Properdin: a tightly regulated critical inflammatory modulator

Blatt, Adam Z.; Pathan, Sabina; Ferreira, Viviana P.

doi:10.1111/imr.12466

Cited by 92 publications

(89 citation statements)

References 224 publications

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“…The alternative pathway amplifies the initial response and maintains a low level of activity through a tick-over mechanism. The alternative pathway might also have a role in initiation of the complement cascade, but the question of whether an initiating PRP acts in this pathway is not yet resolved 7,13 . In settings such as thromboinflammation, complement can be activated via non-canonical routes that bypass these three pathways, for example, by serine proteases with promiscuous enzymatic activity in the intracellular space or in the vasculature 14 .…”

Section: The Role Of Complement In Host Defencementioning

confidence: 99%

The renaissance of complement therapeutics

et al. 2017

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The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

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Section: The Role Of Complement In Host Defencementioning

confidence: 99%

The renaissance of complement therapeutics

et al. 2017

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“…Such modulators typically contain pattern recognition regions and binding sites for complement components, activators, and/or regulators. For example, although properdin is best known for its ability to stabilize the C3bBb convertase, the protein has also been reported to act as an initiator that binds markers such as LPS and recruits soluble C3b (as a starter molecule) to the target surface (Figure B); however, the relevance of this bridging function is still debated . Although the molecular details remain to be elucidated, there is increasing evidence for a recruitment of C3b by P‐selectin on platelets and endothelial cells that could induce or exacerbate complement activation .…”

Section: Complement C3: a Functional Hub In Innate Immunity And Beyondmentioning

confidence: 99%

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Ricklin

Reis

Mastellos

et al. 2016

Immunological Reviews

330

295

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Summary As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.

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“…In the presence of intact C3, it is virtually impossible to demonstrate whether properdin acts in a recognition manner or subsequently binds to C3b. On the other hand, purified properdin is sensitive to aggregation into sticky multimers, and these aggregates, referred to as activated properdin, do not behave as the native form; thus, results with purified properdin must be judged with care (30,31), especially in unfractionated preparations (32). Early preparations of properdin, such as those used in the initial studies by Pillemer et al (1), were later shown to contain impurities and high molecular aggregates of properdin, which were lost when adsorption to zymosan was omitted from the purification protocols (30,33,34).…”

Section: Significancementioning

confidence: 99%

Properdin binding to complement activating surfaces depends on initial C3b deposition

Harboe

Johnson

Nymo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

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Properdin: a tightly regulated critical inflammatory modulator

Cited by 92 publications

References 224 publications

The renaissance of complement therapeutics

The renaissance of complement therapeutics

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Properdin binding to complement activating surfaces depends on initial C3b deposition

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