Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Complement Factor H (CFH)

  • Eduardo Lamas-Basulto
  • Anne M. Dersch
  • Claudio Cortes
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101784


Historical Background

The complement system, the major noncellular component of the innate immune system, is composed of three different pathways: the classical (CP), the lectin (LP), and the alternative pathway (AP). These pathways participate in several processes, including tagging pathogens for phagocytosis, directing destruction of microorganisms, promoting inflammation, contributing to immune complex regulation, and linking the innate and adaptive immune systems. The complement system has two fundamental properties: discriminates self (e.g., host cells) from nonself (e.g., pathogens) and regulates itself to prevent unwanted damage. These properties, common to all arms of the immune system, are required for proper protection and maintenance of homeostasis. Factor H, a fundamental complement regulatory protein, has the ability to recognize self-surfaces and confer protection from unwanted complement-mediated damage. Regulation of the amplification phase of the AP is exerted by multiple mechanisms, decay of the convertases, stabilization of these enzymes by properdin, and cofactor activity for factor I to inactivate C3b. It was not until 1976 Whaley and Weiler determined that factor H (formerly known as β1H) controls the amplification of the convertases of complement in serum. Since then it has been shown that factor H accelerates the decay of the alternative pathway C3 convertase (C3b, Bb) and is also a cofactor for factor I-mediated cleavage and inactivation of C3b (Pangburn et al. 1977; Weiler et al. 1976; Whaley and Ruddy 1976). Currently, it has been shown that failure of its function leads to tissue damage, progression of certain diseases (atypical hemolytic uremic syndrome and macular degeneration), or an incapacity to fight pathogens.

The Complement System, Regulation, and Associated Diseases

The common characteristics of all complement pathways are covalent attachment of C3b, release of proinflammatory molecules (C3a, C5a), and formation of the membrane attack complex (MAC) on the targeted cell’s surface. The main differences between the pathways are the usage of a unique set of discriminatory molecules in the initial steps for proper activation of the complement system. For instance, the lectin pathway initiates when mannose-binding proteins (MBL), ficolins, or collectins, recognize pattern-associated molecules on the bacterial cell’s surface (Fig. 1). The classical pathway requires that C1q recognizes surfaces targeted by antibodies or C-reactive protein (CRP). The alternative pathway initiates on any surface that allows it, in which C3b deposition can occur on all cells, including both pathogenic organisms and host cells. Nevertheless, further activation of the complement system occurs by default primary on pathogens because they do not express complement regulatory proteins, which protect host cells. The presence of fluid phase (factor H, C4PB, factor I) and membrane-bound regulatory proteins (CD35/CR1, CD46/MCP, CD55/DAF, and CD59) found in host cells assure that the complement system is tightly regulated (reviewed by Schmidt et al. 2016).
Complement Factor H (CFH), Fig. 1

Regulation of the complement system and associated diseases. Complement can be activated through the classical, lectin, and alternative pathways. C1 and MBL (also ficolins and collectins) recognize immune complexes bound to the cell membrane and specific carbohydrates present on the membranes of pathogens, respectively. The C3 convertase [C3(H2O)Bb] is spontaneously generated in plasma and leads to C3b formation, which recognizes hydroxyl and amino motifs on membrane molecules. All pathways lead to the formation of C3 and C5 convertases, which generate opsonin C3b, anaphylatoxins C3a and C5a, and the common terminal component called membrane attack complex or MAC (C5b-C9). Several complement regulatory proteins tightly regulate the complement system. These regulators protect host cells from complement-mediated attack by (a) having a decay-accelerating activity, which displaces Bb from the AP C3 convertase (factor H, CD35/CR1, and CD59) or C2b from the LP and CP C3 convertase (C4BP, CD35/CR1, and CD55/MCP); (b) cofactor activity for factor I, in which complement regulatory factors promote efficient cleavage of C3b (factor H, CD35, and CD46/MCP) or C4b (C4BP, CD35/CR1, and CD46/MCP) to generate inactive C3b (iC3b) or inactive C4b (iC4b), respectively; (c) enabling the MBL-MASPs and C1 complexes, in which C1 inhibitor (C1INH) either removes MASP1 and MASP2 from MBL or C1r and C1s from the C1 complex; and (d) inhibiting the formation of MAC (vitronectin, clusterin, CD59). Deficiencies of complement components associated to the AP, LP, CP, and complement regulatory proteins are indicated

Deficiency of some components of the complement system and of regulatory proteins is associated with certain diseases (Fig. 1). For instance, deficiencies of C1q are associated with systemic lupus erythematosus (SLE), and lack of properdin or components of MAC causes an increased susceptibility to neisserial infection. Deficiencies of complement regulatory proteins include hereditary angioedema (HAE), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), dense deposit disease/membranoproliferative glomerulonephritis (DDD/MPGN), and age-related macular degeneration (AMRD) (Fig. 1). Of all complement regulatory proteins, factor H plays a fundamental role in homeostasis; it has the capacity to discriminate self from nonself, actively confer protection from AP-mediated attack, and regulate the continuous function of all other pathways.

Proteins of the Alternative Pathway that Can Discriminate Host Versus Pathogens

One the most interesting characteristics of the AP, besides being the most ancient of all three pathways to emerge in evolution, is the constant initiation of the AP in plasma. The AP starts with a constant rate of spontaneous cleavage due to hydrolysis of the thioester bond found in C3. A small percentage of C3 in plasma (~1%) is hydrolyzed to form intermediate C3 (iC3 or C3H2O), leading to an important conformational change that allows binding of factor B, which is then cleaved by factor D to generate a fluid phase C3 convertase [C3(H2O)Bb]. This C3 convertase cleaves C3 forming C3b fragments that bind covalently to any nearby membranes and C3a, which is a potent anaphylatoxin. The conformational structure of C3b is similar to C3(H2O), and this is why the latter is also called “C3b-like”. C3b is recognized by factor B, which is then cleaved by factor D, generating a membrane-bound C3 convertase or C3bBb. This C3 convertase amplifies the deposition of C3b on the surface of the targeted cells (Reviewed in Ferreira et al. 2010).

The AP of the complement system can discriminate self from nonself structures via properdin, C3b, and factor H. Properdin, the only positive regulator of the AP that stabilizes the C3 and C5 convertases, initiates the AP complement activation (Cortes et al. 2013) and has been shown to bind and recognize damage- and pattern-associated molecular patterns (DAMPs/PAMPs) in host cells and pathogens. C3b contributes in the process of amplification, generation of C3 and C5 convertases, and opsonization tagging pathogens, immune complexes, and apoptotic cells for phagocytosis. C3b, during the process of complement activation, attaches covalently to and shows a strong preference for certain highly hydroxylated structures, resulting in more aggressive activation depending on their polysaccharide and protein composition (Reviewed in Ferreira et al. 2010).

Factor H

Factor H is a serum glycoprotein (~150–550 μg/ml) that is expressed constitutively in the liver (Schwaeble et al. 1987) and locally by a variety of cell types (Reviewed in Ferreira et al. 2010). Factor H accelerates the decay of the alternative pathway fluid [C3(H2O)Bb] and membrane-bound C3 convertases (C3bBb). It is also a cofactor for factor I-mediated cleavage and inactivation of C3b, generating iC3b and iC3(H2O) that can no longer bind factor B and hence not form additional AP C3 convertases (Fig. 2).
Complement Factor H (CFH), Fig. 2

Main functions of factor H. Factor H attaches with higher affinity to host cells’ surfaces when both C3b and polyanion (e.g., sialic acid) are present. Short consensus repeat (SCR)19–20 and SCR7 are important in recognizing polyanions. SCR19–20 is considered essential in recognizing self from nonself surfaces. Decay-accelerating activity takes place when factor H displaces Bb from its binding to C3b and forms a C3b-factor H complex. Factor H has cofactor activity for factor I, in which C3b-factor H complex is recognized by a serine protease called factor I. Factor I cleaves C3b to form the inactive form of C3b, or iC3b, which can no longer form a C3 convertase. SCR1–4 domain is important in both activities: dissociation of the convertase into C3b and Bb and cofactor to factor I in degradation of C3b into iC3b and C3d (not shown)

Factor H is the only soluble complement regulatory protein of the alternative pathway that protects host cells from complement AP-mediated attack and also participates in the homeostasis of all pathways, as a deficiency or malfunction of factor H leads to massive complement activation (consumption of C3 and factor B) (Schreiber et al. 1978), affecting the classical and lectin pathways.

In addition to its function as a regulator of alternative pathway activation in the fluid phase, factor H can recognize specific markers on host cells and control complement on self-surfaces.

Factor H detects and binds the initial C3b deposits in the context of unique-specific markers found only on the surface of host cells (e.g., polyanion). Factor H binds weakly to polyanion found on host cells, but it will bind efficiently when C3b is deposited, through CP, LP, and CP activation, to the host surface. The consequence of effective factor H binding is disrupting the formation of C3 convertase due to decay and cofactor activities (Fig. 2). Since pathogens do not have identical surface markers for factor H to bind, C3b deposition proceeds unchecked, allowing uncontrolled AP activation on pathogens or surfaces not protected by other complement regulatory proteins (Reviewed in Pangburn et al. 2008). For instance, it has been shown that removal of surface sialic acid inhibits factor H binding to cell surfaces and allows activation of the alternative pathway (Fearon 1978). Highly sulfated heparin (HS), dermatan sulfate (DS), and glycosaminoglycan (GAG) chains of proteoglycans have also been shown to enhance factor H-mediated control of complement activation on surfaces (Reviewed in Pangburn et al. 2008).

The regulation of the AP is essential to prevent excessive inflammation and tissue damage, especially considering that the AP is spontaneously initiated and has the ability to amplify all complement activity through the amplification loop (Fig. 1). Factor H has been shown to be critical in limiting AP activation on the surface of several cell types, even in the presence of other fluid and membrane-bound regulators. For example, red blood cells lacking CD59 and DAF (CD55) in PNH disease barely survive complement-mediated attack, but when factor H function is neutralized in these cells, they are quickly lysed (Ferreira and Pangburn 2007). Factor H is also the primary regulator of the alternative pathway in the fluid phase, preventing complement consumption via uncontrolled alternative pathway activation. Factor H, when compared with most complement regulatory proteins, has the unique dual capacity to protect surfaces (decay-accelerating activity and acting as cofactor for factor I) and to discriminate self from nonself.

The factor H gene is located in chromosome 1 and its cDNA codes for a ~150 kD protein. There are also a number of factor H-related (FHR) molecules and factor H-like proteins (FHL-1), reviewed elsewhere (Józsi et al. 2015), which share homology with factor H and in many occasions similar functions. Factor H is composed of 20 homologous short consensus repeat (SCR), or complement control protein (CCP) units, of highly conserved 60 amino acids in length (Reviewed in Ferreira et al. 2010).

Several studies have been carried out to determine the structure-function of factor H (Table 1). It has been determined that factor H has a three C3b-binding site located at the SCR1–4, SCR7–15, and SCR19–20, in which SCR1–4 also possesses the decay-accelerating and cofactor activities for factor I. SCR19–20 interacts with C3b, iC3b, C3d, and polyanion (e.g., sialic acids), which are key regions for interactions with host surfaces (Pangburn et al. 2008). In addition, SCR7 binds polyanion and, together with SCR19–20, interacts with several pathogens and with other host molecules. A recombinant protein representing the C-terminal SCR19–20 (rH19–20) has been shown to compete with full-length factor H for binding to C3b and host polyanions, leading to increased complement activation on host surfaces in vitro and in vivo (Ferreira et al. 2006; Pickering et al. 2007), strongly suggesting that SCR19–20 accounts for most of the host cell’s recognition/discrimination abilities of factor H.
Complement Factor H (CFH), Table 1

Interaction of complement factor H with multiple targets (pathogens and molecules). Pathogens and molecules that bind factor H are indicated. The domain of factor H responsible for this interaction is also indicated. Due to constraints of allowed references in this paper, those beyond the ones cited here can be found in Ferreira et al. (2010)


Binding region(s)



Gram negative

Acinetobacter baumannii

Bacillus anthracis (spores)

Bordetella spp.

Escherichia coli

Francisella tularensis

Fusobacterium necrophorum

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Neisseria meningitidis

Pasteurella spp.

Salmonella enterica spp.

Yersinia pseudotuberculosis

Yersinia enterocolitica

Treponema denticola

Factor H

Factor H

5–7; 19–20

Factor H

Factor H

6–7; 19–20


Factor H

6–7; 19–20


6–7; 19–20

5–7; 19–20

5–7; 19–20

6–7; factor H

Factor H





PorB 1A; PorB 1B-LOS



Rck, PgTE


Ail, Yad


Ferreira et al. (2010)

Wang et al. (2016)

Amdahl et al. (2011)

Li et al. (2016)

Ferreira et al. (2010)

Bernhard et al. (2014)

Ferreira et al. (2010)

Ferreira et al. (2010); Sahagún-Ruiz et al. (2014)

Ho et al. (2010), Riva et al. (2015)

Ho et al. (2012)

Ferreira et al. (2010)

Gram positive

Leptospira interrogans

Listeria interrogans

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus suis

5–7; 19–20; 1–4



8–11; 12–15

8–11; 12–15

Factor H

LigAC, BC, BN, LigBC


Sbi, SdrE

Beta protein

PspC, Hic


Castiblanco-Valencia et al. (2012)

Ferreira et al. (2010)

Ferreira et al. (2010), Sharp et al. (2012)

Ferreira et al. (2010)

Ferreira et al. (2010)

Pian et al. (2012)

Gram neutral

Borrelia spp.

Mycobacterium bovis

5–7; 19–20

Factor H

CRASPs 1–2; CRASPs 3–5

Ferreira et al. (2010)

Abdul-Aziz et al. (2016)


Aspergillus spp.

Candida albicans

1–7; 19–20

6–7; 19–20

Pra1, Gpm1p

Ferreira et al. (2010)


Plasmodium falciparum

Echinococcus granulosus

Trypanosoma cruzi

Loa loa

Onchocerca volvulus

5–7; 5–20

Factor H

Factor H

Factor H


PfGAP50 (gametocytes), schizonts,

Pf92 (merozoites)

Simon et al. (2013)

Rosa et al. (2016)

Kennedy et al. (2016)

Ferreira et al. (2010)


West Nile virus


Factor H

Factor H


gp41, gp120

Ferreira et al. (2010)




7, 19–20

Factor H

Factor H




Factor H


Factor H

6–8, 16–20


6–8; 19–20

1–4, 6–8, 8–15

6–8; 19–20

7; 12–13; 20

6–8, 19–20

1–4, 19–20

Factor H




Von Willebrand

Sialylated glycans, ganglioside




Integrin alphaIIbbeta3

C-reactive protein




Sialoprotein, osteopontin


Heparan sulfate

S-regions > NA-regions


Chondroitin sulfate

Ferreira et al. (2010)

Heurich et al. (2016)

Shaw et al. (2012)

Feng et al. (2013)

Blaum et al. (2015)

Haapasalo et al. (2015)

Weismann et al. (2011)

Ferreira et al. (2010)

Pangburn et al. (2008)

Clark et al. (2013)

Perkins et al. (2014)

Ferreira et al. (2010)

Hamad et al. (2010)

Factor H also interacts with DNA, histones, annexin II, C-reactive protein, and pentraxin 3, which may be important in the recognition of apoptotic cells to assure excessive complement activation during the process of removal of dying cells (Table 1). Factor H may interact with neutrophils, B-lymphocytes, monocytes, and platelets through complement receptor 3 (CR3; CD11b/CD18), integrins (αvβ3, αIIbβ3), and L-selectin (Reviewed in Ferreira et al. 2010; Blatt et al. 2016), which may mediate cell adhesion and cytokine induction.

Factor H has been shown to be essential in controlling tissue damage and has been used as a targeted therapeutic agent. Factor H plays a protective role in experimental autoimmune encephalomyelitis, atherosclerosis, insulin resistance, IgA nephropathy, kidney glomerulopathies in murine models of collagen antibody-induced arthritis, intestinal ischemia-reperfusion injury, and basolateral and apical tubular epithelial damage in ischemic injury of the renal tubular epithelial cells (Reviewed in Ferreira et al. 2010; Renner et al. 2011). Factor H also has been shown to be important in choroidal neovascularization, complement-mediated injury of retinal pigment epithelial cells, and allergen-induced airway inflammation (Ferreira et al. 2010). More recently, it has been shown that factor H plays an important role in regulating AP activation on platelets and platelet-granulocyte aggregate formation (Blatt et al. 2016). In addition, it has been shown that inhibition of binding of factor H to retinal epithelial cells promotes proinflammatory cytokine production, reinforcing the overall knowledge that factor H not only discriminates between cell surfaces but also acts as modulator or “anti-inflammatory molecule” in inflammatory processes.

Mutation in factor H results in disease, such as atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (ARMD), and dense deposit disease (membranoproliferative glomerulonephritis type II) (de Cordoba and de Jorge 2008; Holers 2014). aHUS affects adults and children and is characterized by a systemic thrombotic microangiopathy, hemolytic anemia, thrombocytopenia, and blood clotting in small vessels, which can lead to stroke, heart attack, kidney failure, and death. Most mutations are located on the SCR19–20 region, specifically in domain 20 (Nester et al. 2015). These mutations impair the ability of factor H to bind either C3b, polyanions, or both, suggesting that a defect in binding (negative or positive) to either of its ligands, C3b/C3d and polyanions (reviewed in Ferreira et al. 2010), may affect the formation of dimers or tetramers which may then affect its binding to cell surfaces (Pangburn et al. 2009).

ARMD, the leading cause of vision loss affecting elderly worldwide, is strongly associated to single amino acid mutations of factor H (Y402H, I62V, and R1210C), in which the most important is the variant Y402H located in domain SCR7 (Maller et al. 2006; Kondo et al. 2009; Xing et al. 2008; Raychaudhuri et al. 2011). ARMD is characterized by soft drusen and pigmentary changes in the retinal pigment epithelium that progresses into geographic atrophy or choroidal neovascularization, and the mechanism causing the damage is under current investigation. It has been shown that factor H fragments containing the Y402H mutation have impaired ability to interact with various ligands, including heparin, C-reactive protein, and fibromodulin. In addition, these fragments have increased binding to DNA and necrotic cells (Pangburn et al. 2008). Full factor H variant with I62V mutation has impaired cofactor activity for factor I. More recently, it has been shown that factor H binds to oxidized phospholipid (oxPL), which is a reliable biomarker for oxidative stress and proinflammatory molecules. More specifically, factor H variant H402Y interacts with less affinity with oxPL, leading to an increased inflammatory burden of the eye, which results in increased proinflammatory cytokine production (Shaw et al. 2012; Du et al. 2016).

H402Y has also been associated in other pathologies, including glomerulonephritis intracerebral hemorrhage, hearing loss, and lung cancer (Appelboom et al. 2011; Nishio et al. 2012). Membranoproliferative glomerulonephritis type II or dense deposit disease (DDD) is due to massive complement activation of the alternative pathway that can lead to complete organ failure. A lack of factor H has been shown to be fatal, causing acute renal failure and spontaneously developing membranoproliferative glomerulonephritis. Pathogens have evolutionarily developed strategies to interact with factor H (Table 1) through mainly SCR67 and SCR19–20 domains, suggesting a common mechanism used by microbes to resist to AP-mediated attack. Cancer cells manage to escape complement-mediated attack by upregulating factor H expression, secreting proteins to recruit factor H, and interacting with factors that may promote cancer (e.g., adrenomedullin) (reviewed in Ferreira et al. 2010).


In the last 5 years, further progress to define the molecular mechanisms of cell recognition by factor H has been achieved. The mechanisms involved in factor H-associated diseases have come to light, along with the study of disease-associated mutations and polymorphisms in factor H, particularly the polymorphisms related to AMRD and aHUS. This information will increase in importance as it can be incorporated in genetic testing to identify whether an individual is at risk for a particular disease, allowing healthcare providers to plan strategies to ameliorate or delay the presentation of disease. More pathogens have recently been discovered to bind factor H to evade the complement system. Once the ligands of factor H on these pathogens are identified, efforts to develop vaccines against these ligands are warranted. Finally, studies to promote factor H binding to host cells or tissues may be used as a therapeutic strategy to ameliorate inflammatory processes.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

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