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Chapter 24 Complement and Immunoglobulin Biology Leading to Clinical Translation 265

C5 convertase for its substrate C5 such that its Michaelis constant membranes. The transfer of complexes is enhanced by cleavage of
(K M ) is now well below the physiologic concentration of C5 in C3b to iC3b by FI, as iC3b is a poor ligand for CR1, but is a good
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plasma. C5b is the initiating component of the membrane attack ligand for CRIg, a complement receptor of the Ig superfamily present
complex (MAC). The MAC is a multiprotein complex whose on tissue-resident phagocytic cells (see later for further discussion of
components are C5b, C6, C7, C8, and multiple C9s. 39,40 The CRIg).
constituent components of the MAC associate in the numeric order Given its central position in the complement cascade, the presence
C5b–C6–C7–C8–C9. of C3b is tightly regulated. This regulation is brought about by
The MAC, when viewed by electron microscopy, resembles a cleaving C3b into inactive derivatives that cannot participate in
cylinder that possesses a hydrophobic outer face and a hydrophilic forming an active convertase. One of the conformationally altered
central core. If assembled near a lipid bilayer, such as a cell or the inactive derivatives of C3b, iC3b (see Fig. 24.2B), can act as an
bacterial membrane of a gram-negative strain, the MAC can associate opsonin in its own right for complement receptors CR2 (CD21),
with and insert into the lipid bilayer. Such insertion can be thought CR3 (CD11b/CD18), and CR4 (CD11c/CD18). CR3 binds iC3b
as “punching holes” into the membrane, allowing for passage of water and plays a major role in inducing phagocytosis but probably not
and small ions into the cell. Osmotic equilibrium is thereby lost, activation in the absence of a second signal (e.g., Fc receptor or
leading to eventual lysis of the targeted cell or bacterium. C5b678 are pattern recognition receptor). CR4 also binds iC3b-opsonized par-
sufficient to form small pores in the target membrane. The role of C9 ticles, resulting in direct endocytosis. Although its role as a phagocytic
appears to be to enlarge the channel through multiple C9 polymeriza- receptor is not well characterized, CD11c is the major marker for
tion, thereby causing more rapid loss of membrane function and lysis. DCs. It is important to understand the functional importance of this
Deficiencies in complement components C5 to C9 have only been complement receptor on DC and how it participates in uptake of
associated with increased susceptibility to Neisseria species–based antigen for presentation to T lymphocytes.
infections, such as gonorrhea and bacterial meningitis. Also, the CR2 expressed on B cells augments cognate antibody receptor
extended cell wall peptidoglycan layer of gram-positive strains of signaling (see later section). This receptor recognizes targets that are
bacteria make them resistant to the lytic arm of complement. It can coated with iC3b, as well as the subsequent degradation products
be concluded from these observations that the requirement for MAC C3dg and C3d, all of which remain covalently bound to the target
is limited in host protection. (see Fig. 24.2B). CR2 is the only complement receptor that recognizes
C3d/TED on its own as its ligand. However, the CR2 binding site
Complement Receptors and Their Role in Immune on TED only becomes accessible after degradation of C3 to at least
the iC3b stage. Activation of complement plays a contributing role
Complex Clearance and Activation in producing a strong antibody response. An interesting aside is that
CR2 is the cell surface receptor on human B cells that is recognized
As described in the previous section, complement can act by the by the Epstein-Barr virus. 44
direct lysis of targeted cells. Another important function of comple- CRIg is a recently described complement receptor that plays an
ment in host protection is facilitating the uptake and destruction important role in the clearance of C3b opsonized complexes by
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of pathogens by phagocytic cells. This occurs by the specific rec- phagocytic cells of the liver. It is also expressed on subsets of mac-
ognition of C3b/C4b–coated (opsonized) particles by complement rophages, but less is known about this role. The recent cocrystalliza-
receptors. 41,42 tion of C3b and CRIg revealed binding to the C3b β chain, which
The best characterized complement receptor for the uptake of is in contrast to all other known C3-interacting partners, in which
C4-coated immune complexes is CR1 (CD35). CR1 binds C4b/ binding to the activated C3 occurs via the α chain.
C3b–bearing immune complexes. CR1, similar to most proteins that
bind activation products of C4 and C3 molecules, shares a structural
motif known as the short consensus repeat (SCR). Each short con- Biologic Activity of C3a and C5a
sensus repeat consists of approximately 60 amino acids. CR1 in
humans is composed of 30 linked short consensus repeats. CR1 The role of the complement fragments C3a and C5a in the immune
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possesses three binding sites for C4b and two for C3b. response is to produce localized inflammation. C3a and C5a are
CR1 is expressed on a wide variety of cell types in humans, anaphylatoxins and are structurally similar to chemokines. When
including erythrocytes, macrophages, polymorphonuclear leukocytes, produced in large amounts or injected systemically, they induce a
B cells, monocytes, and FDCs. The role of CR1 expression on B cells generalized circulatory collapse and shock-like syndrome similar to
and FDCs in activating and maintaining the adaptive immune that seen in a systemic allergic reaction involving IgE antibodies. 47
response is detailed subsequently. For now, the focus is on the other Of the two fragments, C5a is the most stable and possesses the
cell types that express CR1. best characterized and possibly highest specific biologic activity. Both
Because CR1 is not directly associated on its cytoplasmic side with C3a and C5a induce smooth muscle contraction and increased vas-
any intracellular signaling molecules, binding of C3b by CR1 cular permeability. C5a and C3a also act on endothelial cells lining
expressed on phagocytic cells is not in itself capable of inducing blood vessels to induce adhesion molecule expression. 48,49 In addition,
endocytosis of the C3b-opsonized target. A secondary signal is C3a and C5a can activate the mast cells that populate submucosal
required to induce phagocytosis. This second signal can be provided tissues and line vessels throughout the body to release histamine,
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by IgG binding to the phagocyte’s Fc receptor, by carbohydrates tumor necrosis factor α (TNF-α), and protease. The changes
commonly found on bacterial surfaces, or by exposure of the phago- induced by C3a and C5a recruit antibody, complement, and phago-
cytic cell to the appropriate cytokines. In addition, some phagocytic cytic cells to the site of infection, thereby hastening the adaptive
cells, such as macrophages, are activated by binding of C5a through immune response. C5a also induces the upregulation of CR1 and
C5a receptor (C5aR, [CD84]) (see Biologic Activity of C3a and C5a, CR3 on the surfaces of these cells. C5a is the only complement
later). What these secondary ligands have in common is that they all chemotactic agent for neutrophils, macrophages, and basophils. By
bind to receptor domains that are the ligand recognition units of a contrast, both C3a and C5a possess chemotactic activity for mast
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cell signaling molecule or complex. cells. Although a similar fragment, C4a, is produced in the course
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The largest pool of CR1-expressing cells is erythrocytes. Erythro- of C4 activation, its physiologic relevance as an anaphylatoxin is
cytes bearing opsonized material are removed from the circulation highly questionable. First, human C4a binds to neither C3aR nor
presumably to prevent deposition in tissue sites such as the renal C5aR, the two well-characterized complement anaphylatoxin recep-
glomerulus. Erythrocytes bearing opsonized material traverse the tors, and a specific C4a-binding entity has not been identified.
sinusoids of the liver and spleen, where they come into close contact Second, anaphylatoxin activity for human C4a has only been reported
with fixed phagocytic cells. These phagocytic cells affect the transfer on guinea pig targets, but even there, it is two to three orders of
of opsonized material from the erythrocyte onto their own magnitude less potent than human C3a. 50