63

C H A P T E R

Complement
CHAPTER CONTENTS

Introduction Anaphylatoxin
Activation of Complement Cytolysis
Regulation of the Complement System Enhancement of Antibody Production

Biologic Effects of Complement Clinical Aspects of Complement

Opsonization Self-Assessment Questions
Chemotaxis Practice Questions: USMLE & Course Examinations

INTRODUCTION the enzyme that leads to the production of the membrane

attack complex; (2) it opsonizes bacteria because phagocytes
The complement system consists of approximately 20 proteins have receptors for C3b on their surface; and (3) its derivatives
that are present in normal human (and other animal) serum. bind to a receptor on B cells and provide “signal 2” for T-cell–
The term complement refers to the ability of these proteins to independent B-cell activation (see Chapter 61).
complement (i.e., augment) the effects of other components of
the immune system (e.g., antibody). Complement is an impor- (1) In the classic pathway, complement proteins first
tant component of our innate host defenses. become fixed (bound) to an antigen–antibody complex (see
There are three main effects of complement: (1) lysis of cells Figure 63–1). Only IgM and IgG can fix complement proteins,
such as bacteria, allografts, and tumor cells; (2) generation of because only the Fc regions of the γ and μ heavy chains have a
mediators that participate in inflammation and attract neutro- C1 binding site. Complement fixation is the gathering together
phils; and (3) opsonization (i.e., enhancement of phagocytosis). of bound proteins, starting a chain reaction of proteases.
Complement proteins are synthesized mainly by the liver. In the classic pathway, C11 binds and is cleaved to form an
active protease, which cleaves C2 and C4 to form a C4b,2b com-
plex. The latter is C3 convertase, which cleaves C3 molecules
ACTIVATION OF COMPLEMENT into two fragments, C3a and C3b. C3a, an anaphylatoxin, is
Several complement components are proenzymes that must be discussed later. C3b forms a complex with C4b,2b, producing
cleaved to form active enzymes. Activation of the complement a new enzyme, C5 convertase (C4b,2b,3b), which cleaves C5 to
system can be initiated either by antigen–antibody complexes form C5a and C5b. C5a is also an anaphylatoxin and a chemo-
or by a variety of nonimmunologic molecules (e.g., endotoxin). tactic factor (see later). C5b binds to C6 and C7 to form a com-
Sequential activation of complement components (Figure 63–1) plex that interacts with C8 and C9 to produce the membrane
occurs via one of three pathways: the classic pathway, the lectin attack complex (C5b,6,7,8,9).
pathway, and the alternative pathway (see later). Of these pathways, This protein complex forms a pore in whichever cell mem-
the lectin and the alternative pathways are more important the brane contained the original antigen that was bound by anti-
first time we are infected by a microorganism because the antibody body. The pore causes leakage of water and electrolytes, leading
required to trigger the classic pathway is not present. The lectin to cytolysis. Note that for each complement protein, the “b”
pathway and the alternative pathway are, therefore, participants in fragment continues in the main pathway, fixed to the target,
the innate arm of the immune system. whereas the “a” fragment is split off and has other activities.
All three pathways lead to the production of C3b, the central
molecule of the complement cascade. The presence of C3b on
1
the surface of a microbe marks it as foreign and targets it for C1 is composed of three proteins, C1q, C1r, and C1s. C1q is an aggregate of
18 polypeptides that binds to the Fc portion of IgG and IgM. It is multivalent
destruction. C3b has three important functions: (1) It combines and can cross-link several immunoglobulin molecules. Calcium is required for
with other complement components to generate C5 convertase, the activation of C1.

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 538 PART VII Immunology

Classic Lectin Alternative

Antigen–antibody Microbial Microbial surfaces
complexes surfaces (nonspecific activators
e.g., endotoxin)
Bind Bind

C1 Mannan-binding Bind
lectin

C3(H2O) + B
C1 Protease
cleaves C4 and C2
C4 C2 D (protease)

C4b,2b C3 C3 C3b,Bb
(C3 convertase) (C3 convertase)
+
C2a,C4a

C4b,2b,3b C5 C3b,Bb,C3b
(C5 convertase) (C5 convertase)
+ +
C3a C3a

C5a + C5b

C6 C7

C5b,6,7

C8 C9

C5b,6,7,8,9 (membrane attack complex)

Lysis, cytotoxicity

FIGURE 63–1 The classic and alternative pathways of the complement system indicate that proteolytic cleavage of the molecule at the
tip of the arrow has occurred; a line over a complex indicates that it is enzymatically active. Note that all small fragments are labeled “a,” and all
large fragments are labeled “b.” Hence, the C3 convertase is depicted as C4b,2b. Note that proteases associated with the mannan-binding lectin
cleave C4 as well as C2.

(2) In the lectin pathway, mannan-binding lectin (MBL) convertase to generate more C3b. Like the lectin pathway, the
(also known as mannose-binding protein) binds to the surface alternative pathway is antibody independent and therefore is
of microbes bearing mannan (a polymer of the sugar, man- protective before antibody is formed.
nose). This activates proteases associated with MBL that cleave
C2 and C4 components of complement, converging with the
classic pathway (see Figure 63–1). Note that this process REGULATION OF THE COMPLEMENT
bypasses the antibody-requiring step and so is protective early
in infection before antibody is formed.
SYSTEM
(3) In the alternative pathway, many unrelated cell surface Unrestrained complement activation can cause severe tissue
substances (e.g., bacterial lipopolysaccharides [endotoxin], fun- injury and even systemic anaphylaxis. The first regulatory step in
gal cell walls, and viral envelopes) can initiate the process by the classic pathway is the antibody. The complement-binding
binding C3(H2O) and factor B. This complex is cleaved by a site on the heavy chain of IgM and IgG is unavailable to the
protease, factor D, to produce C3b, Bb. This acts as a C3 C1 component of complement if antigen is not bound to these

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 CHAPTER 63 Complement 539

antibodies. This means that complement is not activated by IgM Cytolysis

and IgG despite being present in the blood at all times. However,
Insertion of the C5b,6,7,8,9 membrane attack complex into
when antigen binds to its specific antibody, a conformational
the cell membrane forms a “pore” in the membrane. This
shift occurs and the C1 component can bind and initiate the
opening in the membrane results in the killing (lysis) of many
cascade.
types of cells, including erythrocytes, bacteria, and tumor cells.
Several serum proteins regulate the complement system at
Gram-negative bacteria, especially Neisseria species, are very
other stages.
susceptible to the membrane attack complex. Cytolysis is not
(1) C1 inhibitor is an important regulator of the classic an enzymatic process; rather, it appears that insertion of the
pathway. It serves as a constant activation threshold by inacti- complex results in disruption of the membrane and the entry of
vating the protease activity of C1. This means that initiation of water and electrolytes into the cell.
the classic pathway can proceed only if sufficient C1 is fixed to
overwhelm the inhibitor. (See below for discussion of clinical Enhancement of Antibody Production
syndrome of C1 inhibitor deficiency.)
The binding of C3b derivatives to its receptors on the surface
(2) Regulation of the alternative pathway is mediated by the
of activated B cells (complement receptor 2 [CR2]) provides
binding of factor H to C3b and cleavage of this complex by fac-
the signal 2, which greatly enhances antibody production com-
tor I, a protease. This reduces the amount of C5 convertase
pared with that by B cells that are activated by antigen alone (see
available. Like the C1 inhibitor, factors H and I serve as a thresh-
Chapter 61). The clinical importance of this is that patients who
old requirement that sufficient C3b attaches to the cell mem-
are deficient in C3b produce significantly less antibody than
brane for the alternative pathway to proceed. Attachment of C3b
do those with normal amounts of C3b. The low concentration
to cell membranes protects it from degradation by factors H and
of both antibody and C3b significantly impairs host defenses,
I. Another component that enhances activation of the alterna-
resulting in multiple, severe pyogenic infections.
tive pathway is properdin, which protects C3b and stabilizes the
C3 convertase.
(3) Protection of human cells from lysis by the membrane CLINICAL ASPECTS OF COMPLEMENT
attack complex of complement is mediated by decay-
accelerating factor (DAF, CD55)—a glycoprotein located on (1) Inherited (or acquired) deficiency of some complement
the surface of human cells. DAF acts by binding to C3b and C4b components, especially C5–C8, greatly enhances susceptibil-
and limiting the formation of C3 convertase and C5 convertase. ity to Neisseria bacteremia and other infections that are par-
This prevents the formation of the membrane attack complex. ticularly sensitive to killing by the membrane attack complex. A
deficiency of C3 leads to severe, recurrent pyogenic sinus and
respiratory tract infections.
BIOLOGIC EFFECTS OF COMPLEMENT (2) Deficiency of C1 esterase inhibitor results in angio-
edema. When the amount of inhibitor is reduced, the activation
Opsonization threshold for C1 esterase is also reduced. (In the absence of
Microbes, such as bacteria and viruses, are phagocytized inhibitor, C1 continues to act on C4 to generate C4a and subse-
much better in the presence of C3b because there are C3b quently additional vasoactive components such as C3a and C5a.)
receptors on the surface of many phagocytes. This leads to capillary permeability and edema in several organs.
Laryngeal edema can be fatal. The syndrome of C1 inhibitor
Chemotaxis deficiency can occur as an acquired disease or, rarely, as a genetic
disease called hereditary angioedema.
C5a and the C5,6,7 complex attract neutrophils. They migrate
(3) Acquired or inherited deficiency of decay-accelerating
especially well toward C5a. C5a also enhances the adhesiveness
factor (DAF) on the surface of cells results in an increase in
of neutrophils to the endothelium.
membrane attack complex activity and increased complement-
mediated cell lysis, particularly lysis of red blood cells (i.e.,
Anaphylatoxin hemolysis). Clinically, this appears as the disorder paroxysmal
C3a, C4a, and C5a cause degranulation of mast cells with nocturnal hemoglobinuria. This disease is characterized by
release of mediators (e.g., histamine), leading to increased vas- episodes of brownish urine (hemoglobinuria), which reflects
cular permeability and smooth muscle contraction, especially hemolysis, particularly early in the morning. The complement-
contraction of the bronchioles, leading to bronchospasm. mediated hemolysis occurs especially at night because the lower
Anaphylatoxins can also bind directly to smooth muscle cells oxygen concentration (and low pH) in the blood during sleep
of the bronchioles and cause bronchospasm. C5a is, by far, increases the susceptibility of the red cells to lyse.
the most potent of these anaphylatoxins. Anaphylaxis caused (4) In transfusion mismatches (e.g., when type A blood is
by these complement components is less common than ana- given by mistake to a person who has type B blood), antibody to
phylaxis caused by type I (IgE-mediated) hypersensitivity (see the A antigen in the recipient binds to A antigen on the donor
Chapter 65). red cells, complement is activated, and large amounts of

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 540 PART VII Immunology

anaphylatoxins and membrane attack complexes are generated. 4. Of the following, which one is the most important function of the
The anaphylatoxins cause shock, and the membrane attack complex formed by complement components C5b,6,7,8,9?
complexes cause red cell hemolysis. (A) To enhance antibody production
(5) Immune complexes formed by antigens and antibodies (B) To inhibit immune complex formation
can bind complement, and thus, complement levels are often (C) To opsonize viruses
low in immune complex diseases (e.g., acute glomerulonephritis (D) To perforate bacterial cell membranes
(E) To release histamine from mast cells
and systemic lupus erythematosus). Binding (fixing) of comple-
5. A deficiency of which one of the following complement compo-
ment attracts polymorphonuclear leukocytes, which release
nents predisposes to bacteremia caused by members of the genus
enzymes that damage tissue. Neisseria?
(6) Patients with severe liver disease (e.g., alcoholic cirrhosis
(A) C1
or chronic hepatitis B), who have lost significant liver function (B) C3b
and therefore cannot synthesize sufficient complement proteins, (C) C5a
are predisposed to infections caused by pyogenic bacteria. (D) C5b
(E) C5b,6,7,8,9
6. Your patient is a 20-year-old woman who complains of swellings
on her arms and legs and a feeling of fullness in her throat that
SELF-ASSESSMENT QUESTIONS makes it difficult to breath. The swellings are not red, hot, or ten-
1. Regarding the complement pathway, which one of the following is der. You suspect she may have angioedema caused by a comple-
the most accurate? ment abnormality. Of the following, which one is the most likely
(A) C3 convertase protects normal cells from lysis by complement. explanation?
(B) C3a is a decay-accelerating factor and causes the rapid decay (A) She has too little C1 inhibitor.
and death of bacteria. (B) She has too little C3b.
(C) In general, gram-positive bacteria are more likely to be killed (C) She has too little factor B.
by complement than gram-negative bacteria. (D) She has too much C5a.
(D) The membrane attack complex is formed as a result of activa- (E) She has too much C9.
tion of the classic pathway but not by activation of the alterna-
tive pathway.
(E) The first time a person is exposed to a microorganism, the ANSWERS
alternative pathway of complement is more likely to be acti-
(1) (E)
vated than the classic pathway.
2. Of the following complement components, which one is the most
(2) (C)
important opsonin? (3) (D)
(A) C1
(4) (D)
(B) C3a (5) (E)
(C) C3b (6) (A)
(D) C5a
(E) C5b
3. Of the following complement components, which one is the most PRACTICE QUESTIONS: USMLE &
potent in attracting neutrophils to the site of infection (i.e., acting COURSE EXAMINATIONS
as a chemokine)?
(A) C1
Questions on the topics discussed in this chapter can be found
(B) C2 in the Immunology section of Part XIII: USMLE (National
(C) C3b Board) Practice Questions starting on page 735. Also see Part
(D) C5a XIV: USMLE (National Board) Practice Examination starting
(E) Mannan-binding lectin on page 753.

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