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CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 305

SIPRα. However, none has been definitively established as a
receptor in the classic sense. 1,5,16,31
Complement Receptor 1 (CR1, CD35)
There are five identified receptors for bound fragments of C3
s s
CR3 and/or C4. CD35 is a large protein composed of a linear string
CR1 CD11b of CCPs, a transmembrane region, and a short intracytoplasmic
CD35 CD18 domain. Different allelic forms of CD35 are found, the most
32
CRIg CR2 common being composed of 30 CCPs with a molecular weight of
CD21 190 kDa. These CCPs are organized into groups of seven, creating
C3b iC3b structures termed long homologous repeats (LHRs), each of which
contains a single binding site. The predominant allele of CD35
SS S S SS S S contains two binding sites for C3b, three for C4b, and one for
C1q. CR1 is expressed on human erythrocytes, monocytes and
C3dg macrophages, neutrophils, B lymphocytes, a small percentage of
HS C=O HS C=O HS C=O T lymphocytes, eosinophils, FDCs, and glomerular podocytes.
O O O CD35 on primate erythrocytes provides a mechanism for
clearing soluble immune complexes from the circulation. Although
the number of receptors on each erythrocyte is low, the large
number of erythrocytes provides the major pool of CR1 in the
circulation. Soluble immune complexes that fix complement attach
quickly to erythrocytes in the circulation, bypassing monocytes
FIG 21.5 Receptors for Bound C3b and Its Cleavage Products. and neutrophils. These erythrocyte-bound complexes are taken
Receptors shown are CD35 and CD21 composed of CCP (SCR) to the liver, where they are transferred to Kupffer cells expressing
subunits; CD11b/CD18 (CR3), a β 2 integrin; and CRIg with one Fc and complement receptors and destroyed. The erythrocytes
or two immunoglobulin domains. The specificities of the receptors exit into the circulation to pick up more immune complexes.
are CD35 for C4b and C3b, (C4b > C3b), CRIg for iC3b > C3b; This clearance pathway is impaired in patients with SLE because
CD11b/CD18 for iC3b; CD21 for C3dg and C3d. CD11c/CD18 of decreased complement in the circulation, decreased CD35 on
(CR4) is similar to CD11b/CD18 and is not shown. Receptors erythrocytes, and saturated Fc receptors in the liver and spleen.
are not drawn to scale. Their molecular weights are listed in CD35 on monocytes and neutrophils promotes binding of
Table 21.1. microbes carrying C3b and C4b on their surface (immune
adherence reaction), facilitating their phagocytosis through Fc
receptors. CD35 can directly mediate the uptake of microbes
when phagocytic cells have been activated by chemokines or
proteins. These include receptors for the small soluble complement integrin interactions with matrix proteins. CD35 is a member
fragments, C5a and C3a, and receptors for bound complement of the RCA family and has decay-accelerating and cofactor activity
fragments, C1q and C4b and C3b and their cleaved fragments. in addition to its function as a receptor. It differs from the
Receptors are specific for C3b and for its further breakdown membrane regulatory proteins DAF (CD55) and MCP (CD46)
products generated by the enzymatic processing by FI in conjunc- in its ability to also bind to C3b and C4b extrinsically (on targets
tion with the cofactor proteins mentioned above. The breakdown other than the cell expressing it) and in its cofactor activity for
of C3b and intermediate products are shown in Fig. 21.4 and iC3b processing. CD35 is the most effective cofactor for FI cleavage
the receptors for these components in Fig. 21.5. of C3b and iC3b to the smallest covalently bound fragment
C3dg. C3dg is the major ligand for CR2 on B lymphocytes
C1q Receptors (described below). The cofactor activity of CD35 on B lympho-
C1q is one of a family of proteins termed soluble defense col- cytes can process bound C3b to C3dg, facilitating binding to
lagens, which includes the “collectins” (MBL, surfactant proteins CR2 and lowering the threshold for B-cell activation. 29,33,34
A and D, conglutinin), and the ficolins. Each of these proteins
is composed of a collagen-like linear stem region terminated Complement Receptor 2 (CR2, CD21)
by multiple globular recognition domains or head groups. The CD21 is also an RCA family protein composed of 15–16 CCPs.
collectins recognize carbohydrates with their C-type lectin head CD21 has a limited range of expression that includes B lympho-
groups, and the ficolins recognize acetyl groups on carbohydrates cytes, FDCs, and some epithelial cells. CD21 is specific for the
and other molecules with fibrinogen-like recognition domains. smallest covalently bound C3 fragments, C3dg and C3d, and
In contrast, the globular head groups of C1q do not recognize has weaker binding to iC3b. CD21 is also the Epstein-Barr virus
carbohydrates but, rather, bind to amino acid motifs on IgG, (EBV) receptor on B cells and nasopharyngeal epithelial cells
IgM, and pentraxins. In general, the soluble defense collagens and binds to CD23, a low-affinity IgE receptor. 33,34
broadly recognize pathogen-associated carbohydrate patterns and CD21 on B lymphocytes serves a costimulatory role. It is
damaged or apoptotic cells. Reported direct effects of this group expressed on mature B cells as a complex with CD19 and CD81
on leukocytes include the enhancement of phagocytosis, triggering (TAPA-1). Coligation of CD21 and the B-cell antigen receptor
of the respiratory burst, and regulation of cytokine responses. induces the phosphorylation of CD19, activating several signaling
Several cell surface proteins have been proposed to facilitate these pathways and strongly amplifying B-cell responses to antigen.
activities, including CD93 (C1qRp), CD35 (CR1), α 2 β 1 integrin, This role of CD21 is believed to contribute to the strong adjuvant
calreticulin in complex with CD91, gC1q binding protein, and effect produced by attaching C3d to antigen. 33,34