Pathogenic Role of Complement in Antiphospholipid Syndrome and Therapeutic Implications

Abstract

Antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by thromboembolic events, pregnancy morbidity, and the presence of antiphospholipid (aPL) antibodies. There is sound evidence that aPL act as pathogenic autoantibodies being responsible for vascular clots and miscarriages. However, the exact mechanisms involved in the clinical manifestations of the syndrome are still a matter of investigation. In particular, while vascular thrombosis is apparently not associated with inflammation, the pathogenesis of miscarriages can be explained only in part by the aPL-mediated hypercoagulable state and additional non-thrombotic effects, including placental inflammation, have been described. Despite this difference, evidence obtained from animal models and studies in APS patients support the conclusion that complement activation is a common denominator in both vascular and obstetric APS. Tissue-bound aPL rather than circulating aPL-beta2 glycoprotein I immune complexes seem to be responsible for the activation of the classical and the alternative complement pathways. The critical role of complement is supported by the finding that complement-deficient animals are protected from the pathogenic effect of passively infused aPL and similar results have been obtained blocking complement activation. Moreover, elevated levels of complement activation products in the absence of abnormalities in regulatory molecules have been found in the plasma of APS patients, strongly suggesting that the activation of complement cascade is the result of aPL binding to the target antigen rather than of a defective regulation. Placental complement deposits represent a further marker of complement activation both in animals and in patients, and there is also some suggestive evidence that complement activation products are deposited in the affected vessels. The aim of this review is to analyze the state of the art of complement involvement in the pathogenesis of APS in order to provide insights into the role of this system as predictive biomarker for the clinical manifestations and as therapeutic target.

Mitigating placental injuries through up-regulating DAF in experimental APS mice: new mechanism of progesterone

“…However, aPL can not only activate blood cells and blood coagulation factors, but can also mediate complement activation directly or indirectly [9,10]. Despite thrombosis and ischaemic damage, complement over-activation in placenta has gradually been revealed to be another important mechanism in forming APS pathological injuries [9][10][11][12]. aPL has complicated cross-reactions among complement, coagulation and inflammation systems [13].…”

“…β2GPI can immobilize on anionic phospholipid surfaces such as endothelial cells , platelets and monocytes to expose specific epitopes for aPL to bind, thereby activating them to produce a procoagulant and proinflammatory phenotype . However, aPL can not only activate blood cells and blood coagulation factors, but can also mediate complement activation directly or indirectly . Despite thrombosis and ischaemic damage, complement over‐activation in placenta has gradually been revealed to be another important mechanism in forming APS pathological injuries .…”

Lung Disease in Antiphospholipid Syndrome

“…9 Activation of the complement cascade is an additional critical effector mechanism in aPL-associated thrombosis, amplifying aPL deleterious effects by stimulating the generation of potent proinflammatory mediators such as C3a, C5a, and the C5b-9 membrane attack complex (MAC). 34 The management of APS patients with VTE parallels the therapeutic approach reserved to the general population. Thrombolysis or pulmonary embolectomy should be the preferred therapeutic option for hemodynamically unstable patients, such those presenting with right ventricular hypokinesis and hypotension.…”

“…104 aPL-mediated complement initiation may also lead to C5a-mediated neutrophil activation, which further contributes to this process. 34 The pathogenic action of aPLs in the lungs might be facilitated by the pulmonary microbiota: indeed, microorganisms might activate TLRs, thus acting as a second hit. 9,105 Microvascular thrombosis and rupture of small pulmonary vessels have also been suggested as potential pathogenic mechanisms of DAH in APS.…”

From Superficial Damage to Invasion of the Nucleosome: Ranking of Morbidities by the Biosemiotic Depth Hypothesis

“…Of course, in addition to depth of penetration into the body's biosemiotic regulating systems, it is also necessary to take account of the timing of damage with respect to the developmental growth spiral. All else being equal, biosemiotic damage occurring earlier in the growth spiral (unless it can be repaired), must be ranked as more harmful than later damage on account of the proportion of self-cells to be impacted downstream [149], [224]. Similarly, if timing and the extent of damage to particular self cells is held equal, earlier and therefore deeper penetration of the damage into regulating systems, provided it cannot be repaired, the more harmful it can be downstream.…”