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Contents lists available at SciVerse ScienceDirect

Molecular Immunology

jo urnal homepage: www.elsevier.com/locate/molimm

Review

Complement factor H related proteins (CFHRs)

a,∗ a b,c b,d,e

Christine Skerka , Qian Chen , Veronique Fremeaux-Bacchi , Lubka T. Roumenina

a

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany

b

Centre de Recherche des Cordeliers, INSERM UMRS 872, Paris, France

c

Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France

d

Université Paris Descartes Sorbonne Paris-Cité, Paris, France

e

Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France

a b s t r a c t

a r t i c l e i n f o

Factor H related proteins comprise a group of five plasma proteins: CFHR1, CFHR2, CFHR3, CFHR4 and

Article history:

CFHR5, and each member of this group binds to the central complement component C3b. Mutations,

Received 1 May 2013

genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with a

Accepted 8 May 2013

Available online xxx number of diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3

glomerulonephritis (C3GN), dense deposit disease (DDD) and CFHR5 nephropathy), IgA nephropathy, age

related macular degeneration (AMD) and systemic lupus erythematosus (SLE). Although complement

regulatory functions were attributed to most of the members of the CFHR protein family, the precise

role of each CFHR protein in complement activation and the exact contribution to disease pathology is

still unclear. Recent publications show that CFHR proteins form homo- as well as heterodimers. Genetic

abnormalities within the CFHR gene locus can result in hybrid proteins with affected dimerization or

recognition domains which cause defective functions. Here we summarize the recent data about CFHR

genes and proteins in order to better understand the role of CFHR proteins in complement activation and

in complement associated diseases.

© 2013 Elsevier Ltd. All rights reserved.

1. The complement system further C3 molecules, generate C3a and amplify C3b deposition.

Further complement activation leads to the C5 convertase forma-

The complement system is a central immune surveillance sys- tion and cleavage of C5 to C5b and C5a. A fourth complement path-

tem of the vertebrate organism as complement recognizes and way directly activates C3 and C5 due to convertase independent

eliminates foreign particles and modified host cells. Upon infection cleavage by thrombin (Huber-Lang et al., 2006). C5b initiates the

with microorganisms, complement is activated to induce inflam- terminal complement complex (TCC) on foreign surfaces resulting

mation and to allow their elimination. In case of altered self cell in cytolysis (Muller-Eberhard, 1986; Bhakdi and Tranum-Jensen,

material, complement assures a silent, non inflammatory clear- 1988; Morgan, 1999; Ward, 2009) The cleavage products C3a and

ance by phagocytic cells (Zipfel and Skerka, 2009; Ricklin et al., C5a are potent anaphylatoxins that are chemotactic for immune

2010). In addition, the activated complement system interacts with cells, such as macrophages and neutrophils and that modulate via

the coagulation cascade and contributes to the regulation of the receptor binding the immune response. In addition C3a, but not C5a

adaptive immune response and T cell differentiation (Kemper and displays anti microbial activity (Diaz-Guillen et al., 1999).

Atkinson, 2007). Surface recognition is mediated by deposition of Once activated, the complement system needs tight control,

C3b (alternative pathway), antibody binding or surfactant proteins as newly generated complement activation products can induce

(the classical pathway), or by mannose binding lectins (the lectin severe inflammation and cell damage. A number of soluble as well

pathway). All three pathways converge into the generation of a C3 as membrane bound complement regulators ensure regulation of

convertase, which cleaves the central complement component C3 complement activation at the surface of self cells and control dif-

into the activation product C3b, which forms together with factor B ferent activation phases and sites of action (Walport, 2001a,b).

the C3 convertase (C3bBb) (Fig. 1). These convertases rapidly cleave Abnormalities in any of these regulators can lead to pathological

reactions (Zipfel and Skerka, 2009).

∗

Corresponding author at: Department of Infection Biology, Leibniz Institute

2. The factor H/CFHR gene family

for Natural Product Research and Infection Biology, Hans Knoell Institute, Beuten-

bergstrasse 11, D-07745 Jena, Germany. Tel.: +49 0 3641 5321164;

The factor H/CFHR family comprises a group of highly related

fax: +49 0 3641 5320807.

E-mail address: [email protected] (C. Skerka). proteins that includes the five Complement Factor H Related

0161-5890/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.molimm.2013.06.001

Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001

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Fig. 1. Complement activation pathways

Complement is activated via three main pathways, the alternative, classical and lectin pathways. All pathways result in the assembly of an active C3 convertase and C3b

amplification loop, leading to opsonization via C3b and iC3b for enhanced phagocytosis, to C5a generation and inflammatory reactions as well as to the assembly of the

terminal complement complex.

proteins, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, factor H and the cesses that result in rearrangements within this chromosomal

spliced variant factor H-like protein 1 (FHL-1). Each single gene of region with diverse outcomes. Deletions as well as duplications

the family members (CFHR1, CFHR2, CFHR3, CFHR4, CFHR5 and fac- of chromosomal fragments were identified, which harbor either

tor H) is located on a distinct segment on human chromosome 1q32 complete CFHR genes, or gene fragments. Such recombination

within the RCA (Regulation of Complement Activation) gene cluster processes can lead to loss of single or several CFHR genes, but also

(Fig. 2) (Diaz-Guillen et al., 1999; Male et al., 2000). The five CFHR form new gene-compositions including in some cases also the

genes are located downstream of the factor H gene and each CFHR factor H gene and their translations into the corresponding proteins.

gene codes for a plasma protein that is exclusively composed out of All five CFHR proteins show a high degree of sequence iden-

short consensus repeat domains. The entire chromosomal segment tity in their two N-terminal regions (36–94%). The two C-terminal

with the CFHR genes is characterized by several large genomic SCR domains of the CFHRs are very similar to the factor H C-

repeat regions, which have a high degree of sequence identity. terminus (36–100%). Such sequence homology suggests conserved

These repeat regions allow non-homologous recombination pro- domains as well as related functional roles of the proteins. The

Fig. 2. The CFHR protein family

The genes of the factor H family encode proteins that are composed exclusively of short consensus repeat (SCR) domains. The complement regulatory region in factor H SCRs

1–4 (Reg I) is not conserved in the CFHR proteins, but CFHR proteins harbor three regions that show high identity to factor H. The N-terminal SCR domains of CFHR proteins

share sequence homologies to SCRs 6–9 (Reg II), SCRs 10–14 (Reg III) of factor H and the C-terminal SCRs of the CFHRs to the C-terminus of factor H SCRs 18–20 (Reg IV). The

CFHR proteins are presented in two groups. CFHR1, CFHR2, CFHR5 are members of group I, as these molecules form homo-dimers via their N-terminal two SCR domains.

CFHR1 likely also forms heterodimers with CFHR5. The second group, group II, includes CFHR3 and CFHR4, that do not express the dimerization motif in the N-terminus. The

colors of the SCR domains reflect the degree of amino acid identity to factor H.

Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001

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Fig. 3. CFHR proteins in human plasma (Western blot)

Due to the high sequence identity to factor H and to each other the CFHR plasma proteins show immune crossreactivity with polyclonal antiserum. Normal human plasma

was separated by SDS gel electrophoresis and blotted to a membrane. Incubation with polyclonal antiserum or monoclonal antibodies to the CFHR proteins (as indicated by

numbers, see table lower panel) reveals a specific detection pattern (upper panel). The CFHR proteins are often detected as multiple bands because of different glycosylated

forms as indicated. Plasma probes were separated by SDS PAGE (12%) and immunoblotted with indicated antibodies.

high amino acid identity among the family members is also to factor H, discriminate between self and non self cell surfaces

reflected by the fact that antibodies raised against factor H detect (Hellwage et al., 1999; McRae et al., 2005; Heinen et al., 2009;

also different CFHRs in plasma and that the antibodies gener- Eberhardt et al., 2009; Goicoechea de Jorge et al., 2013; Tortajada

ated against CFHRs crossreact with other CFHRs (Fig. 3). Moreover, et al., 2013). The C-terminal SCRs in all CFHR proteins that corre-

auto-antibodies against factor H in aHUS recognize not only fac- spond to SCR19 in factor H are highly conserved, while the most

tor H but also certain CFHRs (Kopp et al., 2012; Blanc et al., C-terminal SCRs which correspond to SCR20 in factor H (Fig. 2) are

2012). This cross-reactivity is a challenge for CFHRs purifica- more diverse. SCR20 of factor H harbors an important heparin bind-

tion from plasma, their concentration determination and in depth ing site (Herbert et al., 2007; Lehtinen et al., 2009), suggesting that

analysis. the CFHRs may recognize and bind to different cell surfaces. The

According to their conserved domains, CFHR proteins are specific features of each CFHR protein are presented and discussed

divided into two major groups. Group I includes CFHR1, CFHR2 and separately.

CFHR5 which are composed of a different number of SCR domains,

CFHR2 has four SCRs, CFHR1 five SCRs and CFHR5 nine SCRs. This 2.1. Group I CFHR proteins

group is characterized by their conserved N-termini (SCR1 and

SCR2) which have more than 80% sequence identity (Fig. 2). These 2.1.1. CFHR1

proteins circulate in plasma exclusively as dimers, as homodimers Composition: CFHR1 is composed out of five short SCRs (Skerka

and most likely also in form of heterodimers. Dimerization of these et al., 1991) and a member of the group I CFHR proteins. SCR1 and

CFHR proteins is mediated by the two conserved N-terminal SCR SCR2 have high amino acid identity to SCR1 and SCR2 of CFHR2

domains (Goicoechea de Jorge et al., 2013; Tortajada et al., 2013, (97% and 100%, respectively) and to SCR1 and SCR2 of CFHR5 (91%

unpublished data). The group II CFHR proteins include CFHR3 and and 83%, respectively). CFHR1 like CFHR2 and CFHR5 has a dimer-

CFHR4. These proteins, as well as factor H, lack the N-terminal ization domain in the N-terminus and forms homo- and likely also

dimerization domains (Goicoechea de Jorge et al., 2013). CFHR3 heterodimers with CFHR2 and CFHR5 (Lea et al., 2013). The amino

and CFHR4 show a high degree of amino acid identity to the SCRs acid identity of CFHR1 SCR1 and SCR2 to SCR6 and SCR7 of fac-

6–8 of factor H (63 to 95%). SCRs 6–8 of factor H mediates bind- tor H (34 and 42% respectively) is not pronounced. In contrast,

ing to heparin and to monomeric C-reactive protein (CRP), which the three C-terminal SCRs of CFHR1, i.e. SCRs 3–5 display almost

is conserved in CFHR4 (Mihlan et al., 2009). sequence identity to the C-terminal recognition region of factor H,

The C-terminal SCR domains of all five CFHR proteins show i.e. SCRs 18–20 (Fig. 2). Two variants of CFHR1 are identified. One

a high level of amino acid sequence identity to the C-terminal CFHR1 variant is encoded by the H36.1 cDNA and also termed acidic

recognition region of factor H. This region represents the central isoform (CFHRA) that expresses the amino acids HLE in SCR3. The

combined cell surface anchoring- and C3b recognition region of second CFHR1 variant, which is encoded by the H36.2 cDNA and is

factor H. All five CFHR proteins, i.e. CFHR1, CFHR2, CFHR3, CFHR4 also termed basic isoform (CFHRB) expresses YVQ in SCR3 (Skerka

and CFHR5 bind to C3b and to C3d and all CFHR proteins, similar et al., 1991; Susukida et al., 2007; Abarrategui-Garrido et al., 2009).

Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001

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SCR5 of both CFHR1 isoforms, have two amino acid differences glycosylated protein of 62 kDa (Fig. 3) (Murphy et al., 2002) and is

to factor H, L290 and A296, that correspond to S1191 and V1197 also associated with lipoprotein particles (Park and Wright, 1996).

in SCR20 of factor H. According to this high C-terminal sequence Function: Complement regulatory activities in form of cofactor

identity between CFHR1 and factor H, CFHR1 may form a J shaped activity for factor I or decay acceleration activity were attributed

structure like factor H with a 122 degree tilt between SCR4 and SCR5 also to CFHR5. However, these activities likely are not main CFHR5

of CFHR1 (Morgan et al., 2012). CFHR1 circulates in two glycosy- functions, as high concentrations of CFHR5 are required for them.

lated forms in human plasma (Fig. 3) (Skerka et al., 1991). CFHR1␤ CFHR5 binds to heparin and C3b thus like factor H and most CFHR

has two and CFHR1␣ has one attached carbohydrate side chain. The proteins recognizes and binds to C3b on self surfaces (McRae et al.,

plasma concentration of CFHR1 is about 70 to 100 ␮g/ml (Heinen 2005). CFHR5 competes with factor H for binding to C3b and binds

et al., 2009). Assuming a concentration of 70 ␮g/ml for a dimer of also to the C3b cleavage product iC3b (Goicoechea de Jorge et al.,

CFHR1 and 500 ug/ml for factor H and considering the two fold 2013). CFHR5 also binds to C-reactive protein (CRP) and is recruited

higher mass of factor H, the molar ratio of the CFHR1 dimer to fac- to sites of tissue damages via CRP to inactivate C3b (Park and

tor H in plasma is about 0.3:1. (CFHR1:factor H). In addition CFHR1 Wright, 1996).

may also form heterodimers with CFHR2 and CFHR5 in plasma and

is associated with high density lipoproteins (HDL) particles (Park

and Wright, 1996) and thus the concentration of CFHR1 in the cir-

2.2. Group II CFHR proteins

culation might even be higher.

Function: CFHR1 binds to C3b components of the C5 conver-

2.2.1. CFHR3

tase and thereby inhibits cleavage of the substrate C5. How this

Composition: CFHR-3 consists of five SCR domains (Skerka et al.,

activity is mediated is still unclear. In addition CFHR1 is a ter-

1993). CFHR3 together with CFHR4 represent the second group

minal pathway regulator and inhibits the assembly of the TCC

of CFHR proteins and the two proteins apparently lack the N-

(Heinen et al., 2009). This activity is mediated by the N-terminal,

terminal dimerization domain. Instead SCRs 1–2 and 3 of CFHR3

homo-dimer forming region, i.e. SCRs 1–2. CFHR1 lacks cofactor

show high amino acid identity to SCR6 (91%), SCR7 (85%) and SCR8

activity for factor I for the cleavage of C3b by factor I and also

(62%) of factor H respectively. SCR4 and SCR5 of CFHR3 display

lacks decay activity in dissociation of the C3 convertase C3bBb

also identities to SCR19 (64%) and SCR20 (37%) of factor H (Fig. 2).

(Timmann et al., 1991). Thus CFHR1 binds in a different way to

CFHR3 is detected in plasma in multiple variants (ranging form 35

C3b than the N-terminal SCRs of factor H (SCRs 1–4) bind to C3b,

to 56 kDa), reflecting the existence of four different glycosylated

which inhibit binding of factor B to C3b. However, CFHR1 can

variants of CFHR3 (Fig. 3). The plasma concentration of CFHR3 is

compete off C3b bound factor H. This is likely mediated by the C-

estimated to be similar to CFHR1 (70–100 ␮g/ml) (Fritsche et al.,

terminus of CFHR1 (Fritsche et al., 2010; Goicoechea de Jorge et al., 2010).

2013).

Function: CFHR3 binds to C3b, C3d and to heparin, but the exact

role CFHR3 plays in complement activation is still unclear. Recom-

2.1.2. CFHR2 binant CFHR3 shows low cofactor activity for factor I in cleavage

Composition: The CFHR2 protein consists of four short consen- of C3b and factor H cofactor enhancing activity were reported

sus repeat domains (Skerka et al., 1992). CFHR2 also displays amino (Hellwage et al., 1999). However these activities probably do not

acid identity to SCRs of factor H. CFHR2 is a member of the group I reflect the main CFHR3 functions. CFHR3 competes like CFHR1 with

CFHR proteins as CFHR2 forms exclusively dimers via the dimeriza- factor H for binding to C3b (Fritsche et al., 2010).

tion domain in SCR1. CFHR2 likely forms also hetero-dimers with

CFHR1 but not with CFHR5. SCR1 of CFHR2 shows also homology to

SCR6 (41%), SCR2 of CFHR2 to SCR7 (34%)and SCR3 of CFHR2 to the

2.2.2. CFHR4

C-terminal SCR19 (89%) and SCR4 of CFHR2 to SCR20 (61%) of factor

Composition: CFHR4 is composed of nine SCR domains (Skerka

H (Fig. 2). The protein has two glycosylated forms, a single glyco-

et al., 1997) and lacks like CFHR3 the N-terminal dimer forming

sylated (24 kDa) and a double glycosylated form (28 kDa) (Fig. 3)

amino acid motif. CFHR4 appears with an internal duplication sim-

(Skerka et al., 1992). The plasma concentration of CFHR2 is esti-

ilar to an internal dimer, as SCRs 1–4 show a high level of identity

mated to be about 1/10 (50 ␮g/ml) of factor H (500 ␮g/ml). CFHR2

to SCRs 5–8 of the same protein. Thus SCRs 1–3 is highly identi-

is like CFHR1 part of high density lipoprotein particles (Park and

cal to SCRs 5–7, and SCR4 is identical to SCR8. SCRs 1–3 of CFHR4

Wright, 1996).

have also sequence identity to factor H SCR6 (71%), SCR8 (62%) and

Function: CFHR2 displays complement regulatory activities.

SCR9 (68%) and SCRs 8–9 to SCR19 (64%) and SCR20 (36%) of fac-

The plasma protein inhibits the C3 convertase activity, so that

tor H (Skerka et al., 1997). The human CFHR4 gene encodes two

the amplification loop of the alternative pathway is inhibited

proteins, CFHR4A and CFHR4B. CFHR4B is derived from an alter-

(Eberhardt et al., 2011, 2012). CFHR2 does not compete with factor

natively spliced transcript of the CFHR4 gene. This spliced variant

H for binding to C3b at physiological concentrations (Goicoechea

CFHR4B, is composed of five SCRs that correspond to half of the SCRs

de Jorge et al., 2013; unpublished data).

of CFHR4A, in detail SCR1 and SCRs 5–9 of CFHR4A. CFHR4B has a

mobility of 42 kDa and CFHR4A of 86 kDa (Jozsi et al., 2005) (Fig. 3).

2.1.3. CFHR5 The plasma concentration of the two variants is not determined so

Composition: CFHR5 is composed of nine SCR domains and far. CFHR4 is also part of triglyceride-rich lipoproteins (Skerka et al.,

is the longest CFHR protein of the CFHR family. CFHR5 together 1997).

with CFHR1 and CFHR2 belongs to the group I proteins and forms Function: The role of CFHR4 in complement is also still unclear.

homodimers via the N-terminal two SCR domains and circulates CFHR4 binds to the central complement component C3b and a

in the plasma as homo- and likely also as heterodimer with CFHR1 complement modulatory activity in form of a factor H cofactor

(Goicoechea de Jorge et al., 2013). CFHR5 is the only CFHR protein enhancing activity was reported (Hellwage et al., 1999). Recently

that has five SCR domains with high sequence identities (46%, also a complement activating effect was observed by CFHR4A

75%, 57%, 48%, and 71%) to SCRs 10–14 of factor H (Fig. 2). The (Hebecker et al., 2010). CFHR4A interacts with C reactive protein

C-terminal SCRs of CFHR5 share an amino acid sequence identity (pentameric CRP) and is recruited to damaged or modified self sur-

to SCR19 (64%) and SCR20 (41%) of factor H. CFHR5 appears as a faces (Mihlan et al., 2009).

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Fig. 4. Genetic recombination types in the factor H/CFHR gene cluster

Genetic modulations in form of non-homologues recombination processes via the recombination regions in the factor H/CFHR gene cluster can lead to loss of complete

genes like CFHR3/CFHR1 (Zipfel et al., 2007; Abarrategui-Garrido et al., 2009) or CFHR1/CFHR4 (Moore et al., 2010) or to loss of chromosomal fragments combined with the

generation of fusion genes like factor H/CFHR1 fusion (Venables 2006), CFHR3/CFHR1 fusion (Malik et al., 2012) or CFHR2/CFHR5 fusion (Chen et al., 2012). New genes were also

generated by duplication processes such as a SCR duplication in CFHR1 (Abarrategui-Garrido et al., 2009; Tortajada et al., 2013) or in CFHR5 (Gale et al., 2010). Interestingly

the novel CFHR fusion genes were identified in patients with C3 glomerulopathy (lower group), while genetic modulations that affect factor H functions (upper group) like

the factor H/CFHR1 fusion or autoantibodies to factor H that can appear upon CFHR3/CFHR1 or CFHR1/CFHR4 deletions are associated with HUS.

3. Association of CFHR proteins with human diseases 3.1. Hemolytic uremic syndrome (HUS)

The human CFHR gene cluster is instable and mutations, HUS is a rare, renal thrombotic microangiopathy, leading to end

deletions, duplications or rearrangements as well as sequence stage renal disease in approximately 60% of patients ((Noris and

polymporphisms and variants in the CFHR gene cluster are associ- Remuzzi, 2009). The disease is characterized by a triad, including

ated with various human disorders like atypical hemolytic uremic hemolytic anemia with fragmented erythrocytes, thrombocyto-

syndrome (aHUS); C3 glomerulopathy (C3G) including dense penia and acute renal failure. Renal failure appears to result from

deposit disease (DDD), C3 glomerulonephritis (C3GN) and CFHR5 platelets rich microthrombi, formed in the small vessels of the kid-

nephropathy; IgA nephropathy, but also age related macular degen- ney. HUS presents in several forms, the typical one, associated with

eration (AMD), systemic lupus erythematosus (SLE) and infections infection by a shiga toxin producing bacteria, the atypical form

with Neisseria microorganisms (Rodriguez de Cordoba et al., 2012). (aHUS) that is linked to genetic mutations and the autoimmune

Thus the interests in the CFHR molecules are increasing, on the form including a special genetic form, DEAP HUS (Deficiency of

genetic and also on the functional level. Understanding the genetic CFHR plasma proteins and Autoantibody Positive form of Hemolytic

variations in the CFHR cluster as well as the exact physiological role Uremic Syndrome), which is linked to auto-antibodies (Dragon-

of each of the CFHR proteins will help to define the pathomecha- Durey et al., 2005; Zipfel et al., 2007; Noris and Remuzzi, 2009;

nism of several diseases. Zipfel and Skerka, 2009). aHUS is associated with mutations partic-

The chromosomal segment on chromosome 1 which includes ularly in the genes coding for complement factor H, factor I, MCP, C3

the CFHR genes together with the factor H gene has multiple and factor B (Roumenina et al., 2011), or recently to mutations and

independent large genomic duplications, also known as low-copy variants of genes outside the complement system (Lemaire et al.,

repeats, resulting in a high degree of sequence identity between 2013; Delvaeye et al., 2009).

factor H and CFHRs genes as well as between the gene interspaced

regions (Diaz-Guillen et al., 1999; Zipfel et al., 2007). These charac- 3.1.1. CFHR3/CFHR1 deletion

teristics explain the frequently observed genetic rearrangements In hemolytic uremic syndrome the homozygous deletion of

in form of deletions, duplications or rearrangements within this CFHR1/CFHR3 is strongly associated with the development of factor

chromosomal segment. Rearrangements are observed predomi- H auto-antibodies (DEAP HUS) (Zipfel et al., 2007; Jozsi et al., 2007,

nantly in renal diseases, such as aHUS and C3G. So far two different 2008; Skerka et al., 2008; Dragon-Durey et al., 2009; Zipfel et al.,

types of rearrangements in the factor H/CFHR gene cluster can 2010). Initially the CFHR3/CFHR1 deletion alone was identified as a

be differentiated according their different outcomes (Fig. 4): (1) marker for aHUS (Zipfel et al., 2007) but later the CFHR3/CFHR1

Rearrangements that result in loss of factor H functions on the deletion was linked to the presence of factor H auto-antibodies

surfaces which triggers aHUS. These cases include the complete in DEAP HUS (Dragon-Durey et al., 2005; Jozsi et al., 2007, 2008;

loss of single CFHR genes with the secondary effect of genera- Fremeaux-Bacchi et al., 2013). Thus a predisposition for the autoan-

tion of auto-antibodies that inhibit factor H surface binding, or tibody generation by the CFHR3/CFHR1 deletion was concluded. The

the loss of chromosomal fragments, which leads to factor H/CFHR CFHR3/CFHR1 deletion was also associated with a particular sub-

hybrid genes and factor H proteins with modified surface recogni- group of patients with Factor I mutations (Bienaime et al., 2010).

tion regions. (2) The second type is rearrangements which include Later, also the deletion of CFHR1/CFHR4 genes was identified in

the generation of different CFHR hybrid genes without affect- patients with DEAP HUS (Moore et al., 2010), suggesting that the

ing the factor H gene. These rearrangements were identified in deletion of CFHR1 alone is involved in auto-antibody formation. The

patients with C3G. (Fig. 4). The following text will focus on these deletion of CFHR3/CFHR1 appears as a polymorphism in the normal

diseases. population, with a frequency depending on the ethnicity. 2% (Spain,

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Germany, France, Asia), 20% (North Africans, Tunisia) and even up to 3.1.4. CFHR5 mutations

33% (Nigeria) individuals of the normal population were identified Genetic variants of CFHR5 were reported in aHUS patients. Three

with this CFHR3/CFHR1 deletion (Leban et al., 2012; Fremeaux- mutations – E75Xaa, L105R, S195T, V277N, V379L and W436C were

Bacchi et al., 2013; Holmes et al., 2013). Thus a second trigger in identified so far, but the functional consequences were not studied

addition to the genetic deletion of the CFHR genes is anticipated (Maga et al., 2010; Westra et al., 2012).

to develop DEAP HUS. The mechanism how the CFHR3/CFHR1 dele-

tion causes the development of factor H auto-antibodies is unclear. 3.2. C3 glomerulopathies

Deletion of the CFHR3/CFHR1 gene segment is observed in about

87% HUS patients with factor H autoantibodies, but the deletion Glomerular pathologies that are characterized by the isolated

is significantly less present in patients with AMD (about 1%) as deposition of C3 are classified as C3 glomerulopathy. This group of

compared to the healthy Caucasian population with a frequency of diseases includes dense deposit disease (DDD), glomerulonephri-

about 5%. The same CFHR3/CFHR1 deletion is also protective to IgA tis with isolated C3 deposits (C3GN) and CFHR5 glomerulopathy

nephropathy (Gharavi et al., 2011) but increases the risk to develop (Fakhouri et al., 2010). These glomerulopathies are characterized

SLE (Zhao et al., 2011). Thus the CFHR3/CFHR1 deletion occurs in the by C3 deposits within or along the glomerular basement membrane

healthy population, but has opposite effects in different diseases. combined with alternative complement pathway overactivation.

The underlying mechanism is poorly understood. Overactivation is primarily due to the presence of autoantibodies

A similar dichotomy in the genetic associations was observed that stabilize the C3 convertase like C3Nef or anti factor B or anti fac-

for the two CFHR1 gene variants – CFHR1A and CFHR1B. While tor C3b (Chen et al., 2011). Rarely mutations in complement factor

the CFHR1A isoform represents a risk factor for AMD (Martinez- H (Licht et al., 2006; Servais et al., 2012) or in C3 genes are reported

Barricarte et al., 2012), CFHR1B elevates the risk for aHUS (Martinez-Barricarte et al., 2010). Several genetic abnormalities in

(Abarrategui-Garrido et al., 2009). This dichotomy may be the CFHR gene cluster are associated with C3 glomerulopathy and

explained to some degree by the fact that CFHR1 and CFHR3 com- therefore CFHR gene mutations seem to play a major role in this

pete with Factor H for binding to C3b on the cell surface (Heinen patient group.

et al., 2009; Fritsche et al., 2010; Goicoechea de Jorge et al., 2013).

Therefore their absence will increase the local levels of factor H and 3.2.1. C3 glomerulonephritis (C3GN)

in consequence regulation by factor H, thus explaining the associ- 3.2.1.1. CFHR3–CFHR1 hybrid, CFHR1 dublication. A hybrid

ation of the deletion with protection against IgA nephropathy and CFHR3–CFHR1 gene was identified in a large family with multiple

AMD. Nevertheless, CFHR1 was also found to inhibit C5 convertase affected individuals having complement-mediated glomeru-

activity with terminal complex formation and CFHR3 possesses a lonephritis (Malik et al., 2012). The hybrid protein comprised the

cofactor activity for Factor I (Heinen et al., 2009; Fritsche et al., first two domains of CFHR3 and all five SCR domains of CFHR1.

2010). Moreover CFHR3 and CFHR1 reduced the generation of C5a The abnormal protein was present in patients’ plasma (Malik

and consequently blocked complement-mediated chemotaxis of et al., 2012). However, plasma C3 levels of the patients were

neutrophils (Fritsche et al., 2010). However, CFHR3 and CFHR1 do normal and a massive fluid phase complement activation was

not exert C3 convertase decay accelerating activity like factor H and excluded. The hybrid protein isolated from the patient plasma

thus do not compensate factor H functions. Furthermore the dele- induced deregulation of the alternative complement pathway

tion of CFHR1 will likely also alter the protein oligomerization state (Goicoechea de Jorge et al., 2013). The investigators indicated

of CFHR2 and CFHR5 in plasma, in case CFHR1 forms heterodimers that the mutant protein competed off factor H from the C3

with CFHR2 and CFHR5. convertase and is thus involved in disease pathogenesis. Also a

duplication of SCR 1–4 of CFHR1 was identified in a familial form

of C3GN (Tortajada et al., 2013), associated with decreased C3

3.1.2. Factor H/CFHR1 hybrid plasma levels. Because of the multiple hybridization domains in

Genetic rearrangements between CFHR1 and factor H, which the mutated CFHR1 molecule unusual multimers were formed,

result in a hybrid factor H/CFHR1 gene and corresponding protein which enhanced binding of mutated CFHR1 to C3b, iC3b, and C3dg

were identified in different aHUS patients (Venables et al., 2006; resulting in enhanced replacement of factor H bound to C3b. Thus

Maga et al., 2011; Nester et al., 2011; Krid et al., 2012; Fremeaux- N-terminal modifications in CFHR proteins can interfere with factor

Bacchi et al., 2013). Two types of factor H/CFHR1 hybrid proteins H regulation contributing to complement dysregulation and C3G

have been described. One hybrid protein comprises the first 18 SCRs pathology.

of factor H linked to the C-terminal two SCRs of CFHR1. The second

fusion protein has the first 19 SCRs of factor H linked to SCR5 of 3.2.1.2. CFHR5 mutation. Recently a heterozygous single

CFHR1. Both the hybrid factor H/CFHR1 proteins differ from their nucleotide insertion in exon 4 of CFHR5 was reported in a

native C-terminal factor H domain 20 by two amino acids only, at particular case of a poststreptoccocal infection glomerulonephri-

positions S1191L and V1197A (Heinen et al., 2006) lack proper fac- tis, resulting in a premature stop codon in CFHR5 (Vernon et al.,

tor H cell binding and protection from complement and is directly 2012). One year after the bacterial infection episode the patient

implicated in the disease pathogenesis (Heinen et al., 2006; Herbert showed membranoproliferative changes, and electron-dense

et al., 2012; Krid et al., 2012). deposits consistent with C3 glomerulopathy. Although the patient

with the mutation had low CFHR5 levels, the parent carrying the

same mutation had normal CFHR5 levels. In vitro studies with

3.1.3. Factor H/CFHR3 hybrid the mutant CFHR5 protein are necessary in order to determine

A hybrid factor H/CFHR3 gene generated by a microhomology- whether and how the CFHR5 mutation is associated with the

mediated deletion was reported in a familial aHUS case (Francis disease.

et al., 2012). The deletion spans from factor H to CFHR3 and results

in a transcript that encodes the signal peptide and SCRs 1–19 of 3.2.2. Dense deposit disease (DDD)

factor H fused to SCRs 1–5 of CFHR3. The new protein product of Association of polymorphisms in CFHR5 was also found with

24 SCRs is secreted, circulates in the plasma, shows normal fluid- DDD (Abrera-Abeleda et al., 2006). Two SNPs in the promoter

phase regulatory factor H activity but lacks regulatory activity at region of CFHR5 (rs942766 and rs9427662), could affect transcrip-

cell surfaces, despite increased heparin binding. tion, potentially by removing a binding site for C/EBP␤ for the one

Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001

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and the other by adding a GATA1 binding site. The other significant and to peroxidized lipids on dead cells combined with reduced anti-

association changes a proline to serine in exon 2 (rs12097550). As inflammatory functions by factor H (Weismann et al., 2011). These

exons 1 and 2 of CFHR5 encode a domain homologous to short con- results underline the involvement of local complement activation

sensus repeat 6 of factor H, which is integral to heparin and CRP and inflammation in AMD pathophysiology.

binding, this change could affect complement activation and con- A role of CFHR proteins in AMD pathology is indicated because of

trol by CFHR5. Functional studies are needed to shed more light on several aspects. First, the homozygous deletion of CFHR1 and CFHR3

the role of these mutations in DDD. is associated with a lower risk for AMD (Hughes et al., 2006). The

positive effect of this deletion on AMD is still not clear and has

3.2.3. CFHR5 nephropathy been explained by the fact that CFHR1 and CFHR3 can compete

CFHR5 nephropathy is a form of C3GN with autosomal domi- with factor H for binding to C3b. Consequently CFHR1 and CFHR3

nant inheritance, described so far in patients of Cypriot origin (Gale deficiency likely enhances factor H presence on C3b and C3 con-

et al., 2010). It is associated with a single genetic abnormality (a vertases. The genetic deficiency of CFHR3 and CFHR1 is in linkage

founder effect), causing an internal duplication in the CFHR5 gene. disequilibrium with the protective variant of factor H (encoding fac-

The mutant CFHR5 protein binds to membrane-associated C3b less tor H 402Y) which suggested that not the deficiency, but the factor

effectively than does the wild-type protein. The disease is charac- H variant is responsible for the reduced risk for AMD (Raychaudhuri

terized with subendothelial and mesangial deposits. Microscopic et al., 2011). However, regression analysis revealed that the dele-

haematuria and episodes of synpharyngitic macroscopic haema- tion of CFHR3 and CFHR1 without the protective polymorphism in

turia, clinically similar to IgA nephropathy, are detected in half of factor H remained significantly associated with the risk for AMD

the cases. About half of the patients progress to chronic kidney dis- (Fritsche et al., 2010). Furthermore on the genetic level a particular

ease, especially over age of 50 (Athanasiou et al., 2011; Deltas et al., CFHR1 variant, CFHR1A, is identified to be strongly associated with

2013). The laboratory complement profile of the patients is normal, AMD (Martinez-Barricarte et al., 2012), while the CFHR1B variant is

without decreased C3 levels. This suggested that the complement associated with hemolytic uremic syndrome (HUS) (Abarrategui-

activation occurs locally in the kidney and indicated that CFHR5 Garrido et al., 2009). As the variant CFHR1A is more different to

plays a prominent role in inhibiting C3 activation at the glomerular factor H than the CFHR1B variant, the balance between CFHR1A

basement membrane and not at a systemic level. and factor H or CFHR1B and factor H in binding to C3b can be dif-

Recent functional studies deciphered the molecular mechanism ferent. However, again the CFHR1A variant is genetically strongly

linking this abnormal CFHR5 protein to the disease (Goicoechea linked to the factor H AMD risk variant (402 H).

de Jorge et al., 2013). CFHRs containing fractions from the serum Deposits in form of drusen are a hallmark feature in AMD and

of the patient deregulated complement stronger as compared to a also in form of dense deposits in DDD. Composition of both deposits

CFHR fraction from normal donors. The duplication of the dimeriza- show striking similarities as they contain a number of complement

tion domain (duplication of SCR1 and SCR2 in CFHR5) may result activation products as well as regulators like factor H. Group I pro-

in formation of abnormal CHFR5, CFHR1 and/or CFHR2 contain- teins CFHR1 and CFHR5 were observed in DDD deposits (Sethi and

ing oligomers, competing stronger with factor H for cell-bound Fervenza, 2011) and the terminal pathway regulators clusterin and

C3b and impairing the cell surface protection from complement vitronectin in both, drusen and deposits (Wang et al., 2010). The

attack. presence of factor H family proteins together with terminal path-

way regulators clusterin and vitronectin confirm the observations

3.3. Age related macular degeneration that deposits are locations of complement activation and regula-

tion.

Age related macular degeneration (AMD) is a most common

cause of blindness in older individuals of the western world. This 3.4. CFHR proteins and infections

retinal disease is a heritable and progressive retinal disease that

affects the photoreceptors and leads to loss of central vision. In the CFHR proteins are recruited to the surface of pathogens and

early stages of the disease, deposits in form of drusen are formed thus their functions are obviously attractive for a number of those

between the retinal pigment epithelium and the Bruch’s membrane microbes. Gram negative, Gram positive bacteria, as well as fun-

(age related maculopathy). When the disease progresses pigment gal surfaces bind CFHR1 (Table 1). CFHR proteins bind similar to

epithelial cells and the overlying photoreceptor cells dye leading to factor H via glycosaminoglycans to human surfaces and can thus

geographic atrophy. As soon as vascular endothelial factor (VEGF) differentiate between self and foreign surfaces. Pathogens express

synthesis is induced and the factor secreted, new vessels grow into specific proteins on their surfaces to recruit CFHR1 and in most

these regions and the disease is called ‘wet AMD’ with aberrant cases these microbial proteins also bind factor H. This phenomenon

choroidal neovascularization (Miller, 2013). AMD is a complement can be explained by the high amino acid identity of CFHR1 and

associated disease and several genes of the alternative comple- factor H in their C-terminal SCR binding domains. Interestingly in

ment pathway on chromosome 1 (factor I, C3, C2/factor B, and C7) case of Borrelia burgdorferi the microbial proteins show a binding

are associated with AMD. In addition a region on chromosome 10 preference for either factor H (CRASP-1) or CFHR1 (CRASP-5) indi-

have been implicated in the susceptibility for AMD (HTRA/ARMS2) cating a special interest and effort by the pathogen to bind both

(Miller, 2013). Recently seven new gene loci (COL8A1, FILIP1L, IER3, proteins to the surface. This is in agreement with complement reg-

DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9, B3G) were identified ulatory activities described for CFHR1 that are likely of interest for

outside the complement pathway for AMD including genes of athe- the pathogen.

riosclerosis signaling or phospholipid degradation (Fritsche et al., Besides CFHR1 also CFHR2, CFHR4 and CFHR5 are recruited to

2013). Age as well as environmental factors also can increase the the surface of human pathogens. B. burgdorferi binds also CFHR2

risk for AMD (Anderson et al., 2002). and CFHR5 from human serum and Candida albicans CFHR4. This

One major risk factor for AMD is the polymorphism in the factor strengthens the concept that B. burgdorferi and C. albicans hijack

H gene at amino acid position 402 in SCR7 which is confirmed in immune regulators to evade host complement attack and to have

several cohort studies (Hughes et al., 2006; Fritsche et al., 2013). The an advantage in dissemination. This concept was also discussed

polymorphism in SCR7 of factor H has been functionally character- when a whole genome association study to meningococcal disease

ized and the exchange of tyrosine to histidine at amino acid position revealed that SNPs from factor H (rs 1065489 (p936D < E) and from

402 revealed a significant loss of binding of factor H to heparin, CRP CFHR3 (rs426736) were associated with decreased susceptibility

Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001

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8 C. Skerka et al. / Molecular Immunology xxx (2013) xxx–xxx

Table 1

Binding of CFHR proteins to pathogenic microorganisms.

Pathogen CFHR1 Other CFHRs Factor H Reference

Candida albicans Pra1 +(CFHR4) Pra1 Meri et al. (2002), Luo et al. (2010,

2011)

Aspergillus fumigatus + + Behnsen et al. (2008), Vogl et al. (2008)

Pseudomonas aeruginosa Tuf, GpD Tuf, GpD Kunert et al., 2007, Hallström et al.

(2012)

Borrelia burgdorferi BbCRASP3 BbCRASP3 BbCRASP1-3 Haupt et al. (2007), Hellwage et al.

BbCRASP4 BbCRASP4 OSPE (2001), Stevenson (2002) BbCRASP5 BbCRASP5

(CFHR2,CFHR5)

Borrelia spielmanii BsCRASP1 BsCRASP1,3 Kraiczy et al. (2004a)

Borrelia hermsii BhCRASP BhCRASP Kraiczy et al. (2004b)

Leptospira sp. Lig Lig Castiblanco-Valencia et al. (2012)

Leptospira interrogans Len A protein LfhA Meri et al. (2005), Verma et al. (2006)

Group A streptococci M protein M5 (CFHR3) M protein Kotarsky et al. (1998), Reuter et al.

Scl1.6, ScL1.55 Fba (2010), Perez-Caballero et al. (2004),

Oliver et al. (2007), Blackmore et al.

(1998), Pandiripally et al. (2003)

Neisseria gonorrhoeae Por1a protein Por1A protein Por1A protein Ram et al. (1999), Ngampasutadol et al.

(2008)

Loa loa microfilariae + + Haapasalo et al. (2009)

to disease for minor allele carriers (Davila et al., 2010). Further show that CFHR proteins can not compensate lost factor H func-

functional studies are necessary to clarify whether these genetic tions, which is in agreement with the fact that CFHR proteins lack

variants affect immune evasion mechanisms of Neisseria meningi- particularly C3 convertase decay accelerating activity.

tidis. Novel functions that were identified for CFHR proteins, such

as terminal pathway regulation (Heinen et al., 2009) and comple-

4. Conclusions ment receptor functions (Losse et al., 2010; Manuelian et al., 2003)

show that normal CFHR proteins act close to factor H but harbor

CFHR proteins are members of the complement factor H fam- additional functions to protect human cells and tissues. This is in

ily and circulate in human plasma. Each CFHR protein binds to C3b agreement with the fact that CFHR5 binds also to iC3b in contrast to

and particularly to C3d and thus acts around or in concert with factor H (Goicoechea de Jorge et al., 2013). Thus identifying the reg-

the main alternative pathway regulator factor H. CFHRs support ulatory functions of the CFHR proteins will certainly help to better

factor H activities such as enhancing cofactor activity of factor H understand the patho-mechanisms of several complement associ-

or have further regulatory activities like the inhibition of the ter- ated diseases and hopefully will offer new strategies for therapy.

minal pathway. However, as members of the CFHR protein family

(CFHR1, CFHR3 and CFHR5) also compete with factor H for binding Conflicts of interest

to C3b, CFHR protein levels have an influence on factor H functions.

Therefore CFHR protein levels are critical and need to be in bal- The authors declare no competing financial interests.

ance with factor H levels. This aspect explains, why in two cases,

the CFHR deficiency and the presence of CFHR hybrid proteins, Acknowledgements

local complement regulation is affected. Deficiency of single CFHR

molecules (in most cases CFHR1 and CFHR3) are associated with

This work was supported by the ‘Deutsche Forschungsgemein-

a reduced risk for AMD and IgA nephropathy obviously because

schaft’ (DFG, Sk 46) Germany and by EU FP7 grant 2012-305608

of reduced competition with factor H followed by an enhanced

(EURenOmics). We thank Heiko Richter and Nadine Flach for West-

presence and regulation by factor H. However, in parallel the same

ern blot analysis for the detailed characterization of the factor

CFHR1 and CFHR3 deficiency also enhanced the risk for diseases like

H/CFHR gene locus. QC is a doctoral researcher at the International

DEAP HUS or SLE, indicating a role of CFHRs in the maintenance

Leibniz Research School (ILRS), part of the Jena school of Microbial

of immune tolerance. The second situation when CFHR proteins

Communication (JSMC), Jena, Germany.

affect complement regulation is the presence of CFHR hybrid pro-

teins with N-terminal modifications. These N-terminal changes due

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Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001