Page 323 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 303

proteases (MASPs), which are structurally and functionally similar covalent attachment to surfaces. C3a and C5a are also structurally
to C1r and C1s. MASP-1 and -2 are active proteases, but only homologous and, as described below, are the most potent proin-
MASP-2 cleaves both C4 and C2 to generate C4b2a, the same flammatory mediators of the complement system. C5b initiates
C3 convertase as the CP. MASP-1 can supplement activation by the formation of the MAC (see Fig. 21.3), a complex of C5b,
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cleaving C2 but not C4. Two nonproteolytic splice products of C6, C7, C8, and multiple (5–10) C9 molecules. This complex,
the MASP2 and MASP1/3 genes, sMAP and MAP-1, compete as indicated by its name, penetrates membrane bilayers to form
with MASP-1 and MASP-2 for binding to MBL to regulate the pores that disrupt the osmotic barrier, leading to swelling and
LP. Subsequent steps in the LP are identical to those in the CP. lysis of susceptible cells. Lysis of Ab-sensitized erythrocytes by
Although still controversial, MASP-1 and MASP-3 likely contribute the MAC is the basis of the total hemolytic complement (THC)
to the AP by cleaving profactor D to active factor D. 7,16,17 assay or CH 50 . C5b initiates the formation of the MAC without
further proteolytic steps. C5b binds to C6, and this complex
Alternative Pathway binds to C7. The C5b67 complex is lipophilic and associates
The AP uses proteins that are structurally and functionally homolo- with cell membranes, if available, or with serum lipoproteins.
gous to those of the CP, but this pathway has unique features Once bound to a membrane, C5b67 recruits C8, and the complex
that play three important roles in the complement cascade. The penetrates more deeply into the membrane. However, efficient
surveillance role of the AP is mediated by a continuous low level of lysis requires C9, a pore-forming molecule with homology to
spontaneous activation that results from the hydrolysis of the C3 perforin, a protein used by cytotoxic T cells and natural killer (NK)
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thioester bond. Hydrolyzed C3, C3(H 2 O), assumes a conformation cells for killing virus-infected targets. The complex of C5b678
similar to that of C3b and can bind factor B (homologous to forms a nidus for C9 binding and polymerization. Although
C2), which is cleaved by factor D (homologous to C1s) to form a complement-dependent lysis of bacteria can be observed in vitro,
fluid-phase C3 convertase. This convertase cleaves C3 to generate many pathogens have evolved mechanisms to circumvent this
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C3b, which can covalently bind to nearby structures and provide activity of complement. Opsonization by C3b is the most potent
the basis for a bound C3 convertase (C3bBb). Because C3b is both mechanism for destruction (adherence followed by ingestion)
a part of this enzyme and a product of the reaction, a positive of bacteria by the complement system. The sublytic MAC is
feedback loop that rapidly deposits more C3b is formed. This proinflammatory because of its membrane perturbing capabili-
low-grade activation process is tightly regulated on host cells and ties for host cells and contributes to the deleterious effects of
tissues by plasma and membrane-bound complement regulatory complement activation in inflammatory diseases. 22
proteins. It is the lack of such regulation that usually restricts AP
activation to microbial targets. The plasma protein factor H (FH) REGULATION OF COMPLEMENT ACTIVATION
is particularly important in controlling AP activation, both in the
fluid phase and on “nonactivating” surfaces. The latter recruits The complement cascade is rapidly activated and highly amplified
FH through its binding sites for polyanions, including sialic acid by the generation of C3 and C5 convertases. There are three
and glycosaminoglycans. “Activating” surfaces, such as microbial main levels of control that limit the potential harm that uncon-
polysaccharides, lipopolysaccharides, and foreign glycoproteins, trolled complement activation might cause: (1) the initiation
provide C3b attachment sites that are protected from regulatory step in the CP and the LP; (2) the C3 and C5 convertases of all
proteins. Similar to the CP, the AP C5 convertase (C3bBb3b) is three pathways; and (3) the assembly of the MAC. Both soluble
formed when a second C3b attaches to the C3 convertase. The and membrane-bound regulatory proteins serve these functions,
AP C3 and C5 convertases are stabilized by P (factor P or P), for which help terminate complement activation and direct it to
which this pathway was originally named. appropriate targets. 23
More recently, an additional role for properdin (P) in initiating
AP activation was rediscovered. 8,18,19 P is a pattern-recognition C1 Esterase Inhibitor
molecule with specificity for microbes and damaged cells. Once C1 esterase inhibitor (C1-INH) is a plasma serine proteinase
bound, P can recruit fluid-phase C3b or C3b (H 2 O), indepen- inhibitor (serpin). C1-INH covalently binds to activated C1r
dent of covalent binding, and thereby provide a platform for and C1s, irreversibly inhibiting their activity and thereby limiting
the assembly of the AP convertase. Thus P binding can direct CP activation. C1-INH inactivation of C1r and C1s also removes
AP activation, similar to MBL in the LP. P binding to certain them from the C1 complex, exposing sites on the collagen-like
Neisseria species potently activates the AP, and this may account region of C1q. Likewise, C1-INH inhibits MASP-1 and MASP-2,
for the susceptibility of P-deficient individuals to infection with kallikrein, factor XIa, factor XIIa, and plasmin of the LP and the
N. meningitidis. contact, coagulation, and fibrinolytic systems. Inherited deficiency
The third important role of the AP is the amplification of of C1-INH is the basis of hereditary angioedema, a disease
C3b deposition and C5 convertase generation that is initiated characterized by recurrent attacks of subcutaneous or submucosal
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by the CP or the LP. This function of the AP is critical in edema (Chapter 42). 24
complement-mediated pathology, as it increases the generation
of C5a and the MAC, the most inflammatory components of Regulators of the C3 and C5 Convertases
the system. It is this amplification role of the AP that makes it The C3 and C5 convertases are central to the generation of the
an attractive therapeutic target. inflammatory and opsonic products of complement activation
and are highly regulated by fluid-phase and membrane-bound
MEMBRANE ATTACK COMPLEX regulatory proteins. The membrane deposited C4b and C3b may
be bound by the regulator to prevent an association with C2 or
All three complement pathways merge with the cleavage of C5 FB. The convertases themselves are complexes of two or three
into C5a and C5b. Although C5 is structurally homologous components, and one mechanism of regulation is the dissocia-
to C3 and C4, it lacks an internal thioester bond that allows tion of these complexes. This type of regulation is termed decay