Page 324 - Clinical Immunology_ Principles and Practice ( PDFDrive )

304 Part two Host Defense Mechanisms and Inflammation

names imply, have decay-accelerating and/or cofactor activity,
respectively, that inhibits complement activation on cell mem-
25
branes. Each has an extracellular domain composed exclusively
of four CCPs. CD55, a glycophosphatidylinositol (GPI)–anchored
protein, and CD46, a transmembrane protein, are widely dis-
tributed on cells in contact with blood, with the notable exception
of erythrocytes that lack CD46. Soluble CD55 is also found in
most biological fluids. Both protect cells from complement-
mediated lysis. CD35 (CR1) has decay-accelerating and cofactor
activity and is a receptor for bound C3b. The function of CD35
as a complement receptor is discussed later in the chapter.
Complement C2 receptor inhibitor trispanning (CRIT) is a
non-RCA membrane regulator of the CP. CRIT was originally
identified on Schistosoma and Trypanosoma parasites and later
FIG 21.4 FI dependent cleavage of C3 showing the structures found to be widely expressed on human tissues and blood cells,
30
of the products and the required cofactors. The cofactor protein except for neutrophils and erythrocytes. CRIT competes with
binds first and then the serine protease Factor I cleaves the C2 for binding to C4b, blocking the formation of the CP C3
C3b. convertase.
Properdin
acceleration. A second mechanism of regulation is the enzymatic In contrast to the regulatory proteins discussed above, the plasma
inactivation of the C4b and C3b components of the convertases protein P (factor P) stabilizes C3 and C5 convertases of the AP,
(Fig. 21.4). This is accomplished by the plasma enzyme factor I increasing their activity. 8,18,19 This enhancer of AP activation is
(FI), which, however, only acts on C4b or C3b in complex with one found as noncovalently linked dimers, trimers, tetramers, and
of several regulatory proteins. The binding of regulatory proteins larger species composed of identical 56-kDa chains. The majority
to C4b or C3b to enable FI cleavage is termed cofactor activity. of this plasma protein consists of a series of six thrombospondin
type 1 modules. P binds to C3b and to Bb, preventing the
Factor I spontaneous or induced decay of the AP C3 and C5 convertases.
FI (C3b inactivator, C3bINA) cleaves C4b and C3b into products Its multimeric structure promotes interaction with clustered C3b.
that are recognized by specific cellular receptors (as discussed As discussed above, bound P can also recruit C3b to provide a
below). The sequential cleavages of C3b by FI to iC3b and C3dg site of assembly for the AP C3 convertase.
are depicted in Fig. 21.4. C4b is cleaved in an analogous manner
to C4d. (The iC4b intermediate is found only transiently.) The Regulators of the Membrane Attack Complex
regulatory proteins that facilitate this cleavage by cofactor activity The MAC is also regulated by both fluid-phase and membrane
and those that inactivate C3 and C5 convertases by decay- regulatory proteins. 1,20,23,29
accelerating activity are members of a family of structurally
related proteins encoded within the regulators of complement Soluble MAC Inhibitors: Vitronectin and Clusterin
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activation (RCA) genetic locus. This family is characterized by Soluble hydrophobic proteins block the incorporation of the
a repeating structure that consists of subunits, termed complement MAC into membranes. Two well-characterized proteins with
control protein repeats (CCP), of about 60 amino acids with a this activity are vitronectin (S protein) and clusterin (SP-40,40,
conserved pattern of two disulfide bonds per repeat and are apolipoprotein J). 23,29 Vitronectin is in plasma and the extracellular
usually encoded by a single exon. matrix and binds to C5b-7. C8 and C9 can still bind to the
complex, but membrane insertion and C9 polymerization are
Soluble Regulatory Proteins, C4b-Binding Protein, and FH prevented. Soluble complexes of vitronectin and C5b-9 are in
C4b-binding protein (C4bp) and FH are fluid-phase regulatory plasma during complement activation, and an enzyme-linked
proteins with both decay-accelerating and cofactor activities. immunosorbent assay (ELISA) specific for this complex has
C4bp is multimeric, being composed of seven identical subunits, been used to monitor activation of the MAC. Clusterin forms
each containing eight CCPs. FH is a single-chain protein composed a complex with C5b-9, preventing membrane insertion. It is found
entirely of 20 CCPs. C4bp is specific for C4b and the C4b- in plasma, in the male reproductive tract, and on endothelial cells
containing convertases of the CP (C4b2b, C4b2b3b), whereas of normal arteries. It is also associated with amyloid deposits,
FH regulates C3b and C3b-containing convertases (C3bBb, including β amyloid in Alzheimer disease.
C3bBb3b, C4b2b3b). FH is essential for regulation of C3 “tickover,”
and FH deficiency results in an acquired deficiency of C3. Membrane MAC Inhibitor CD59
Additional binding sites on FH that recognize polyanions, such The primary membrane-bound inhibitor of the MAC is CD59. 23,29
as sialic acid and glycosaminoglycans, provide targeted regulation CD59 is a GPI-anchored protein expressed by most cells. CD59
of AP activation on surfaces. 23,26-28 binds to C8 and C9, preventing the incorporation and polymeriza-
tion of C9.
Membrane Regulatory Proteins
The RCA family includes the membrane regulatory proteins COMPLEMENT RECEPTORS
decay-accelerating factor (CD55, DAF), membrane cofactor
protein (CD46, MCP), and complement receptors CR1 (CD35) Many of the biological effects of complement activation are
and CR2 (CD21). 25,29 CD55 (DAF) and CD46 (MCP), as their mediated by cellular receptors for fragments of complement