Page 326 - Clinical Immunology_ Principles and Practice ( PDFDrive )

306 Part two Host Defense Mechanisms and Inflammation

Complement Receptors 3 and 4 TABLE 21.2 Cellular targets and Effects of
Complement anaphylatoxins
CR3 and CR4 are the β 2 integrins commonly known as CD11b/
CD18 (Mac-1) and CD11c/CD18. 34,35 β 2 integrins are large het- targets Bearing
erodimers found on neutrophils and monocytes with multiple receptors Effects
roles in adhesion to endothelium and matrix molecules as well as C3a, C5a Mast cells, basophils Degranulation, release of
direct recognition of microbial pathogens. The binding activities vasoactive amines:
of β 2 integrins are regulated by cellular activation often through contraction of smooth
chemokine receptors. Both CD11b/CD18 and CD11c/CD18 are muscle, increased
expressed primarily on neutrophils, monocytes, and NK cells vascular permeability
and bind to iC3b and, to a lesser extent, C3b. CD11b/CD18 C3a Eosinophils Chemotaxis, degranulation
C5a
Endothelium
Increased adhesion of
has been studied more extensively than CD11c/CD18. CD11b/ leukocytes; augmented
CD18 expression, clustering, and conformation are all rapidly chemokinesis and
upregulated by chemokine activation of neutrophils, leading cytokine synthesis
to increased responses to ligand. CR3 plays an essential role C5a Neutrophils, monocytes/ Chemotaxis
in neutrophil attachment to and migration through activated macrophages, eosinophils,
basophils, astrocytes
endothelium to sites in inflammation and in the regulation of C5a Neutrophils, monocytes/ Priming: activation of
neutrophil apoptosis. Deficiency of the β 2 chain (CD18) results in macrophages receptors, assembly of
leukocyte adhesion deficiency, characterized by recurrent pyogenic nicotinamide adenine
infections, and defects in inflammatory and phagocytic responses. dinucleotide phosphate
Complement receptors CD11b/CD18 and CD11c/CD18 provide (NADPH) oxidase;
an essential function for the removal of microbial pathogens activation: degranulation,
following complement activation, since C3b processing to iC3b respiratory burst
often occurs rapidly after deposition. C5a Resident macrophages Regulation of FcγR
expression (↑activating,
↓inhibitory)
Complement Receptor of the Immunoglobulin C5a Hepatocytes Acute phase protein
Superfamily (CRIg) synthesis
CRIg is a receptor for iC3b and C3b present on Kupffer cells in C3a, C5a Lymphocytes (antigen- Regulation of T-cell
the liver as well as other tissue macrophages but is absent from presenting cells) responses to antigen
splenic macrophages, peripheral blood cells, bone marrow–derived
macrophages, and monocyte/macrophage cell lines. 35,36 Two
alternative-spliced forms of human CRIg were identified with basophils, smooth muscle cells, and endothelial cells. If C5a is
one and two Ig domains. The mouse receptor has a single Ig generated locally, for example, in an extravascular site of infection,
domain. CRIg removes C3b or iC3b-opsonized particles from it helps induce an acute local inflammatory response, including
the circulation by the liver. vasodilation, edema, neutrophil chemotaxis, and activation of
neutrophils and macrophages for enhanced phagocytosis and
C5a and C3a Receptors killing. The inflammatory activities of C5a can also contribute
During complement activation, the homologous proteins C3 to complement-mediated pathology in some conditions, such
and C5 are each cleaved near the amino-terminus of the α chains as sepsis, acute respiratory distress syndrome, and ischemia/
to release a soluble peptide fragment of approximately 8 kDa. reperfusion (I/R) injury, making the C5a–C5aR interaction an
These fragments are designated C3a and C5a. C5a may also be attractive therapeutic target.
generated locally by direct cleavage of C5 by thrombin or leukocyte The C5L2 receptor binds to both C5a and C5a desarg . C5L2 was
37
proteases. C3a and C5a are termed anaphylatoxins because of initially believed to be a default or decoy receptor for C5a because
their ability to increase vascular permeability, contract smooth it is uncoupled from G proteins. Genetic deletion of C5L2
−/−
muscle, and trigger the release of vasoactive amines from mast (Gpr77 ) in mice resulted in enhanced neutrophil infiltration
cells and basophils. 38-41 C5a is 10- to 100-fold more active than and cytokine production in the pulmonary Arthus reaction,
C3a. These peptides are also chemotactic: C5a is specific for supporting an antiinflammatory role for C5L2 in immune
neutrophils, monocytes, and macrophages, whereas C3a is specific complex disease, where genetic deletion of C5aR is fully protec-
40
for mast cells and eosinophils. Other biological activities of tive. However, studies in a cecal ligation and puncture (CLP)
complement anaphylatoxins are summarized in Table 21.2. model of sepsis found increased survival in mice lacking either
41
Structurally, anaphylatoxins are compact structures consisting C5aR or C5L2. The results suggest an active proinflammatory
of multiple helices cross-linked by disulfide bonds with more role for C5L2 that requires C5a and results in the release of the
flexible carboxy-terminal regions. The C-terminal peptide of inflammatory signal, high-mobility group box-1 protein (HMGB1)
C3a interacts with the C3aR and can reproduce C3a agonist from phagocytic cells. Thus both C5aR and C5L2 may contribute
activity. In contrast, C5a interacts with the C5aR at multiple synergistically to harmful inflammatory events during sepsis.
sites. Plasma carboxypeptidases cleave the C-terminal arginine
from C3a and C5a producing the des-Arg forms. This inactivates COMPLEMENT IN HOST DEFENSE AND IMMUNITY
C3a; however, C5a desarg retains much of its biological activity.
The C5aR (CD88 and C5L2) and the C3aR are rhodopsin-type Complement in Host Defense
receptors with seven transmembrane-spanning domains coupled Complement activation provides a coordinated response to
to G-protein signaling pathways. C5aR is expressed at high levels infection that results in the opsonization of microbial pathogens
on neutrophils and is also found by macrophages, mast cells, and the attraction and activation of phagocytic cells to kill them.