Activated complement classical pathway in a murine model of oxygen-induced retinopathy

AIM: To investigate whether the complement system is involved in a murine model of oxygen-induced retinopathy(OIR).METHODS: Forty C57BL/6J newborn mice were divided randomly into OIR group and control group. OIR was induced by exposing mice to 75% ±2% oxygen from postnatal 7d(P7) to P12 and then recovered in room air.For the control group, the litters were raised in room air.At the postnatal 17d(P17), gene expressions of the complement components of the classical pathway(CP),the mannose-binding lectin(MBL) pathway and the alternative pathway(AP) in the retina were determined by quantitative real-time polymerase chain reaction(RT-PCR). Retinal protein expressions of the key components in the CP were examined by Western blotting.· RESULTS: Whole mounted retina in the OIR mice showed area of central hypoperfusion in both superficial and deep layers and neovascular tufts in the periphery.The expressions of C1 qb and C4 b genes in the OIR retina were significantly higher than those of the controls. The expression of retinal complement factor B(CFB) gene in OIR mice was significantly lower than those of the controls. However, the expressions of C3 and complement factor H(CFH) genes were higher. The protein synthesis of the key components involved in the CP(C1q, C4 and C3) were also significantly higher in OIR mouse retina. Although MBL-associated serine protease 1(MASP1) and MASP2 were detected in both the OIR and the control groups, the expressions were weak and the difference between the two groups was not significant.CONCLUSION: Our data suggest that the complement system CP is activated during the pathogenesis of murine model of OIR.

Complement activation by phospholipids: the interplay of factor H and C1q

Complement proteins in blood recognize charged particles.The anionic phospholipid(aPL)cardiolipin binds both complement proteins C1q and factor H.C1q is an activator of the complement classical pathway,while factor H is an inhibitor of the alternative pathway.To examine opposing effects of C1q and factor H on complement activation by aPL,we surveyed C1q and factor H binding,and complement activation by aPL,either coated on microtitre plates or in liposomes.Both C1q and factor H bound to all aPL tested,and competed directly with each other for binding.All the aPL activated the complement classical pathway,but negligibly the alternative pathway,consistent with accepted roles of C1q and factor H.However,in this system,factor H,by competing directly with C1q for binding to aPL,acts as a direct regulator of the complement classical pathway.This regulatory mechanism is distinct from its action on the alternative pathway.Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range.Thus factor H,which is regarded as a down-regulator only of the alternative pathway,has a distinct role in downregulating activation of the classical complement pathway by aPL.A factor H homologue,β2-glycoprotein-1,also strongly inhibits C1q binding to cardiolipin.Recombinant globular domains of C1q A,B and C chains bound aPL similarly to native C1q,confirming that C1q binds aPL via its globular heads.

Inhibition of vertebrate complement system by hematophagous arthropods: inhibitory molecules, mechanisms, physiological roles, and applications

In arthropods,hematophagy has arisen several times throughout evolution.This specialized feeding behavior offered a highly nutritious diet obtained during blood feeds.On the other hand,blood-sucking arthropods must overcome problems brought on by blood intake and digestion.Host blood complement acts on the bite site and is still ac-tive after ingestion,so complement activation is a potential threat to the host's skin feed-ing environment and to the arthropod gut enterocytes.During evolution,blood-sucking arthropods have selected,either in their saliva or gut,anticomplement molecules that inac-tivate host blood complement.This review presents an overview of the complement sys-tem and discusses the arthropod's salivary and gut anticomplement molecules studied to date,exploring their mechanism of action and other aspects related to the arthropod-host-pathogen interface.The possible therapeutic applications of arthropod's anticomplement molecules arealsodiscussed.