Initiation of Complement Activation

Lachmann, P. J.; Hughes‐Jones, N. C.

doi:10.1007/978-3-642-82416-6_8

Cited by 51 publications

(49 citation statements)

References 40 publications

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“…The mechanism responsible for this spontaneous activation remains uncertain. However, it is well known that the alternative pathway is continually activated at a low level in plasma (30), and that damage to circulating cells and endothelium is restricted by membrane-bound and circulating complement inhibitors. Indeed, we have previously shown that systemic inhibition of membrane complement regulators in rats permits spontaneous MIZUNO ET AL complement activation and causes severe shock in rats (14).…”

Section: Discussionmentioning

confidence: 99%

The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats

Mizuno

Nishikawa

Goodfellow

et al. 1997

Arthritis & Rheumatism

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Objective. To investigate the roles of CD59 in the synovial tissue by functional suppression of CD59.Methods. Rats treated with cobra venom factor to deplete complement or untreated rats were injected intraarticularly with 0.3 mg of the F(ab'), fraction of a monoclonal antibody, 6D1, that inhibits the function of rat CD59. The circumference of knee joints was measured, and histologic changes in the synovium were studied.Results. Joint swelling, thickening of the synovial tissues, infiltration of inflammatory cells into the synovium, and deposition of membrane attack complex (MAC) on the synovial surface were observed after intraarticular injection of 6D1. The inflammatory reaction reached its peak at 24 hours after injection, and finally subsided to normal within 3 days. It was suggested that functional suppression of CD59 in the synovium induced MAC formation followed by synovitis. Serum complement depletion did not completely suppress this reaction. This indicates that complement existing in the joint space is important for the formation of MAC on the synovial surface and for induction of synovitis.Conclusion. The membrane-bound complement regulatory protein, CD59, plays a key role in the protection of joints against MAC-mediated synovial injury and in maintaining the normal integrity of the joint.The membrane attack complex (MAC; C5b-9) is known to trigger the synthesis and release of various

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Section: Discussionmentioning

confidence: 99%

The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats

Mizuno

Nishikawa

Goodfellow

et al. 1997

Arthritis & Rheumatism

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“…The binding of these recognition proteins then allows C1q to be directly bound, initiating the classical pathway activation cascade (reviewed in Ref. 15; Fig. 1).…”

Section: Mechanisms Of Alternative Pathway Activationmentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

393

350

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The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

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“…8,9,[13][14][15] In addition, the classical and alternative pathways are capable of low grade "tick-over" activity. 16,17 Previous experimental work has focused on the effects of natural or experimental deficiency of individual complement pathway components. Relevant studies are as follows: (1) rabbits with natural deficiency of C6 have been shown to be protected from diet-induced atherosclerosis 18,19 ; (2) although C5 deficiency has been found to have no effect on lesion development in high fat diet-fed ApoE Ϫ/Ϫ mice, 20 a recent study has shown protective effects of an anti-C5 antibody in ApoE Ϫ/Ϫ mice deficient in both Cd59a and ) show accelerated atherosclerosis with increased lesion complexity.…”

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confidence: 99%

Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Leung

Yun

Botto

et al. 2009

The American Journal of Pathology

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Decay-accelerating factor (DAF; CD55) is a membrane protein that regulates complement pathway activity at the level of C3. To test the hypothesis that DAF plays an essential role in limiting complement activation in the arterial wall and protecting from atherosclerosis, we crossed DAF gene targeted mice (daf-1 ؊/؊ ) with low-density lipoprotein-receptor deficient mice (Ldlr ؊/؊ ). Daf-1 ؊/؊ Ldlr ؊/؊ mice had more extensive en face Sudan IV staining of the thoracoabdominal aorta than Ldlr ؊/؊ mice, both following a 12-week period of low-fat diet or a high-fat diet. Aortic root lesions in daf-1 ؊/؊ Ldlr ؊/؊ mice on a low-fat diet showed increased size and complexity. DAF deficiency increased deposition of C3d and C5b-9 , indicating the importance of DAF for downstream complement regulation in the arterial wall. The acceleration of lesion development in the absence of DAF provides confirmation of the proinflammatory and proatherosclerotic potential of complement activation in the Ldlr ؊/؊ mouse model. Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement.

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Initiation of Complement Activation

Cited by 51 publications

References 40 publications

The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats

The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats

The Central Role of the Alternative Complement Pathway in Human Disease

Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

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