Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CFP (Complement Factor Properdin)

  • Anne M. Dersch
  • Eduardo Lamas-Basulto
  • Claudio Cortes
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101783


Historical Background

Complement was first described more than 100 years ago, and since then, findings and controversies have arisen that resulted in the discovery of the components that participate in each pathway of the complement system (alternative, classical, and lectin). It was widely accepted during the 1950s that microbial targets could only be lysed by a mixture of heat-sensitive components of human serum and antibodies, which we now know as the classical pathway (CP). During the same time, the first evidences of an “alternative” pathway capable of activating the complement system on targets without the presence of antibodies emerged. In 1954, Louis Pillemer and collaborators proposed that properdin acted as an initiator of alternative pathway (AP) activity, becoming what was called the “properdin system” (Pillemer et al. 1954). The discovery of this molecule was a major breakthrough in those years as it contributed to the understanding of how human diseases could be controlled and was one of the first examples of natural immunity. Soon after this discovery, Pillemer’s findings were discredited and replaced with the belief that properdin did not initiate the AP, but was only a regulator of the AP. On August 31, 1957, Pillemer took his life, and although posthumous articles suggested that he may have been on the right track, the evidence was not conclusive to confirm the existence of a “properdin system.”

In the 1970s and 1980s, a renewed interest in properdin took place as new reports indicated the existence of an antibody-independent complement activation pathway. Protein purification methods not only made possible the reconstruction of complement activation from purified components but also allowed the elucidation of how the alternative pathway works (explained in Fig. 1). The role of properdin was confined as the only positive regulatory protein of the complement system. The function of properdin is to bind to and stabilize the nascent AP C3 convertase (C3bBb) in order to extend its half-life 5-10 fold (Fearon and Austen 1975; Schreiber et al. 1975). The consequences of this interaction are accelerated and efficient amplification of C3b deposition on surfaces, increased generation of the C5 convertase (C3bBbC3b) and C5a, and more MAC formation on the surface of susceptible targets. Later, it was also shown that the alternative pathway plays a fundamental role in amplifying the other two pathways, as C3b molecules generated by the classical and lectin pathways are also substrate to form AP C3 convertases (Fig. 1). This suggests that properdin not only directly acts on the alternative pathway but also indirectly participates during the AP amplification loop that is essential for proper function of all pathways (reviewed by Cortes et al. 2013).
CFP (Complement Factor Properdin), Fig. 1

A schematic overview of the alternative pathway. The alternative pathway (AP) is independent of antibody and does not require a recognition molecule for initiation. It begins spontaneously in the plasma by hydrolysis of C3 to form C3(H2O). C3(H2O) is also known as intermediate C3 (iC3) or “C3b-like” molecule because it attains a conformation similar to C3b. The C3(H2O) molecule has the ability to bind to factor B and lead to formation of C3(H2O)B. Factor D then cleaves factor B to form a fluid-phase C3 convertase [C3(H2O)Bb], which can cleave C3 to C3b and C3a. C3b can then covalently bind to the cell’s surface and allow the formation of a membrane-bound AP C3 convertase (C3bBb), which cleaves additional C3 to C3b. Covalent deposition of C3b on pathogenic surfaces causes opsonization that enables phagocytosis. Properdin, the only positive regulator of the complement system, stabilizes C3bBb allowing more efficient C3b formation and opsonization. The C1 complex (C1qC1r2C1s2) initiates the classical pathway (CP) by recognizing antibodies or C-reactive protein (CRP) bound to pathogens. C1r activates C1s, which then cleaves C4 and C2 to form the CP C3 convertase (C4bC2b). The lectin pathway (LP) initiates when mannose-binding lectin (MBL), collectins, and ficolins recognize patterns (e.g., carbohydrates or acetylated groups) on the surface of pathogens. MBL-associated serine proteases 1 (MASP-1) and 2 (MASP-2) associate with MBL and MASP-2 cleaves C2 and C4 in a manner similar to C1s of the classical pathway, leading to formation of the C3 convertase (C4bC2b). Notice that C4bC2b from the LP and CP cleaves C3 to generate C3b that potentially can be used as a substrate to form the AP C3 convertase C3bBb, which is called the AP amplification loop that amplifies all three complement pathways. C3b may bind to C3 convertases to form C5 convertases (C3bBbC3b for AP; C4bC2bC3b for both CP and LP), which cleave C5 to C5a (potent chemoattractant, pro-inflammatory molecule, and anaphylatoxin) and C5b. C5b, C6, and C7 form a complex that binds to the cell membrane that has been targeted by all pathways. Then, C8 binds to C5b–C7 complex and inserts in the bilayer membrane. Finally 10–18 C9 molecules polymerize forming the membrane attack complex (MAC; C5b–C9), which lyses the pathogen

During the late 1980s and 1990s, efforts focused on identifying properdin’s sequence, structure, and the source of its production. It was found that properdin, unlike most other complement proteins that are produced mainly in the liver, is synthesized by PMN, resulting in properdin serum levels of 4–25 μg/ml (reviewed by Cortes et al. 2013).

Within the last 10 years, Hourcade and collaborators demonstrated that properdin could subsequently recruit C3b and factor B to form C3bBbP, which was consistent with the complement initiation function proposed over 50 years ago by Pillemer, reopening a controversy regarding the functions of properdin. Since then, recent evidence suggests that properdin not only regulates the AP but also is able to recognize pathogens, initiate AP complement activation, play a role in several pro-inflammatory processes, selectively recognize molecular patterns found on pathogens, damage host cells, and activated platelets (reviewed by Blatt et al. 2016a; Cortes et al. 2013).

Properdin Structure

The highly positively charged protein properdin is present in plasma as dimers (P2), trimers (P3), and tetramers (P4) in a consistent physiological ratio of (26:54:20, P2:P3:P4) (Pangburn, 1989). Each monomer is 26 nm in length × 2.5 nm in diameter, with a molecular weight of ~53 kDa. A monomer contains 442 amino acid residues and 7 thrombospondin repeat type I domains labeled TSR0-TSR6. These properdin oligomers, also called “physiological forms of properdin,” bind with greater affinity to cell membrane-bound C3bBb, C3bB, and C3b than to their fluid-phase correlates. Properdin also binds to C3(H2O) (a C3b-like molecule or iC3), Ba, and factor B, which is essential in the formation of the AP C3 and C5 convertases. TSR0-1 and TSR5-6 may mediate contacts at the vertices of properdin oligomers. TSR4 is essential in stabilizing the AP C3 convertase, while TSR5 functions in both C3b and sulfatide binding. TSR4 and TSR5 are essential to form P3 and P4, but not to form P2. TSR6 is also important in the formation of oligomers. TSR3 has no effect on binding to C3b or sulfatides or oligomer formation. Antibodies against mouse TSR5-TSR6 blocked AP-dependent complement activation in vivo, as measured by LPS-dependent surface deposition of C3 fragments, and attenuated tissue damage using a mouse abdominal aortic aneurysm model. Point mutation on TSR6 (Y387D) abolished the capacity of properdin to bind C3b and regulate AP, and mutations in TSR1 (R73W) and TSR5 (Q316R) affect the stabilization of properdin leading to low levels of plasma levels and defects in oligomerization, but able to form P2. Furthermore, each monomer has 14 C-linked mannosylation sites found on tryptophan residues (TSR0: 56, 59aa; TSR1: 112, 115, 118; TSR2: 169, 172; TSR3: 233, 236; TSR4: 294, 297; TSR5: 355, 358, 361) and an N-glycosylation site (401 and 403aa). Properdin has also been found to interact with the Ba domain of factor B and C3(H2O) (reviewed in Blatt et al. 2016a).

Role of Properdin as an Initiator of the Alternative Pathway and a Selective Recognition Molecule

Hourcade (2006) demonstrated, using surface plasmon resonance, that properdin promoted the association of C3b with factor B and provided a focal point for the assembly of C3bBb on a surface, suggesting that properdin may be also an initiator (Hourcade 2006; Saggu et al. 2012). Furthermore, human embryonic kidney cells of Escherichia coli transfected with a vector expressing a transmembrane form of properdin on the cell surface activated the AP, suggesting that properdin can initiate complement activation (Vuagnat et al. 2000; Spitzer et al. 2007). After these findings, properdin has been shown to bind to various nonself surfaces, including damaged host cell surfaces and bacteria, making properdin a damage-/pattern-associated molecular pattern (DAMP/PAMP) recognition molecule, reviving the notion of a “properdin pathway” or “Pillermer pathway”. In addition, it has been demonstrated that C3(H2O), C3 fragments, clusterin, and immunoglobulins co-immunoprecipitate with properdin in human serum, and also, C3b2-natural IgG complexes stimulate complement amplification in a properdin-dependent manner (Jelezarova et al. 2000). It has also been suggested that surface-bound properdin may lead to complement activation by recruiting C3b molecules derived from any of the three complement pathways or by recruiting soluble C3(H2O) to form a membrane-bound C3(H2O)Bb convertase (Saggu et al. 2012). Thus, properdin has the dual ability to initiate and regulate the AP activation (Fig. 2).
CFP (Complement Factor Properdin), Fig. 2

Properdin functions. Properdin (P) acts as a regulator of the alternative pathway by stabilizing the C3 and C5 convertases. Properdin may bind to C3bBb to form the traditional membrane-bound C3 convertase, to C3(H2O)Bb to form a novel membrane-bound C3(H2O) convertase, or to C3b2 natural complexes in order to promote complement activation. Properdin may also act as an initiator (Pillemer pathway) by binding directly to surfaces and recruiting C3b or C3(H2O) in order to form C3 convertases and further promote C3b deposition on surfaces

One key element to notice is that in many of these studies, unfractionated properdin, which contains the physiological forms of properdin (P2, P3 and P4), and nonphysiological aggregates (Pn) were used. Pn are multiple monomers of properdin with highly positively charged molecules that induce AP activation in solution, leading to complement consumption, and may account for nonspecific ionic interactions with certain DAMPs or PAMPs (reviewed by Blatt et al. 2016a). Therefore, in future studies, the use of physiological forms of properdin is recommended. On the other hand, the use of highly polymerized recombinant (Pn) has shown promise as a potential antimicrobial therapy. In one experiment, mice injected with Pn had decreased levels of sepsis and recoverable bacteria compared with the saline-treated control group (Ali et al. 2014).

Properdin in Pro-inflammatory Processes

Although it has been known for many years that deficiency of properdin in humans leads to increased susceptibility to meningococcal infection and septicemia, recent evaluations have further defined the role of properdin in pro-inflammatory processes by using mouse models (Table 1). It has been shown in mouse models that a lack of properdin can exacerbate colitis using IL10−/− model of inflammatory bowel disease (Jain et al. 2015a), increase damage of colitis by Citrobacter spp. (Jain et al. 2015b), worsen disease in LPS-induced non-septic shock (Ivanovska et al. 2008), and increase morbidity and mortality in a murine polymicrobial sepsis (Stover et al. 2008). In addition, it was found that properdin deficiency in mice with complete factor H deficiency (Cfp−/−, Cfh−/−) or impaired factor H fluid-phase regulation (Cfp−/−, Cfhm/m) exacerbated spontaneous glomerulopathy (Ruseva et al. 2013), suggesting a complex connection between the positive and negative regulators of the AP, properdin and factor H, respectively.
CFP (Complement Factor Properdin), Table 1

Studies of properdin using mouse models

Disease model

Genetic background



Colitis/IBS induced by piroxicam

IL10−/− vs IL10−/−, P−/−

IL10−/−, P−/−: decreased C5a and C9 deposition, worsened colitis, decreased neutrophils, and increased numbers of bacteria

Jain et al. (2015a)

Colitis caused by Citrobacter spp.


P−/−: increased diarrhea and inflammation due to decreased epithelial cell-derived IL-6; increased numbers of bacteria due to decreased production of C5a

Jain et al. (2015b)

Polymicrobial peritonitis


P−/−: more susceptible to death by polymicrobial peritonitis; properdin is produced by mast cells; properdin can associate with E. coli which may lead to increased complement deposition

Stover et al. (2008)



P−/−: decreased development of arthritis

Kimura et al. (2010)

Glomerulonephritis (GN)

P−/− vs CFH−/− vs CFH−/−, P−/−

No significant damage in P−/−

Exacerbation of spontaneous glomerulopathy: CFH−/−, P−/− > CFH−/−

Increased C3 deposition (iC3b/C3d) in glomeruli in CFH−/−, P−/− > CFH−/−

Similar linear glomerular C9 staining on in glomeruli in CFH−/−, P−/−, and CFH−/−

Ruseva et al. (2013)

Glomerulonephritis (GN)

CFH m/m, P −/− vs CFH m/m (reduced expression of CFH)

CFHm/m P−/− developed exacerbated C3 GN and died prematurely

Lesher et al. (2013)

LPS-induced AP complement activation


LPS- and LOS-induced AP complement activation was abolished in P−/− mouse serum; in contrast, zymosan-induced AP complement activation was only minimally diminished

Kimura et al. (2008)

LPS-induced non-septic shock


P−/−: higher mortality due to LPS-induced shock, elevated TNF-alpha, reduced production of IL-10 by peritoneal macrophages, and decreased C5a levels

Ivanovska et al. (2008)

Renal ischemia reperfusion injury (IRI)

DAF−/− CD59−/− P−/−

DAF−/− CD59−/− P−/−: significantly reduced renal IRI – decreased BUN, tubular injury, neutrophil infiltration, and microvascular complement deposition

Miwa et al. (2013)

Recent studies have continued to elucidate properdin’s role in complement activation after infection with various pathogens. Furthermore, studies involving diseases with inappropriate complement activation, such as arthritis, have shown properdin to play a critical role in the development of the disease, and therapeutic targeting of properdin may ameliorate injury; however, this is countered by the finding that properdin deficiency can exacerbate spontaneous glomerulopathy due to factor H deficiency, suggesting a protective role of properdin in this setting. CFH complement factor H, P properdin, DAF decay-accelerating factor

On the other hand, it has been shown also that P−/− mouse has improved outcomes in zymosan-induced non-septic shock (Kimura et al. 2008). In addition, in vitro assays have shown that properdin enhances the activation on Neisseria meningitides and N. gonorrhoeae (Agarwal et al. 2010; Gulati et al. 2012), Chlamydia pneumoniae, fungal glucans (Agarwal et al. 2011), glycan, and Escherichia coli. Some of these studies suggest that properdin selectively recognizes PAMPs, initiates properdin-mediated AP activation, and could help in controlling disease by being directed to certain pathogens.

Ex vivo assays have recently shown that properdin binds specifically to activated platelets, recruits C3(H2O), and initiates properdin-mediated AP activation in platelets. More recently, it has been shown that properdin plays a role in platelet-granulocyte aggregates (PGA) formation (Blatt et al. 2016b) (Fig. 3), a phenomenon seen in several inflammatory process, including acute coronary syndromes, inflammatory bowel disease, inflammatory lung disease, diabetes, and thrombi formation (reviewed by Blatt et al. 2016a).
CFP (Complement Factor Properdin), Fig. 3

Effects of properdin-enhanced AP activation on platelet-granulocyte aggregate formation. (A) The classical pathway activates on the surface of platelets or secreted chondroitin sulfate. The C3b can be used by the amplification loop (B) leading to the deposition of C3b on the granulocyte and platelet surfaces. Similarly, the alternative pathway (C) can activate on the surface of platelets and neutrophils and contribute to the amplification loop. The high levels of properdin oligomers (P2, P3, and especially P4) secreted from neutrophils (D) may enhance alternative pathway activity (properdin as a regulator). It is also possible that properdin acts as an initiator of the alternative pathway (E; Pillemer pathway). All of this (A, B, C, D, E) may contribute to C5a production that further activates neutrophils via C5a receptor (C5aR) to increase CR3 expression (F), which promotes platelet-granulocyte aggregate formation

In vivo studies have also shown that inhibition of endogenous properdin in blood using anti-properdin antibodies reduced C5a production, essential in PGA formation (Hamad et al. 2015), and limited CR3 upregulation on neutrophils, reinforcing the notion that targeting properdin in the local environment may help ameliorate thromboinflammatory processes.


Properdin is the only positive regulator protein of the complement system that acts by stabilizing the C3 convertase of the alternative pathway. Recent evidence suggests that properdin can also be considered a selective PAMP/DAMP recognition molecule and initiator of the alternative pathway, returning to its function initially proposed by Pillemer in 1954. Local production of properdin has also been associated in pro-inflammatory processes, and its emerging role in thromboinflammation is still being investigated. Future work that defines the receptors on host cells targeted by properdin and inhibition of properdin-dependent complement activation may allow for the generation of new therapeutic approaches.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Anne M. Dersch
    • 1
  • Eduardo Lamas-Basulto
    • 1
  • Claudio Cortes
    • 1
  1. 1.Oakland University William Beaumont School of MedicineRochesterUSA