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CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 301

Much complement-mediated pathology revolves around participates with natural IgM in early host defense and provides
disturbances of the AP and thus its potent amplification loop. a mechanism for immune complex and apoptotic cell clearance.
It must be rigorously regulated to prevent activation on normal The lectin pathway (LP) uses most of the CP components but
self and excessive activation on injured self. Even haploinsuffi- is activated by mannan-binding lectin (MBL) and the ficolins,
ciency of its two major inhibitors predisposes to endothelial which are lectins that recognize repeating carbohydrate patterns
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damage in atypical hemolytic–uremic syndrome and retinal on microorganisms. The AP is the most ancient pathway and
damage in age-related macular degeneration (ARMD). also has the broadest recognition ability. The AP is engaged by
In clinical medicine, the complement system participates in surface components of all types of microorganisms, including
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three pathological processes: (1) bacterial infections and/or bacteria, fungi, parasites, viruses, and virus-infected cells. It is
autoimmunity are caused by complete component deficiencies; continuously turning over and autoactivates if its inhibitors are
(2) tissue damage results from complement activation by auto- lacking. Activation of the AP can also be initiated by properdin
antibodies forming immune complexes (e.g., SLE); and (3) (P), a molecule that binds to pathogens and apoptotic cells. This
excessive activation at sites of cellular and tissue injury occurs mechanism further promotes its function as an innate and rapid
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in individuals carrying dysfunctional genetic variants in comple- responder to infection. The AP is an important amplification
ment regulators. mechanism for CP or LP activation, resulting in greater opsoniza-
Knowledge of how complement is activated and how it can tion and generation of the terminal lytic pathway. For example,
be controlled points to opportunities for the development of the initial trigger on a pathogen surface may be IgM or a lectin,
therapeutic agents. One such example is anti-C5 monoclonal but the majority of the C3b deposited is via AP’s amplification
antibody (mAb) therapy, which has been recently approved to or feedback loop that is engaged by just having C3b on a target.
treat several complement-dependent hemolytic disorders. Other The cleavage of C3 to C3a and C3b is central to all three
new complement therapeutics and diagnostics are on the horizon pathways of complement activation. This enzymatic step exposes
as biotechnology companies pursue novel complement inhibitors a highly reactive thioester bond through which C3b covalently
and genetic evaluations are increasingly utilized for helping to attaches to nearby molecules (Fig. 21.2). Activation of C3 to
define diseases in which the complement system is involved. C3b also exposes sites for interactions with other complement
proteins, inhibitors, and receptors. Recent results have shed new
COMPLEMENT PATHWAYS light on the structural basis for C3 activation. In 2006, several
studies reported the first x-ray structure of C3b, the activated
The three pathways of complement activation are the CP, AP, product C3. 10,11 The results revealed a major conformational
1-4
and lectin cascades (Fig. 21.1). The CP is initiated by IgM or change in C3 upon cleavage to C3b that exposes the reactive
IgG Ab binding to antigen. The CP can also be activated by thioester group as well as cryptic binding sites for complement
innate pattern recognition molecules, such as the pentraxins, receptors and regulatory proteins. Moreover, the crystal struc-
cross-reactive protein (CRP) and serum amyloid P (SAP) tures of five binding proteins in complex with C3b have now
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component, and the membrane-bound lectin, SIGN-R1. It been solved. 12

Classical pathway
Recognition
IgG
IgM
CRP C1q,r,s Inflammation
SAP C4, C2
Opsonization
C3 Convertase C5 Convertase
C4b2a and C4b C4b2a3b
Lectin pathway Membrane
MASP-1
MASP-2 Perturbation
MASP-3
MBL
Ficolins C3 C3a C5 C5a C6 C7 C8 C9n

Alternative pathway Membrane attack
C3b C5b complex C5b-9
C3

C3 (H 0) B
2
C3 Convertase C5 Convertase
C3 (H 0) Bb Factor D C3bBbP (C3b) 2 Bb
2
C3 C3b Properdin
FIG 21.1 Overview of the complement pathways indicating components required for recognition,
the enzymatically active fragments and complexes and the major opsonic, inflammatory, and
membranolytic products.