipid syndrome (APS) related valvulopathy involves treatment with systemic corticosteroids. We describe four such patients and their dramatic clinical and hemodynamic response to treatment with prednisone when symptomatic measures failed.