scholarly journals Activator-specific requirement of properdin in the initiation and amplification of the alternative pathway complement

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 732-740 ◽  
Author(s):  
Yuko Kimura ◽  
Takashi Miwa ◽  
Lin Zhou ◽  
Wen-Chao Song
Keyword(s):  
Gene Targeting ◽  
Binding Affinity ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Meningococcal Infection ◽  
Mouse Serum ◽  
Specific Requirement ◽  
Cobra Venom Factor ◽  
Complement Activity

Properdin is a positive regulator of alternative pathway (AP) complement. The current understanding of properdin function is that it facilitates AP complement activation by stabilizing the C3 convertase C3bBb. Properdin-deficient patients are susceptible to lethal meningococcal infection, but the mechanism of this selective predisposition is not fully understood. By gene targeting in the mouse, we show here that properdin is essential for AP complement activation induced by bacterial lipopolysacharride (LPS) and lipooligosacharride (LOS) and other, but not all, AP complement activators. LPS- and LOS-induced AP complement activation was abolished in properdin−/− mouse serum, and properdin−/− mice were unable to clear Crry-deficient erythrocytes, which are known to be susceptible to AP complement–mediated extravascular hemolysis. In contrast, zymosan- and cobra venom factor–induced AP complement activation, and classical pathwaytriggered AP complement amplification were only partially or minimally affected in properdin−/− mice. We further show that the ability of human properdin to restore LPS-dependent AP complement activity in properdin−/− mouse serum correlated with the human properdin-binding affinity of the LPS. These results reveal a novel role of properdin in AP complement initiation and have implications for understanding the selective predisposition of properdin-deficient patients to meningococcal infection.

ROLE OF THE ALTERNATIVE PATHWAY IN THE EARLY COMPLEMENT ACTIVATION FOLLOWING MAJOR TRAUMA

Shock ◽  
2007 ◽  
Vol 28 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Michael T. Ganter ◽  
Karim Brohi ◽  
Mitchell J. Cohen ◽  
Lisa A. Shaffer ◽  
Mary C. Walsh ◽  
...  
Keyword(s):  
Complement Activation ◽  
Major Trauma ◽  
Alternative Pathway

scholarly journals Complement Activation via Alternative Pathway Is Critical in the Development of Laser-Induced Choroidal Neovascularization: Role of Factor B and Factor H

2006 ◽  
Vol 177 (3) ◽  
pp. 1872-1878 ◽  
Author(s):  
Nalini S. Bora ◽  
Sankaranarayanan Kaliappan ◽  
Purushottam Jha ◽  
Qin Xu ◽  
Jeong-Hyeon Sohn ◽  
...  
Keyword(s):  
Choroidal Neovascularization ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Factor H ◽  
Factor B

scholarly journals Primer komplementdefektusok által okozott atípusos haemolyticus uraemiás szindróma

2018 ◽  
Vol 159 (23) ◽  
pp. 929-936 ◽  
Author(s):  
György Reusz
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Critical Role ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Genetic Diagnostics ◽  
Activation Process ◽  
Phagocytic Cells ◽  
Uremic Syndrome ◽  
The Complement System

Abstract: Complement is one of the most archaic parts of the innate immune system, which enhances the ability of antibodies and phagocytic cells to clear cell debris, and microorganisms. The complement system promotes inflammation and attacks the pathogen’s plasma membrane. Malfunction of the system may lead to the development of autoimmunity or uncontrolled infections. Further, dysregulation of the tightly controlled complement activation process may lead to thrombotic microangiopathies with consequent multiorgan involvement. The present paper gives a short overview of the different pathways of complement activation. It focuses on primary genetic defects of components of the alternative pathway that result in dysregulation as well as on pathomechanism, classification, diagnostics and treatment of atypical hemolytic uremic syndrome (aHUS) based on the most recent international recommendations and guidelines. Finally the critical role of complement in host immunity and genetic diagnostics of complement deficiencies are illustrated with two cases of aHUS. Orv Hetil. 2018; 159(23): 929–936.

scholarly journals Complement Factor D protects mice from ethanol-induced inflammation and liver injury

2018 ◽  
Vol 315 (1) ◽  
pp. G66-G79 ◽  
Author(s):  
Rebecca L. McCullough ◽  
Megan R. McMullen ◽  
Megan M. Sheehan ◽  
Kyle L. Poulsen ◽  
Sanjoy Roychowdhury ◽  
...  
Keyword(s):  
Liver Injury ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Chronic Ethanol ◽  
Apoptotic Cells ◽  
Complement Factor ◽  
Complement Protein ◽  
Short Term ◽  
Pathway Activation

Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa−/−, lacking classical pathway activation), complement protein 4-deficient ( C4−/−, lacking classical and lectin pathway activation), complement factor D-deficient ( FD−/−, lacking alternative pathway activation), and C1qa/FD−/− (lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa−/−, C4−/−, or C1qa/FD−/− mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD−/− mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD−/− mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD−/− mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.

scholarly journals C3b-Independent Complement Activation in Ischemia/Reperfusion Mesenteric Tissue Injury in Autoimmune Prone (B6.MRL/lpr) Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
J. Tofferi ◽  
S. Peng ◽  
C. M. Moratz
Keyword(s):  
Lupus Erythematosus ◽  
Complement Activation ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cobra Venom ◽  
Cobra Venom Factor ◽  
Inflammatory Tissue

Complement plays a critical role in the development of tissue injury in systemic lupus erythematosus. The B6.MRL/lpr mouse, an autoimmune prone mouse, exhibits accelerated and intensified tissue injury in the ischemia/reperfusion (IR) model. It has been demonstrated in nonautoimmune mice that inhibition of complement attenuates inflammatory tissue injury in IR models. The role of complement is not as clear in the B6.MRL/lpr strain. B6.MRL/lpr-C3 deficient animals are susceptible to injury, but long-term use of C3 inhibitors in B6.MRL/lpr-C3 competent animals restrained the development of nephritis. To clarify the role of complement in the B6.MRL/lpr strain, initial and midpathway inhibitors were evaluated. C1 inhibition attenuated tissue injury, thrombin deposition, and C5a generation in the B6.MRL/lpr strain. Downstream of C1 inhibition of C3 activation by administration of cobra venom factor suppressed IR injury in immune competent mice, but was not as effective in B6.MRL/lpr mice. C3 levels in both strains were decreased after cobra venom factor treatment; however, C5a generation, thrombin deposition, and tissue injury were observed in the B6.MRL/lpr strain. These studies suggest that in the B6.MRL/lpr autoimmune prone strain C1 activation leads to C3-dependent and C3-independent pathways of complement activation.

Possible role of glucocorticoids in a complement-activated state induced by cobra venom factor in rats

1986 ◽  
Vol 112 (1) ◽  
pp. 122-129 ◽  
Author(s):  
Kiwao Nakano ◽  
Seiji Suzuki ◽  
Oh Chanho ◽  
Kazuo Yamashita
Keyword(s):  
Complement Activation ◽  
Serum Levels ◽  
Iron Chelator ◽  
Cobra Venom ◽  
Cyclooxygenase Inhibitors ◽  
Cobra Venom Factor ◽  
Deferoxamine Mesylate ◽  
Thromboxane Synthetase ◽  
Activated State

Abstract. Activation of the complement system of adrenalectomized rats with an injection of cobra venom factor (CVF) caused death of the rats within 2.5 h. Morphologically, this activation provoked distinct congestion of the gastric glandular mucosa and pulmonary leukostasis. Pretreatment of the animals with dexamethasone abolished the undesirable responses completely. Injection of CVF to intact rats produced only slight responses, but caused a marked increase in the serum levels of corticosterone. Dexamethasone was found to be replaced by promethazine (H1-antihistamine) or dimethylsulphoxide (scavenger of hydroxyl radicals) but not by indomethacine, ibuprofen (cyclooxygenase inhibitors), deferoxamine mesylate (iron chelator) or imidazole (thromboxane synthetase inhibitor). These results suggest that glucocorticoids protect the animals from the adverse effects of excessive complement activation and that they act as an inhibitor of the production or action of histamine and toxic oxygen products induced by complement activation.

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