Activation of the alternative pathway of human complement by autologous cells expressing transmembrane recombinant properdin

Vuagnat, Bernard B; Mach, Jean‐Pierre; Doussal, Jean-Marc Le

doi:10.1016/s0161-5890(00)00069-9

Cited by 17 publications

(13 citation statements)

References 46 publications

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“…Properdin functions in the alternative path by stabilizing the fluid phase C3 convertase. Recent studies indicate that properdin can directly activate the alternative pathway by binding sulfated glycoconjugates (Holt et al, 1990) and specific target surfaces (Spitzer et al, 2007; Vuagnat et al, 2000). C3 was detected in the immunocomplex in the intestinal tissues of I/R-treated mice (I/R=105±14 Unit/mg.ml −1 , n=8, vs. Sham=45±19 Unit/mg.ml −1 , n=8, p<0.05) (Fig.5a).…”

Section: Resultsmentioning

confidence: 99%

“…A recent view is that there are two models for alternative pathway: 1) the standard model by C3 hydrolysis, and 2) the properdin-directed model (Holt et al, 1990; Spitzer et al, 2007; Vuagnat et al, 2000). The first model also needs properdin (Factor P) to stabilize the fluid phase C3 convertase, C3(H2O)Bb.…”

Section: Discussionmentioning

confidence: 99%

“…The alternative pathway is activated by spontaneous hydrolysis of C3 which allows the binding of factor B (Janeway et al, 2004). Some recent studies also suggested that properdin (factor P) may directly activate the alternative pathway (Holt et al, 1990; Spitzer et al, 2007; Vuagnat et al, 2000). The lectin complement pathway is triggered by MBL recognizing certain patterns of carbohydrate structures (Gadjeva et al, 2004; Roos et al, 2003; Tsutsumi et al, 2005; Turner, 2003; Worthley et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury

Lee

Green

Lai

et al. 2010

Molecular Immunology

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Recent work reveals that the innate immune system is able to recognize self targets and initiate an inflammatory response similar to that of pathogens. One novel example of this innate autoimmunity is ischemia/reperfusion (I/R) injury, in which reperfusion of the ischemic tissues elicits an acute inflammatory response activated by natural IgM (nIgM) binding to ischemia-specific self antigens, which are non-muscle myosin heavy chains type II (NMHC-II) subtype A and C. Subsequently, the complement lectin pathway is activated and eventually tissue injury occurs. Although earlier studies in the intestinal model showed that the classical complement pathway did not initiate I/R injury, C1q deposition was still observed in the local injured tissues by imaging analysis. Moreover, the involvement of the alternative complement pathway became unclear due to conflicting reports using different knockout mice. To explore the immediate downstream pathway following nIgM-ischemic antigen interaction, we isolated the nIgM-ischemic antigen immunocomplexes from the local tissue of animals treated in the intestinal I/R injury model, and examined the presence of initial molecules of three complement pathways. Our results showed that mannan-binding lectin (MBL), the early molecule of the lectin pathway, was present in the nIgM-ischemic Ag immunocomplex. In addition, C1q, the initial molecule of the classical pathway was also detected on the immunocomplex. However, Factor B, the early molecule in the alternative pathway, was not detected in the immunocomplex. To further examine the role of the alternative pathway in I/R injury, we utilized Factor B knockout mice in the intestinal model. Our results showed that Factor B knockout mice were not protected from local tissue injury, and their complement system was activated in the local tissues by nIgM during I/R. These results indicated that the lectin complement pathway operates immediately downstream of the nIgM-ischemic antigen interaction during intestinal I/R. Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury

Lee

Green

Lai

et al. 2010

Molecular Immunology

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“…In principle, the AP could be activated wherever properdin is bound (26,41). To test this prediction, we constructed a bifunctional recombinant protein consisting of a human properdin domain fused to a single-chain Ab (scFv) domain that recognizes the abundant E M surface Ag GPA (31).…”

Section: Directing Complement Activation With Properdinmentioning

confidence: 99%

Properdin Can Initiate Complement Activation by Binding Specific Target Surfaces and Providing a Platform for De Novo Convertase Assembly

Spitzer

Mitchell

Atkinson

et al. 2007

The Journal of Immunology

262

243

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Complement promotes the rapid recognition and elimination of pathogens, infected cells, and immune complexes. The biochemical basis for its target specificity is incompletely understood. In this report, we demonstrate that properdin can directly bind to microbial targets and provide a platform for the in situ assembly and function of the alternative pathway C3 convertases. This mechanism differs from the standard model wherein nascent C3b generated in the fluid phase attaches nonspecifically to its targets. Properdin-directed complement activation occurred on yeast cell walls (zymosan) and Neisseria gonorrhoeae. Properdin did not bind wild-type Escherichia coli, but it readily bound E. coli LPS mutants, and the properdin-binding capacity of each strain correlated with its respective serum-dependent AP activation rate. Moreover, properdin:single-chain Ab constructs were used to direct serum-dependent complement activation to novel targets. We conclude properdin participates in two distinct complement activation pathways: one that occurs by the standard model and one that proceeds by the properdin-directed model. The properdin-directed model is consistent with a proposal made by Pillemer and his colleagues >50 years ago.

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“…This goes beyond the “convertase stabilizer” function, in which properdin binds only once the convertase is already formed. Additional evidence supporting the ability of properdin to initiate complement activation (by forming de novo C3 convertases on cell surfaces) comes from studies where human embryonic kidney cells (Vuagnat et al, 2000) or Escherichia coli (Spitzer et al, 2007) were transfected with a vector expressing a transmembrane form of properdin on the cell surface, turning the cell surface into an activator of the AP.…”

Section: Properdin: An Ancient Complement Regulatory Molecule Of the mentioning

confidence: 99%

Local release of properdin in the cellular microenvironment: role in pattern recognition and amplification of the alternative pathway of complement

Cortés¹,

Ohtola²,

Saggu³

et al. 2013

Front. Immun.

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Properdin, the only positive regulatory protein of the complement system, acts as both a stabilizer of the alternative pathway (AP) convertases and as a selective pattern recognition molecule of certain microorganisms and host cells (i.e., apoptotic/necrotic cells) by serving as a platform for de novo C3b,Bb assembly. Properdin, a highly positively charged protein, normally exists as cyclic dimers (P2), trimers (P3), and tetramers (P4) of head-to-tail associations of monomeric 53 kDa subunits. While most complement proteins are produced mainly in the liver, properdin is synthesized primarily by various cell types, including neutrophils, monocytes, primary T cells, and shear-stressed endothelial cells resulting in properdin serum levels of 4–25 μg/ml. Multiple inflammatory agonists stimulate the release of properdin from stimulated leukocytes into the cellular microenvironment. Concentrated, focused increases in properdin levels may lead to stabilization and initiation of AP convertases, thus greatly amplifying the complement response to a local stimulus. This review highlights current knowledge related to these properties and discusses the implications of properdin production in a pro-inflammatory microenvironment.

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Activation of the alternative pathway of human complement by autologous cells expressing transmembrane recombinant properdin

Cited by 17 publications

References 46 publications

Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury

Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury

Properdin Can Initiate Complement Activation by Binding Specific Target Surfaces and Providing a Platform for De Novo Convertase Assembly

Local release of properdin in the cellular microenvironment: role in pattern recognition and amplification of the alternative pathway of complement

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