REVIEW ARTICLE

Self-nonself discrimination by the complement system

Seppo Meri1,2,3
1 Immunobiology, Research Programs Unit, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Finland
2 HUSLAB, Helsinki University Hospital, Finland
3 Humanitas University, Milan, Italy

Correspondence
S. Meri, Immunobiology, Research
Programs Unit, Department of Bacteriology
and Immunology, Haartman Institute,
University of Helsinki, Helsinki 00014,
Finland
Fax: +358 9 191 26382
Tel: +358 50 5812462
E-mail: seppo.meri@helsinki.fi
(Received 20 June 2016, revised 29 June
2016, accepted 6 July 2016, available online
19 July 2016)
doi:10.1002/1873-3468.12284
Edited by Wilhelm Just
The alternative pathway (AP) of complement can recognize nonself structures
by only two molecules, C3b and factor H. The AP deposits C3b covalently
on nonself structures via an amplification system. The actual discrimination is
performed by factor H, which has binding sites for polyanions (sialic acids,
glycosaminoglycans, phospholipids). This robust recognition of ‘self’ protects
our own intact viable cells and tissues, while activating structures are recog-
nized by default. Foreign targets are opsonized for phagocytosis or killed.
Mutations in factor H predispose to severe diseases. In hemolytic uremic syn-
drome, they promote complement attack against blood cells and vascular
endothelial cells and lead, for example, to kidney and brain damage. Even
pathogens can exploit factor H. In fact, the ability to bind factor H discrimi-
nates most pathogenic microbes from nonpathogenic ones.
Keywords: escape; hemolytic uremic syndrome; sialic acid

Distinguishing structures of ‘self’ from ‘nonself’ is one
of the very fundamental processes in biology and a
property of the immune system. Sensor molecules for
fine structures, like antibodies in the classical pathway
of complement, usually recognize nonself. This
requires a large repertoire of different molecules. For
more robust recognition of targets, certain types of
pattern-recognition molecules are used, for example,
scavenger receptors, Toll-like receptors, Nod-like
receptors, and C-type lectins, which are molecules that
bind sugars in a calcium-dependent manner. The latter
include, for example, mannan-binding lectin (MBL),
ficolins, and DC-SIGN [1,2].
The alternative pathway (AP) of complement can
recognize a broad spectrum of nonself structures by
default. Anything not actively recognized as self is
considered as nonself and will be labeled for destruc-
tion (opsonophagocytosis or direct killing). Molecu-
larly, this type of active self-recognition requires far
less effort than maintaining a large repertoire of speci-
fic recognition molecules. A similar strategy is used in
the actions of natural killer cells (NK cells), where for-
eign structures are recognized according to the so
called ‘missing self’ concept. Thereby, NK cells recog-
nize cells that lack or have lost host-specific major his-
tocompatibility complex (MHC) molecules [3].
Subsequently, NK cell recognition has been observed
to depend on both the presence and absence of specific
molecular markers [4].
The discrimination between host and nonhost (or
‘self and nonself’) structures by the immune system is
also essential for the maintenance of the integrity of

Abbreviations
aHUS, atypical hemolytic uremic syndrome; AMD, age-related macular degeneration; AP, alternative pathway; CCP, complement control pro-
tein; DAF, decay-accelerating factor; DDD, dense deposit disease; DMBT1, deleted in malignant brain tumor 1; FHBP, factor H binding pro-
tein; FHL-1, factor H-like protein 1; FHRs, factor H-related proteins; MBL, mannan-binding lectin; MCP, membrane cofactor protein; NK,
natural killer; PNH, paroxysmal nocturnal hemoglobinuria; SAG, salivary agglutinin; SALSA, salivary scavenger and agglutinin; TEP1, thioester
protein 1.

2418 FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
S. Meri
our body. In addition to surveillance against microbes,
complement plays an important role also as a general
clearance mechanism [5]. Even in the absence of
microbes an inability to distinguish borders of host
structures or an inappropriate loss of protection
against complement underlies many human diseases. A
disturbance in self-recognition is involved in distinct
syndromes like atypical hemolytic uremic syndrome
(aHUS), dense deposit disease (DDD), age-related
macular degeneration (AMD), and paroxysmal noctur-
nal hemoglobinuria (PNH) [6]. Complement activation
against self-structures may also occur in pregnancy
complications often involving endothelial cell dysfunc-
tion [7].
While the human complement system distinguishes
between human cell surfaces in general (‘self’) and exter-
nal foreign molecular structures (‘nonself’), another
level of ‘self-nonself’ distinction occurs between individ-
uals. In pregnancy, as well as in transplantation, a con-
tact between the complement system from one person
(future mother, transplant recipient) with cells from
another person may lead to incompatibility problems.
This may become reflected as a pregnancy disorder or
rejection of the transplant organ or cells. The problems
currently are thought of being due to adaptive immune
responses (antibody or T cell-mediated rejection) but
part of the problem could also be related to polymor-
phic variations in complement activating and regulating
components leading to incompatibility between self and
nonself [8]. With the emerging easier and cheaper ways
for efficient DNA sequencing, it may become possible
to analyze the role of these incompatibilities, for exam-
ple, in organ rejection.
Malignant tumor cells and pathogenic microbes
cause different kinds of problems but common to both
is that they usually manage to escape complement
attack. Thus, they resemble ‘self’. For tumor cells this
is natural, because most molecules that they carry on
the surfaces are present also on normal nonmalignant
cells. It is, however evident, that this is not the whole
truth. Some tumors have additional mechanisms to
protect themselves against complement attack, like
secretion of complement inhibitors or production of
additional protective layers of carbohydrates (like
mucins) on their surfaces. There is an urgent need to
obtain new information about the complement evasion
mechanisms so that monoclonal antibody-based tumor
immunotherapy could be improved [9,10].
A feature of pathogenic microbes is that they exploit
different mechanisms to escape complement attack and
thereby avoid being opsonized and phagocytosed. The
information on microbial complement resistance mech-
anisms is valuable because it can be used for the
FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
Self-nonself discrimination by the complement system
development of new vaccines or ways to overcome
microbial resistance to complement [11].
As is evident from the above, it is very important to
know in detail the mechanisms how complement can
distinguish between self and nonself, what happens
when errors occur and how do tumor cells and
microbes manage to avoid being recognized by com-
plement. Both in malignancies and in invasive infec-
tions, there is a need to neutralize the target’s ability
to block complement activation to allow utilization of
complement for attack against the unwanted cells. In
contrast, the opposite situations, where complement
unnecessarily attacks self (autoreactivity, autoimmu-
nity), require means to correct the errors or to provide
therapy for the diseases they cause. For any interven-
tions, it is essential to understand in detail the molecu-
lar mechanisms how complement recognizes or does
not recognize its targets.
The complement system–a key innate
immune recognition system
The parenteral spaces of the normal healthy human
body are kept free of microbes and other foreign mate-
rial by innate immune defense mechanisms. As a cen-
tral component of innate immunity, complement is
capable of destroying and invading microbes, generat-
ing inflammation, and acting as a ‘waste-disposal’ sys-
tem [12]. Altogether the complement system consists of
up to 50 different molecules in plasma and on cell
membranes (Fig. 1). Each have their specific roles by
acting as activating components, regulators or recep-
tors in the system.
Complement can become activated through three
distinct pathways. In the classical pathway, foreign
materials are recognized by IgM or IgG antibodies,
whereafter the first component C1q binds and initiates
the complement activation cascade. Some structures,
like bacterial lipopolysaccharides [13], C-reactive pro-
tein [14], and degradation products of cells [15] can
bind C1q independently of antibodies. In the lectin
pathway, sensor molecules recognize structures con-
taining carbohydrates, like mannose or N-acetylgluco-
samine (MBL), for example, on yeast cell surfaces, or
acetylated sugars by ficolins (ficolins 1, 2, and 3)
[1,16,17]. The alternative pathway (AP) is able, in a
robust manner, to discriminate normal human cells
from microbes (e.g., bacteria, fungi, parasites) and
from damaged or transformed human cells (e.g., virus-
infected or apoptotic cells) in an antibody-independent
fashion. Another key feature of the AP is that, it can
amplify its own activation regardless of which pathway
it was initiated [18].
2419
Self-nonself discrimination by the complement system S. Meri

Fig. 1. The different pathways, components and regulators of the complement system. For simplicity, no receptors (except for CR1, the
C3b/C4b receptor, which also acts as a regulator) or factor H-related proteins (FHR1-5) are shown in the figure.

Recognition of targets by the classical
and lectin pathways
The classical and lectin pathways use sensor molecules
for the recognition of distinct patterns on target sur-
faces [19]. The C1q family of proteins includes C1q,
MBL, ficolins 1, 2, and 3 (M, L, and H, respectively),
and surfactant proteins SpA and SpD [20]. In addi-
tion, molecules like adiponectin and a family of C1q
and TNF-like receptor proteins with 15 members
(CTRP 1–15) show similarities to C1q [21]. In their
structures, separate polypeptide chains (A, B, and C in
C1q) form collagenous triple helices. At the C-terminal
end of each polypeptide, there is another part that
forms a globular domain that often acts as a carbohy-
drate-recognizing lectin. Hence, these proteins are
often collectively called as collectins. Individual helices
with a collagenous tail and globular end domains in
turn assemble into bundles with a variable number of
subunits. The final protein product looks like a bunch
of flowers. The recognition part is located in the glob-
ular domains, whereas the collagenous tail interacts
with effector molecules (C1r and C1s in complement
C1) [22] or receptors for phagocytosis (C1q receptors)
[23]. Because there are multiple globular recognition
domains, an average of 6 9 3 in C1q, the molecules
can bind to targets with high avidities.
C1q has multiple targets. Of these, the traditional
ones are IgG (primarily IgG1 and IgG3 subclasses)
and IgM class antibodies. Antibody-independent bind-
ing of C1q occurs, for example, to exposed phospho-
lipids on apoptotic or injured cells and to various
intracellular structures, like mitochondria, chromatin,
and cytoskeletal filaments, exposed upon cell damage.
This contributes to the clearance of injured tissue
materials by the reticuloendothelial system. Macro-
phages that have phagocytosed materials opsonized by
C1q and other complement activation components,
particularly iC3b, secrete immunosuppressive cytoki-
nes, like TGF-beta and IL-10, with the apparent aim
of carrying out homeostatic cleaning without causing
unnecessary inflammation or immune activation [24].
Suppression of immunoinflammatory responses is
mediated by the integrin-type iC3b receptor CD11b/18
or complement receptor type 3 (CR3) [25]. C1q also
binds directly to many types of lipopolysaccharides

2420 FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
S. Meri
and other bacterial components to help in the phago-
cytosis of microbes by blood or tissue leukocytes,
neutrophils, and macrophages.
MBL binds to surfaces coated with carbohydrates
containing mannose and/or N-acetyl-glucosamine [26].
These sugar assemblies, collectively termed as mannan,
are typically found on the surfaces of yeasts, like the
common human pathogen Candida albicans. Also,
some bacteria and their specific serotypes (like Sal-
monella enterica O:6,7 serotype) can have mannose (te-
tramannose repeats) in their lipopolysaccharides,
although this is not common [27]. Ficolins have their
own specificity repertoires [28]. Structures that usually
are recognized contain acetylated monosaccharides.
Additional molecules in the family include collectin-10
and collectin-11 (CL-K1) that bind to fucose or man-
nose. Interestingly, mutation in the collectin-11 gene
(colec11), as well as in MASP-3 have been found to
associate with the rare 3MC syndrome with develop-
mental defects [29]. Whether the association is related
to complement activity or something else is not yet
clear.
C1q, MBL, and ficolins operate primarily in par-
enteral spaces. The surfactant proteins, SpA and SpD,
instead, are found on mucosal surfaces like in the res-
piratory tract and in the intestines. Mucosal surfaces
contain also a soluble scavenger family protein called
variously gp340, deleted in malignant brain tumor 1
(DMBT1), salivary agglutinin (SAG) or salivary scav-
enger, and agglutinin (SALSA) [30,31]. We named the
protein as SALSA, as it was found to bind to
microbes, recruit MBL, the surfactant proteins, SpA
and SpA, and to regulate complement activation [32].
SALSA is thus yet another sensor protein for the com-
plement system, but operating principally in the
intestines, respiratory tract and on other mucosal sur-
faces [33,34]. When bound to targets it can activate
complement, but when in solution it inhibits the lectin
pathway [32,35].
Adiponectin and the C1q and TNF-related proteins
(CTRPs) are an interesting family of collectins,
because they have been indicated in the metabolism of
lipids and carbohydrates [21]. Adiponectin is an antidi-
abetic, antiatherogenic and antiinflammatory molecule.
As such it has been considered to have hormone-like
properties. Its structural similarity to other collectins,
however, points more toward a clearance function,
possibly in the removal of potentially harmful lipids or
glycolipid particles. The functions of the 15 CTRPs
are still partially unknown. They have been implicated,
for example, in increasing glucose uptake, decreasing
fat mass or enhancing insulin sensitivity [36]. The
recognition specificities of these molecules and possible
FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
Self-nonself discrimination by the complement system
interactions with complement need to be comprehen-
sively worked out. This would be an important task
because of the potential role of these molecules in the
development of atherosclerosis or metabolic distur-
bances, diseases of major importance.
Activation mechanisms of the
alternative pathway
The AP is an ancient system, and as such very impor-
tant in protection against microbial infections. In addi-
tion to all vertebrates, some invertebrates, like
ascidians and chordates have an AP-like system [37].
A C3 homolog, called thioester protein 1 (TEP1), has
been found in mosquitoes [38] and probably exists in
other insects, as well. The functions of TEP1 and C3
are only partially similar. Both are involved in antimi-
crobial defense, but they are activated and regulated
by different mechanisms. In fact, TEP1 is more similar
to a membrane-associated thioester protein, CD109,
than to C3. The function of CD109 is still unknown.
Because of efficient amplification the AP complement
activation can lead to inflammation and tissue damage.
Therefore, the AP needs to be strictly targeted only to
structures that need to be eliminated. The mechanism
of self-nonself (or host-nonhost) discrimination by the
alternative pathway of complement has been studied
originally using purified proteins. The actual activation
system is composed of six main components: C3, B,
D, factor H, factor I (C3b inactivator), and P (prop-
erdin) [39].
C3 is the central molecule in AP activation. It is
abundant in blood plasma with an average concentra-
tion ranging from 0.5 to 1.2 g
L 1. Because of its role
in continuous surveillance for potential invaders or
damaged tissue structures as much as 50% of its
plasma pool may be regenerated every 1–2 days [40].
C3 is spontaneously activated by slow hydrolysis to
generate a form C3(H2O), where an internal thioester
bond (formed by side chains of cysteine 988 and glu-
tamine 991) has become disrupted. C3(H2O) resembles
C3b except that the C3a part has not become dissoci-
ated from the molecule. Functionally, C3(H2O) is able
to act in manner similar to C3b in that it can bind fac-
tor B and generate an initial C3 convertase, C3(H2O)
Bb, where factor B has become cleaved and activated
by factor D [41,42]. The C3(H2O)Bb convertase will
activate native C3 molecules to C3b by binding factor
B in the presence of magnesium ions will generate the
actual AP C3 convertase, C3bBb, once factor B is
cleaved by factor D. The inherent half-life of the
C3bBb convertase is only 1.5 min [43]. The displaced
Bb can no longer bind back to C3b. Instead, factor H
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Self-nonself discrimination by the complement system
binds to C3b and promotes its inactivation by factor I.
Factor H and the membrane protein CD55 (decay-
accelerating factor, DAF) can shorten the half-life of
the convertase by rapidly dissociating Bb [44].
Control of AP activation
If the target surface supports AP activation, C3 activa-
tion will become amplified in cycles and the target
coated by C3b molecules within minutes. In contrast,
if the surface is a nonactivating one, the generated
C3b molecules will become inactivated by factors H
and I, and activation stops. The fate of C3b is deter-
mined only by relatively minor differences in the affin-
ity of factor H for C3b depending on whether C3b is
in the fluid phase, bound to an activating surface or to
a nonactivating surface [45,46]. Soluble C3b and non-
activating surface-bound C3b molecules have similar
affinities for factor H, exceeding the affinity for factor
B. This leads to C3b inactivation to iC3b, followed by
further degradation to C3c and C3dg.
On an activating surface, the affinity of factor H for
C3b is relatively low. Thus, factor B binds to C3b
rather than factor H and participates in forming
C3bBb, a convertase that can be further stabilized by
properdin (P). It is important to note that the differ-
ence in affinity between nonactivator and activator
bound C3b for factor H is crucial. Factor H binding
depends on the context of the structure to which C3b
has become bound. It is not only an interaction with
C3b but simultaneous binding to C3b and the surface
in the immediate neighborhood of covalently bound
C3b. C3b itself does not seem to undergo a conforma-
tional change for increasing its affinity for factor H.
Instead, a tripartite complex is formed of the surface,
C3b and factor H. In solution, C3b apparently can
accommodate factor H binding via multiple sites to
have high enough affinity to prevent factor B binding
[47,48].
AP activation progresses as individual C3b mole-
cules deposit randomly on the target surface. After the
formation of a C3 convertase via the activation of C3b
bound factor B by factor D, more C3 molecules can
be activated. These new C3b:s will generate a cluster
of C3b:s around the initial C3b molecules (Fig. 2).
Although C3b can bind covalently to another C3b
molecule to generate C3b dimers, multiple layers of
C3b:s do not become deposited on the target. C3b has
more preference to bind to C4b or IgG than to C3b
[49]. Also, the susceptibilities of the two individual
C3b molecules in the C3b dimer to inactivation by fac-
tors H and I differ [49]. A natural mechanism to
restrict excessive C3b deposition and to limit it to a
2422 FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
S. Meri
certain density can be extrapolated from the elongated
structure of factor H. Once two C3b:s on a surface are
sufficiently close to each other, a single factor H could
bind simultaneously to two C3b molecules via its N-
terminal binding site [in complement control protein
(CCP) domains 2–5] and the C-terminal site (in
domains 19–20). Alternatively, in case, factor H forms
dimers under physiological conditions, they could rec-
ognize two C3b molecules when they are sufficiently
close to each other. In fact, early studies could demon-
strate a ‘density effect’, a relative increase in binding
of factor H (but not of factor B), when the density of
C3b molecules reached a distinct threshold value [50].
On a self cell surface, also the membrane cofactor
protein (MCP, CD46) on most cells (excluding ery-
throcytes) or complement receptor type 1 (CR1,
CD35) on all blood cells and, for example, glomerular
podocytes, can replace factor H as cofactors [51].
These molecules reside on host cells and thereby pro-
vide additional protection against attack by autolo-
gous complement. The protection is limited to cell
membranes, and mostly only to those cells that express
them. An exception is CR1 that can reach the surfaces
of neighboring cells to provide a helping hand in C3b
inactivation. Additional regulators operating at the C3
step of AP (decay-accelerating factor, DAF/CD55)
and terminal pathway activation (protectin, CD59)
further guarantee the safety of viable self cells against
Random target “Self”
X NA
C3b H, I iC3b
C3b iC3b
C3b C3b iC3b iC3b
C3, B, D, Mg++
A C3b clusters C5 A
C6
C7 MAC
“Nonself” MAC
C8
C9 MAC
X = any surface, A = activator, NA = nonactivator
Fig. 2. Discrimination between activating (nonself) and
nonactivating (self) surfaces by the alternative pathway of
complement. Initial binding of C3b to any surface (depicted X)
occurs randomly. If the surface supports binding of factor H (self,
nonactivator) the C3b molecules become proteolytically inactivated
by factor I and activation stops. If the surface does not bind factor
H, factor B forms a C3bBb convertase enzyme with the deposited
C3b and cleaves further C3 molecules to a cluster of C3b:s. These
in turn can generate new C3 convertases, whereby activation
becomes amplified. As an end result, the target becomes
opsonized by C3b molecules and also membrane attack complexes
(MAC) are formed.
S. Meri
complement [52]. These two regulators are attached to
cell membrane phospholipids via a glycophosphoinosi-
tol-linkage. An acquired defect in the anchoring sys-
tem and consequent lack of DAF and CD59 causes a
disease called paroxysmal nocturnal hemoglobinuria
(PNH) [53,54]. In PNH, descendants of the mutated
cell clone become susceptible to complement attack
[55,56]. In this disease, attacks may be precipitated, for
example, by infections that put the AP activation
ongoing. The night-time has been suggested to pro-
mote disease attacks, because of low pH that has been
suggested to increase AP activity. In reality, attacks
are not restricted to night-time and wide variation in
the disease spectrum exists. Clinical problems in PNH
are related to a tendency for thrombosis in blood ves-
sels [57]. This indicates that the complement and coag-
ulation systems are closely interconnected.
Binding of factor H to surface-
associated C3b–key to discrimination
The first clue to the possible mechanism for protecting
self cells from complement attack came when it was
shown that human and sheep red blood cells used sia-
lic acid for their protection against AP attack [58,59].
Subsequently, it was shown that factor H in the AP
was the factor that directly interacted with the surface
to mediate the discrimination between activators and
nonactivators [45]. Factor H recognized sialic acids
and other polyanions, like heparan sulfate on surfaces,
where prior deposition of C3b had occurred. Further-
more, factor H showed specificity in its binding to
polyanions, the mere negative charge was not sufficient
for the interaction [60]. Binding can occur to gly-
cosaminoglycans (e.g., hyaluronan, heparan sulfate,
chondroitin sulfate, dermatan sulfate) or proteoglycans
(e.g., versican, syndecan, decorin) [60] Later studies
were able to demonstrate that there were actually mul-
tiple binding sites for polyanions in factor H [61–63].
Factor H has three binding sites for the main comple-
ment factor C3b and two to three for polyanions
[48,64] (Fig. 3). One heparin site is located on domain
7 [61]. Using site-directed mutagenesis, the endothelial
cell, C3d- and heparin-binding sites were fine-mapped
to domains 19–20 of factor H [62,64–66]. Studies on
the lipo-oligosaccharide sialic acid of Neisseria gonor-
rhoeae [67] suggested that the region containing the
domain 20 is more selective for sialic acid than the site
at domain 7. Sialylated molecules include proteins, car-
bohydrates, and lipids like gangliosides and glycosph-
ingolipids [68]. Although less studied, additional
protection may be provided by negatively charged
phospholipids.
FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
Self-nonself discrimination by the complement system
C3b
CRP
C3c C3d
PTX3
Factor H 1 4 7 8 11 12 13 14 19 20
++ ++ ++
DDD AMD HUS
(MPGN2)
Fig. 3. Schematic structure of factor H. Binding sites for C3b,
polyanions (marked with ++) and pentraxins CRP and PTX-3 are
distributed along the chain of 20 complement control protein
domains (CCP). Locations of sites, whose disturbances because of
mutations or autoantibodies predispose to diseases. DDD, dense
deposit disease (membranoproliferative glomerulonephritis type 2,
MPGN2); AMD, age-related macular degeneration; HUS, hemolytic
uremic syndrome.
Furthermore, ligands for factor H include the pen-
traxins C-reactive protein and PTX-3. They have a
major binding site on domain 7 of factor H [69–71]
and a secondary site on domains 8–11 [69] or 19–20
[72]. Thereby, factor H can wrap itself around CRP
and bind to a different site than C1q [70]. The pro-
posed function for the pentraxin-factor H interaction
may be related to labeling an area of tissue damage,
where the pentraxins bind to injured tissue compo-
nents and activate the classical complement pathway
via C1q. To avoid excessive inflammation and to
delineate the area of damage for clearance, the
pentraxins would recruit factor H, which can inhibit
AP activation and promote inactivation of C3b to
iC3b, which acts as a high affinity ligand for the
macrophage receptor CR3 (CD11b/18). Phagocytic
clearance mediated by CR3 occurs in a noninflamma-
tory fashion, because upon engagement of this inte-
grin receptor macrophages are signaled to produce
immunosuppressive cytokines TGF-beta and inter-
leukin 10 [24].
The N terminus of factor H (domains 1–4) was
found to bind to C3b and contain the functional activ-
ities, both the cofactor activity for C3b inactivation
and the decay-accelerating activity for the C3bBb con-
vertase [73]. Additional binding sites for C3b are
apparently employed for allowing more dynamic inter-
actions with soluble or surface-associated C3b in the
context of different kinds of surfaces [65,66]. An alter-
natively spliced product of the factor H gene, factor
H-like protein 1 (FHL-1), contains the first seven
domains of factor H and four unique amino acids [73].
Thereby, it contains the major functional domains of
the N terminus but lacks the most critical self-recogni-
tion domains of the C terminus. It is a form of factor
H that seems to lack the activator-nonactivator dis-
criminating capacity, despite the presence of the hep-
arin-binding site on domain 7.
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Self-nonself discrimination by the complement system
The ability to restrict AP activation is not limited to
healthy normal cells but also malignant tumor cells
have means to protect themselves. Tumor cells usually
express sialic acids, mucins, and sulfated polyanions at
least as much as normal cells. In addition, for exam-
ple, glioblastoma and ovarian tumor cells can produce
FHL-1 in higher relative amounts than normally
observed in blood [74,75]. Strikingly, factor H has
been found to be the tumor antigen that is recognized
by the BTA-STAT and BTA-TRAK tests that are
used for the detection of urinary bladder cancer [76].
Also tumors originating from skin have been found to
produce factor H [77]. Thus, while most tumor cells
bind the soluble complement inhibitors FHL-1 and
factor H, some are even capable of synthesizing them
into their immediate vicinity. The local production of
factor H and FHL-1 may create ‘a complement-free
zone’ around the tumors. Increased angiogenesis may
bring more blood and complement to such sites,
whereas altered metabolism and relative ischemia may
increase complement activity at such sites, for example,
by lowering pH or providing targets for complement
attack. FHL-1 does not recognize its targets on the
basis of sialic acid expression but rather by sulfated
molecules like glycosaminoglycans. Factor H/FHL-1
production and binding to tumor cells should be kept
in mind when designing complement-activating mono-
clonal antibodies for therapy.
Structural analyses of the recognition
process
Most recently, the AP recognition system has been
explored with the help of structural analyses, princi-
pally by X-ray crystallography. These have shed light
on the actual interacting amino acids in the different
factor H domains, target polyanions and C3b and
other details of the recognition process. Crucial for all
studies on complement was the elucidation of the X-
ray crystal structures of C3 and C3b by the group of
Piet Gros [78,79]. C3 has 13 domains that undergo
changes upon conversion into C3b. The biggest
changes are the release of C3a (a chemotaxin and an
anaphylatoxin) and transfer of the C3d part (the thi-
olester-containing domain, TED) to another region of
the molecule to allow its access to the surface where it
can bind covalently either to exposed hydroxyl (pre-
ferred) or amino groups [79]. Otherwise, C3b does not
seem to have any special surface recognition domains,
which is in line with previous studies showing that
recognition and discrimination is dependent on a sub-
sequent interaction of factor H with the C3b-target
complex [45,46].
2424 FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
S. Meri
The atomic resolution structure of a complex
between factor H C terminus and complement C3d
has been solved by two groups [80,81]. These studies
revealed the structural basis, whereby the AP can dis-
criminate between host and nonhost structures
(schematically depicted in Fig. 4). This occurs by a
joint dual recognition of distinct negatively charged
host structures and the C3d domain of C3b by factor
H. If the target is not recognized as ‘self’, it will
rapidly be attacked by the alternative AP amplification
system. Both groups found a C3d-binding site on fac-
tor H domain 19, whereas Kajander et al. demon-
strated that there is an additional binding site for C3d
also on domain 20. Domain 19 is apparently the pre-
ferred site for C3d because in domain 20 the surface
polyanion recognition site overlaps with that of C3d.
In the absence of polyanions, however, binding of fac-
tor H to a layer of C3d molecules could signal a satu-
ration of the surface with deposited C3b/d to prevent
unnecessary further C3b deposition. Surface-associated
C3d could thus compensate for the lack of polyanions
by attracting factor H through domain 20. Thereby, it
is possible that once a sufficient layer of C3d, and pos-
sibly of C3b molecules, as well, has been deposited,
AP activation no longer continues and stops. In solu-
tion, C3b is fully accessible to factor H and becomes
rapidly inactivated by factor I. Interestingly, when
C3b is bound covalently to an activating surface or,
for example, to IgG, C4b or another C3b, the access
Fig. 4. Discrimination between self and nonself on cell surfaces by
factor H. On nonself surfaces like microbes (above), complement
activation proceeds by default. On self surfaces, factor H binds to
the C3b-polyanion complex and inhibits complement activation by
three different mechanisms: (1) inhibition of factor B binding, (2)
decay dissociation of Bb from the C3 convertase, C3bBb and (3)
promotion of inactivation of C3b by factor I.
S. Meri
of factor H to C3b is restricted [49]. This makes the
bound C3b more resistant to inactivation and subjects
to become a subunit of the C3/C5 convertase leading
to AP activation, amplification, and initiation of the
terminal pathway. Thus, the AP has elegant mecha-
nisms to (a) promote activation on nonself surfaces
and (b) stop it when sufficient and to (c) block activa-
tion on self surfaces and (d) by soluble C3b to prevent
self tissue damage and excess inflammation. Further-
more, the acute phase protein CRP can regulate and
direct the inhibitory activity of factor H to areas of tis-
sue damage during acute inflammation [69]. The other
pentraxins, like PTX-3, may have this activity, as well
[71].
Errors in discrimination–the basis for
hemolytic uremic syndrome
The importance of the AP recognition and amplifica-
tion mechanism is apparent in the disease atypical
hemolytic uremic syndrome (aHUS). aHUS is an
experiment of nature, where single amino acid muta-
tions in the recognition domains of FH or in C3d
predispose vascular endothelial cells, blood cells, and
platelets to damage [66,82–84]. Factor H mutation-
associated aHUS is a severe disease that even in
heterozygous form can lead to end stage renal failure,
brain edema, and death of the patient. Factor H
mutations underlie approximately 50% of aHUS
cases that have a genetic background. Other causes
for aHUS are mutations in factor I, MCP/CD46, C3,
factor B or thrombomodulin [85–88]. Also, autoanti-
bodies against the C terminus of factor H can cause
a similar yet somewhat milder form of aHUS [89]. In
about a third of cases, the underlying reason is still
unknown. aHUS is distinct from the more common
‘typical’ form of HUS that is caused by Shiga-like
toxins produced by certain serotypes of enterohemor-
rhagic E. coli (EHEC, e.g., O157 or O104 serotypes)
or Shigella bacteria. The role of complement in this
‘eHUS’ is still uncertain [90]. Common to all forms
of HUS, however, is endothelial, blood cell and plate-
let damage, which predisposes to thrombosis, an
entity collectively referred to as thrombotic microan-
giopathy (TMA). Other forms of TMA can occur in
thrombotic thrombocytopenic purpura (TTP), PNH,
secondary to transplantation, infection, drug treat-
ment, malignancy or as a complication of pregnancy
[87].
Errors (mutations, polymorphisms) in factor H or
autoantibodies against it can predispose also to dense
deposit disease [91–93] and age-related macular degen-
eration (AMD) [94–97]. In DDD, the functional
FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
Self-nonself discrimination by the complement system
activity of factor H (in the N terminus) is disturbed or
the activity of the C3bBb convertase is enhanced. The
underlying reasons can be mutations in factor H [98]
or autoantibodies against C3bBb (C3 nephritic factor
[99]; or factor H N terminus [92]. Reduced factor H
control function or enhanced C3bBb activity can lead
to overactivation of the AP in the fluid phase, binding
and accumulation of C3b molecules and the membrane
attack complex at sites that are not protected by the
membrane-associated complement inhibitors. Typi-
cally, this occurs at the glomerular basement mem-
branes (GBM) of kidneys. Eventually, obstruction and
thickening of the GBM leads to glomerular damage
and loss of kidney function.
While the pathogenetic processes in aHUS and
DDD are now relatively well understood, that of
AMD still remains unclear. A predisposing factor to
both major forms of AMD, geographic atrophy (dry
AMD) or neovascular, wet AMD, is a polymorphic
variant that changes amino acid tyrosine on position
402 to histidine in domain 7 of factor H [94–97]. This
influences the binding of factor H to C-reactive protein
[70,72,100] and to glycosaminoglycans [101]. In princi-
ple, factor H function could be disturbed in the retinal
epithelial cells (RPE), the Bruch’s membrane beneath
the RPE, the lipofuscin particles themselves or in the
small capillaries behind the epithelial cell layer. The
high turnover of retinal pigment into lipofuscin and
other degradation products requires an efficient clear-
ance system. In AMD, the clearance is compromised
and deposits of lipofuscin accumulate in the retina
gradually obstructing the vision of the patients. Factor
H abnormality could predispose to inflammation or
lack of clearance of the retinal pigment remnants or
both.
Role for sialic acid
The factor H-mediated protection of glomerular and
other types of endothelial cells, blood cells (erythro-
cytes and leukocytes) as well as platelets against com-
plement was for a long time assumed to be due to
glycosaminoglycans, especially heparin or heparan sul-
fate. Heparin was also used as a model polyanion in
studies addressing self-nonself discrimination and self-
protection by the AP. It was, however, puzzling that
some mutations in the FH C terminus associated with
aHUS (like L1189R and E1198A) did not disrupt
binding of factor H to heparin but rather increased it
[102] . Recently, we found that these mutations inter-
fere most specifically with the ability of factor H to
bind to sialic acid [103]. Removal of sialic acid from
platelets and endothelial cells was found to reduce
2425
Self-nonself discrimination by the complement system
their ability to bind factor H and be protected against
complement attack. Thus, the fundamental defect in
aHUS associated with factor H mutations seems to
be an inability of the mutated factor H C terminus to
recognize sialic acid on the surfaces of cells in contact
with the plasma complement system. Sialic acids are a
group of carbohydrates that are regulated dynamically
at different times, ages, and conditions [68]. The
GM3 type ganglioside seemed to be the preferred sia-
lic acid recognized by factor H [104]. Some viruses,
like the influenza viruses, have sialic acids both as
their receptors on host respiratory tracts as well as
targets for their major enzymes, neuraminidases. Also,
some non-shigatoxin-producing bacteria associated
with aHUS, like pneumococcus, have neuraminidases.
The finely tuned self-recognition mediated by factor
H can thus have implications beyond the typically
complement-associated kidney diseases. By implica-
tion, the maintenance of self-barriers and ability to
discriminate between self and nonself by complement
may play a role in other common diseases, where sub-
tle changes on cell surfaces or other host structures
may occur.
Factor H-like protein 1 and factor
H-related proteins
As indicated above, factor H has the ability to distin-
guish between activators and nonactivators by the
self-recognition domains in the C terminus of the
molecule (domains 19–20), while the actual functional
activities (cofactor and decay-accelerating activity)
reside in the N-terminal domains 1–4 [73]. The alter-
natively spliced product from the factor H gene
FHL-1 is always active in the fluid phase but lacks
the discriminatory ability on surfaces. Its blood con-
centration is usually only about 10% of that of factor
H but at local sites it can be present at higher con-
centrations. Also, some tumor cells produce equal
amounts of FH and FHL-1. FHL-1 may thus have
different clearance kinetics than FH and it may also
be produced in different quantities at different sites
or conditions [105]. The tumor cells may use FHL-1
for their own protection in the local microenviron-
ment where it is being produced [74].
In addition to factor H/FHL-1, five different factor
H-related proteins (FHRs 1–5) are encoded by their
own genes in chromosome 1 (1q31-32) in the regula-
tors of complement activation (RCA) gene cluster,
where genes for most other complement regulators are
located, as well [106]. The FHRs vary in length and
number of CCP domains. Each may have their own
properties, but reports on their functional activities are
2426 FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
S. Meri
variable. Usually, the FHR proteins have relatively
low plasma concentrations, that of FHR1 being the
highest (approximately 50 µg
mL 1). At local sites and
during inflammation, like in the middle ear fluid dur-
ing otitis media, the concentrations may, however, be
higher [107].
Strikingly, while the FHRs lack the N-terminal
functional domains, they all have homologs of the two
most C-terminal CCP domains of factor H [108].
Thus, they may have an ability to distinguish between
AP activators and nonactivators. But, why would they
do this if they do not have the actual functional
domains? The answer to this puzzling question may be
related to an ability to ‘fine-tune’ and regulate the
actual factor H-mediated control of complement acti-
vation [107]. At times, factor H may unnecessarily
strongly inhibit complement attack against a target.
FHRs have an ability to compete out the C terminus
of factor H, whereby the factor H-mediated control is
released and complement activation is temporarily
enhanced. The dimerization and heterodimerization of
FHRs would further make this effect stronger [109].
This may be a way to enhance attack, for example,
against microbes that have an ability to bind factor H
via the C terminus [110]. FHRs could then act as ‘de-
coys’ to prevent factor H binding and allow comple-
ment attack against the invader. The function of
FHRs could thus represent a rational evolutionary
step for fine-tuning the regulatory activity of factor H.
Abnormalities in FHRs have been described, and
some of them are related to distinct disease conditions.
Because of many similar sequence areas, the RCA
cluster in chromosome 1 is prone to genomic rear-
rangements through gene conversion and nonhomolo-
gous recombination [106]. The deletion of FHR1-3
gene is relatively common leading to a deficiency of
both FHR1 and FHR3 [111]. Interestingly, a large
majority of individuals, who develop anti-factor H
antibodies and aHUS have this deletion. The anti-fac-
tor H antibodies appear to partially disrupt the self-
protective ability of factor H. The reason for this con-
nection is not entirely clear, but it is possible that
FHRs 1 and 3 somehow induce or maintain tolerance
to factor H. Alternatively, the interaction of factor H
in the absence of competing FHRs with microbial fac-
tor H-binding proteins (FHBPs) could generate
neoepitopes against which antibodies develop, among
those also anti-factor H antibodies [112]. The emerging
anti-factor H antibodies are primarily directed against
the C terminus of factor and thus prevent its ability to
control complement activation on blood cells and
endothelial cells. This leads to aHUS, which–luckily–in
most cases is less severe than in cases related to FH
S. Meri
mutations. Also, removal of antibodies with plasma-
pheresis provides an additional method of therapy.
The role of FHRs in regulating factor H is sup-
ported by the recent observations of abnormal oligo-
mers or hybrids of the FHR molecules associated with
C3 glomerulopathy [113,114]. C3 glomerulopathy
patients have C3 deposits in their kidney glomeruli in
the absence of antibody deposits. DDD is considered
as one form of C3 glomerulopathy. C3 glomeru-
lonephritis (C3GN) is another one, but without dense
deposits. This form is associated with FHR abnormali-
ties (oligomers, hybrids, mutations, deletions). FHR5
mutation has been found to cause a glomerular dis-
ease, FHR5 nephropathy, which is endemic in Cypri-
ots [113]. FHR-1 mutation and abnormal FHR
oligomerization have been found in connection with
C3 glomerulopathy [114]. Some forms may even be
related to C3 mutations. Common to all these disor-
ders is that they disturb AP regulation and predispose
to glomerular disease.
Protecting self by membrane
regulators of complement
Discrimination between self and nonself by the com-
plement system is not limited to factor H, although it
has the unique ability to ‘sense’ a variety of targets
and operate from the fluid phase. On human cell mem-
branes, complement activation is inhibited by comple-
ment receptor type 1 (CR1, CD35), membrane
cofactor protein (MCP, CD46), and decay-accelerating
factor (DAF, CD55). Their task is to limit comple-
ment activation at the C3 step [52]. Another regulator,
protectin or CD59, inhibits formation of the mem-
brane attack complex by binding to intermediate C5b-
8 and C5b-9 terminal complement complexes and pre-
venting incorporation and polymerization of C9
[115,116]. These molecules specifically protect ‘self’.
They are to some extent species selective, that is, tuned
principally to protect against complement of homolo-
gous species. While mixing cells from one species and
blood plasma from another is an artificial situation,
attempts have been made to transplant organs across
species, for example, from pigs to humans. This usu-
ally fails because there may be natural antibodies
(antigalactose, for example) against the other species’
cells and because the complement regulators in the
transplanted organ may not protect against the recipi-
ent complement. Attempts to overcome this problem
by genetic engineering to remove antigen targets or to
add transgenic human DAF or MCP to pigs have been
under development, but so far the approach has not
been adopted to general use [117].
FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
Self-nonself discrimination by the complement system
Microbial escape of complement by
mimicry of self
Despite the potent antimicrobial effects of the comple-
ment system many microbes are resistant to
opsonophagocytosis or direct complement-mediated
killing. Often, the complement resistant microbes are
pathogens for humans. The reasons why certain
microbes are virulent pathogens and others, often even
close relatives, are not has remained obscure in many
cases. Apparently, part of the species specificity and
virulence spectra of microbes is dependent on resis-
tance to complement [118,119]. Many common patho-
gens escape complement attack using specific proteins
and mechanisms. For example, we identified a new
family of complement inhibitors from the Lyme dis-
ease Borrelia burgdorferi spirochetes [120,121]. The
proteins belong to the OspE family of outer membrane
proteins that have the ability to hijack factor H from
the human or animal host [118]. Subsequently, other
groups made similar observations and another FHBP
family, CspA was also found [122–126]. Factor H
binding molecules have since been found from many
different kinds of bacteria, including different types of
pathogenic streptococci [127] and Gram-negative bac-
teria [128–130].
Group B meningococcus, during recent years, has
been the most important causative agent of meningitis
and meningococcal sepsis in the Western world. The
development of vaccines against this bacterium has
been delayed because its polysialic acid capsule is non-
immunogenic and potentially cross-reactive with
human brain [131]. In addition to having an antiop-
sonic capsule, group B meningococcus was found to
bind the complement inhibitor C4 bp by porin A
[132]. This could prevent both antibody-mediated clas-
sical and lectin pathway activation. Using whole gen-
ome screening methodology and systematic analysis,
so called reverse vaccinology, proteins with potential,
as vaccines, were found from meningococcus [133].
One of the most promising vaccine candidates turned
out to be a FHBP [128]. Subsequently, the FHBP was
included in a new multicomponent vaccine against
group B meningococcal infections [129]. This vaccine
(Bexsero, Novartis) has now been approved for use in
several countries. Another vaccine containing two out
of the three main variants of FHBP (Trumenba,
Pfizer) has also been developed [130].
In retrospect, a concept that was developed earlier
from functional hypothesis-driven studies [121,134] led
to the same conclusions as unbiased genome-wide
searches for vaccine candidates [133]. The most elegant
feature of the FHBP-based vaccines is that antibodies
2427
Self-nonself discrimination by the complement system
developed against the proteins not only recognize the
target microbe but they also neutralize an important
virulence property, that is, recruitment of factor H by
the microbe. Vaccines against group B meningococcus
represent a breakthrough, because they complement
the existing vaccines against other capsule types of
meningococci. It is particularly important for use in
individuals who lack AP or terminal pathway comple-
ment components or who are treated with eculizumab
(anti-C5) antibody therapy. Otherwise, complement
deficiency in these situations would lead to a signifi-
cantly increased (around 1000-fold) risk for meningo-
coccal meningitis and sepsis.
From the self-nonself discrimination point of view,
microbes that bind factor H can be considered to
mimic ‘self’. A comparison of microbial FHBPs has
shown that they fall into two major structural cate-
gories: alpha-helical coiled-coil structures (such as yer-
sinial YadA, group A streptococcal M-protein and
group B streptococcal Bac-protein) or beta-barrel-type
membrane proteins (Rck of salmonella, Ail of Yersi-
nia, and OspE of borrelia) [134]. The binding sites of
the proteins on factor H are usually located in the
heparin-binding domains 7 or 20. The site on domain
7 is used, for example, by the meningococcal FHBP.
The domain 20 is used by the borrelial OspE and
many other microbial proteins. A survey of the finger-
prints of several different bacterial proteins and
microbes on the domain 20 of factor H (using a panel
of mutants) showed that the microbes use, not only
the same domain, but to a large extent also the same
amino acid side chains for the interaction [135]. It is
astonishing that microbes as distant as borrelia, strep-
tococcus, haemophilus, pseudomonas, and even the
yeast Candida albicans use a common site on factor H
to recruit this inhibitor for their protection against
complement attack.
Conclusion
The classical and lectin pathways of complement use
antibodies and other sensor molecules for specific
recognition of targets. Somewhat miraculously, how-
ever, the alternative pathway (AP) relies only on two
molecules, C3b and factor H, to distinguish between
a wide variety of nonself structures from self. The
AP deposits covalently bound C3b on activating
(nonself) structures via a positive feedback loop
amplification system. The actual discrimination is per-
formed by the key regulator factor H, which has
binding sites for cell surface polyanions (sialic acids,
glycosaminoglycans, phospholipids) in addition to
those for C3b and C3d. This robust recognition of
2428 FEBS Letters 590 (2016) 2418–2434 ª 2016 Federation of European Biochemical Societies
S. Meri
markers of ‘self’ provides protection to our own
intact viable cells and tissues. In contrast, activating
structures are recognized by default: anything not
positively recognized by factor H is being attacked
upon. This fundamental mechanism leads to
opsonization and phagocytosis or direct killing of
microbes and other targets. Even senescent, ischemic,
injured or apoptotic ‘self’ cells can be recognized in
this way for removal by macrophages. An indication
of the importance of the recognition system is muta-
tions in factor H that predispose to severe diseases,
where complement attacks autologous cells. In aHUS,
alterations in the recognition system predispose to
complement attack against blood cells and vascular
endothelial cells causing thrombotic microangiopathy
and damage to many tissues (e.g., kidneys and brain).
Most specifically, the factor H mutations affect sialic
acid recognition. Pathogenic microbes have also
learned to use factor H to escape C attack. Thus,
many bacteria express specific proteins with a similar
ability to exploit factor H. The ability to bind factor
H is so far the best described feature that discrimi-
nates pathogenic microbes from nonpathogenic ones.
Acknowledgements
Matti Laine is kindly acknowledged for drawing Fig. 1.
All current and previous members of my research
group and collaborators are gratefully acknowledged.
Especially, the following have contributed to studies
presented in this review: Sakari Jokiranta, Hanna
Jarva, Martin Reichhardt, Matti Laine, Sami Jun-
nikkala, Taru Meri, Livija Deban, Jens Hellwage,
Derek Ho, Satu Hyv€ arinen, Adrian Goldman, Veli-
Pekka Jaakola, Tommi Kajander. Especially I want to
thank prof Michael Pangburn, University of Texas
Health Science Center. The author has received finan-
cial support from the Academy of Finland, The Sigrid
Juselius Foundation, The Stockmann Foundation,
Signe and Ane Gyllenberg Foundation, Helsinki
University Hospital Grants (EVO), Finland and
Humanitas University, Milan, Italy.
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