Immunology Letters 138 (2011) 3537

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Immunology Letters
journal homepage: www.elsevier.com/locate/immlet

Review

Role of complement in innate immunity and host defense

Leendert A. Trouw a , Mohamed R. Daha b,
a
b

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands

a r t i c l e

i n f o

Article history:
Available online 17 February 2011
Keywords:
Complement
Innate immunity
Regulation
Autoimmunity
Infections

a b s t r a c t
The complement system is an important part of the innate immune defense. Next to its role as an effector
mechanism of the innate immune system, complement also plays a major role in shaping the adaptive
immune response. The complement system is also involved in several other physiological processes such
as tissue regeneration and clearance of immune complexes and dead cells. Unfortunately complement
is also involved in pathology by contributing to tissue damage, induction of autoimmune reactions and
chronic inammation. Tight regulation of complement activation by both uid-phase and membrane
bound complement inhibitors is essential to maintain a good balance between optimal protection with
as little as possible damage to the host. Alterations in this balance and hence the function of complement,
by inuence of auto-antibodies, or genetic variants, may render the complement system into a harmful
player in tissue damage and pathology.
2011 Elsevier B.V. All rights reserved.

The complement system is one of the major effector mechanisms of our innate immune system and also plays an important
role in the instruction of the adaptive immune response [1,2]. These
functions are required for a good defense against viruses and especially bacteria. In addition to its role against infections, complement
is also involved in a wide array of physiological and pathological
processes. Clearance of immune complexes and apoptotic cells and
tissue regeneration are examples of its physiological role. Tissue
damage, induction of (auto)-immune reactions and chronic inammation are examples of a pathological role.
Complement activation proceeds via three distinct pathways.
Initiation of these pathways occurs by the binding and activation
of the recognition unit of each pathway to ligands that are largely
specic for each pathway [2,3]. The classical pathway is initiated
by binding of C1q to its ligands such as immune complexes or dead
cells. The lectin pathway is initiated by Mannan Binding Lectin
(MBL) or colins binding to its specic ligands that are mostly
specic carbohydrate structures often present on pathogens. The
alternative pathway, is by default activated spontaneously and constantly inhibited by factor H. When factor H cannot bind to inhibit
this pathway, as the case on the surface of bacteria, then the alternative pathway is uninhibited and therefore activated [2]. Recently
the possibility of direct alternative pathway activation by properdin is suggested [35]. This review will discuss some of the new

Corresponding author at: LUMC, Room L-01-039, Postzone C3-P, PO-Box 9600,
2300 RC Leiden, The Netherlands.
E-mail address: m.r.daha@lumc.nl (M.R. Daha).
0165-2478/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.imlet.2011.02.014

insights in complement activation and the role complement plays

in disease progression and prevention.
1. Complement activation
The classical pathway of complement is initiated following
binding of the C1q components of the C1 complex to its specic ligands (Fig. 1). Next to the traditional ligands such as IgM
and immunecomplexes [2] C1q also binds to C-reactive protein
(CRP) [6], the long pentraxin-3 (PTX3) [7], dead cells [8] matrix
components [9,10] and SIGN-R1 (a lectin that binds to microbial
saccharides in the spleen and phosphatidyl serine exposed on apoptotic cells) [11].
The lectin pathway is activated when MBL or colins interact
with carbohydrates on microbial surfaces [2] (Fig. 1). The colins have another carbohydrate binding specicity than MBL [12].
While MBL reacts with mannose residues and sugars like N-acetyld-glucosamine, colin 2 and 3 recognize more specically acetyl
groups. Therefore, these complement initiation/activation components C1q and MBL can be regarded as specic soluble pattern
recognition molecules that distinguish in the rst place self from
non-self and additionally recognize altered self such as modied self-tissue following for instance apoptosis or modulation of
the carbohydrate landscape on host tissue that has been altered
for instance reduced oxygen pressure followed by re-oxygenation.
Binding of C1q or MBL to their respective ligands leads to the
activation of the classical and lectin pathway, respectively, and
subsequently generates a common C3 convertase, called C4b2a.
A third pathway of complement is initiated by the slow and continuous turnover of the central component of complement, C3, to

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L.A. Trouw, M.R. Daha / Immunology Letters 138 (2011) 3537

form C3b and C3a. This initially generated C3b then reacts directly
via its labile thioester with activating structures [2]. Once C3b is
deposited on the activator, for instance on specic microorganisms, it can interact directly with factor B and D to form a labile
C3bBb convertase (the amplication C3-convertase) that can cleave
additional C3 molecules. This inherently labile C3bBb convertase
can be stabilized by Properdin (P), which results in enhancement
of C3 activation and deposition of large numbers of covalently
bound C3b molecules to the alternative pathway activator. This
alternative pathway is by default activated spontaneously and is
also constantly inhibited by factor H [13]. When factor H cannot bind to inhibit this pathway, as is the case on the surface of
bacteria, then the alternative pathway is uninhibited and therefore activated [13]. Recent studies [5,14] have indicated that next
to direct binding of C3b to the activator, complement activation
can be focused on a substance by properdin itself. Elegant studies by Hourcade and Kemper have highlighted that properdin
binds directly to a large number of bacteria [4]. Once properdin
is bound, properdin can easily polymerize, and then can recruit
C3b and focus C3-amplication directly on pathogens and facilitate their interaction with cellular C3-receptors. It is therefore
clear that the three pathways of the complement system are
all initiated by a pattern-like recognition process involving soluble pattern-recognition molecules such as C1q, MBL, Ficolins and
Properdin.
Independent of the initiation of complement activation, all the
three pathways form the important C3-convertases namely C4b2a
and C3bBb, which lead to the most important step, that is activation of C3 into C3b and C3a (Fig. 1). Once sufcient C3b is
generated the formation of the membrane attack complex (MAC)
C5b-C9, also called terminal complement complex (TCC), can take
place. Activation of the terminal complement pathway is associated
with the generation of C5a which is a highly chemotactic fragment of C5 and which in addition is responsible for the activation
of phagocytic cells like polymorphonuclear leukocytes (PMNs).
The C5b-9-complex was initially thought to be involved mainly in
cytolytic processes of either pathogens or host cells [2]. More recent
studies have shown that low numbers of C5b-9 induce activation
of host cells [15]. Whereas intermediate amounts of C5b-9 induce
apoptosis of host cells [15], which is involved in tissue turnover,
homeostasis and regeneration.

Classical Pathway
Antibody complex

Lectin Pathway
Carbohydrates

C1q

Alternative Pathway
Spontaneous C3b

MBL

C3H2O

C4b2a

C3bBb

C3
Chemotactic
factors

Amplification
Loop

C3a

C3b

C5a

Opsonisation

C5b-9 (MAC)
Lysis
Fig. 1. Activation pathways of the complement system.

2. Complement inhibition
In the absence of inhibitors complement would quickly be completely consumed leaving the host unprotected against infections.
For this purpose and for the protection of host tissue to autologous complement attack, the human body is also equipped with
a large array of both uid-phase and membrane bound complement inhibitors (CD35, CD46, CD55, CD59) [2]. The expression of
these molecules is regulated via an intricate network of cytokines
[16]. Several complement inhibitors inuence the decay of the
C3-convertases, whereas others are co-factors for the enzymatic
inactivation of complement activation fragments C3b and C4b by
complement factor I. In plasma there are two main regulators of
the alternative pathway of complement activation namely factor I
and factor H. These are able to convert C3b into iC3b [13]. Besides
factor I and H other important complement regulators are C1inhibitor that controls activation of the classical and lectin pathway
by inhibiting the activity of the innate proteases while C4b-binding
protein (C4bp) functions as another cofactor of factor I in facilitating the inactivation of the classical/lectin pathway C3 convertase
(C4b2a) through cleaving of C4b [17]. Dead cells down-regulate
the expression of membrane bound complement inhibitors and
gradually acquire protection from uid-phase inhibitors for protection against excessive complement activation [18]. It is important
to realize that it is essentially the balance between complement
activation triggers and complement inhibition strength that determines if complement activation takes place [17]. Since, humans
and pathogens have evolved side by side, pathogens are now
equipped with strategies to inhibit the action of complement [19].
The strategies involve the binding of host derived complement
inhibitors to their surface, expression of pathogen derived complement inhibitors or enzymes that degrade complement factors
[19].
3. Complement signaling
As mentioned earlier activation of C3 by a pathogen, independent of the pathway of activation, results in the covalent binding of
large numbers of C3b molecules to pathogens. These bound C3b
molecules mediate recognition of the pathogen by cellular C3b
receptors (CR1, CD35). Following cleavage of C3b by factor I iC3b
is formed. This can no longer contribute to complement activation but iC3b interacts strongly with another set of C3-receptors
namely CR3 [1]. These receptors are found mainly on phagocytic
cells such as macrophages and PMNs [2]. Via these receptors iC3bbearing pathogens can be phagocytosed and eliminated. Therefore,
it is easily imaginable that either primary or secondary deciencies of C3 are associated with increased susceptibility of the host
to pathogenic infections. The small cleavage fragments C3a and
C5a trigger their specic receptors resulting in cellular activation
and migration [20]. Triggering of these complement receptors has
a major impact of the adaptive immune response to these targets.
4. Complement going wrong
The above described functions of complement are important
for the benecial clearance of pathogens and the maintenance of
homeostasis. This is in vivo underscored by the problems that arise
when complement is not working properly because of, for example,
genetic variations or autoantibodies. In case of primary deciencies
of many complement components the main clinical presentation
is recurrent infections [2]. Interestingly, a similar clinical picture
emerges in case of secondary complement deciencies because of
excessive consumption. For other deciencies the primary presentation is autoimmune disease as evidenced by a high frequency of

L.A. Trouw, M.R. Daha / Immunology Letters 138 (2011) 3537

Systemic Lupus Erythematosus [1]. In case of (partial) deciencies

of complement inhibitors, tissue damage takes place accumulating into the clinical pictures of, for example, many renal diseases
such as atypical Haemolytic Uremic Syndrome (aHUS) or in the
eye disease age-related macular degeneration (AMD). Although
clear genetic association have been found, it is not yet completely
clear how such genetic variants contribute to the overall disease
process. Next to genetic deciencies also autoantibodies against
complement components can have major impact on complement
activity and clinical presentation. C3-Nephritic factor (C3-Nef) is a
well known example, where an autoantibody to the C3-convertase
stabilizes this convertase which results in excessive complement
activation, depletion of C3 and tissue damage to the kidney [21].
5. Concluding remarks
The complement system is an intricate enzymatic cascade
that, when working properly, provides essential protection against
infections and supports tissue homeostasis. Alterations in the function of complement by either genetic variants or autoantibodies
results in pathology. In the coming years we hope to have more
insight into the relative contribution of the complement system to
complex diseases.
Acknowledgement
Dr. L.A. Trouw is supported by an NWO-ZonMW VENI grant.
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