Page 56 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 3 Innate Immunity 41

KEY CONCEPTS The Complement System
Humoral Innate Immunity The complement system comprises a collection of plasma proteins

• Cytokines and chemokines are essential mediators of the innate immune activated by microbes (Chapter 21). It helps mediate microbial
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response. destruction and inflammation. Complement activation can
• Cytokines are redundant and pleiotropic. To avoid host tissue response, occur via three pathways: the classical pathway (CP), the alterna-
their synthesis is tightly controlled. tive pathway (AP), and the lectin pathway (LP).
• Acute phase reactants (i.e., cross-reactive protein [CRP]) are induced In the CP, complement C1 detects immunoglobulin M (IgM),
by cytokines (interleukin [IL]-6) and play roles in opsonization of IgG1, or IgG3 bound to the surface of a microbe. C1 is composed
microbes. Plasma CRP is used to monitor infections and
inflammation. of the C1q, C1r, and C1s subunits. These form multimeric
• Defects in the complement system result in invasive bacterial infections, complexes that recognize IgM or IgG bound to microbial surfaces.
primarily from encapsulated bacteria. C1r and C1s are serine proteases. Activated C1s generates a C3
convertase composed of C4b and C2b (C4b2b) bound to the
microbial surface. C3 convertase cleaves C3, generating C3b.
C3b binds covalently to C4b2b, generating C5 convertase. C5
necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induce convertase then activates the late steps of complement activation
production of acute phase reactants in hepatocytes, including leading to assembly of the membrane attack complex (MAC)
members of the pentraxin family (e.g., serum amyloid A [SAA], and subsequent cytolysis.
serum amyloid P [SAP], and cross-reactive protein [CRP]). These The AP is initiated by small amounts of C3b, which are
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pentraxins bind to components of the bacterial cell wall. TNFα spontaneously generated in plasma. C3b that remains unbound
and IL-1β also induce production of IL-6 from mononuclear to a cell surface is rapidly hydrolyzed and inactivated. C3b bound
phagocytes, endothelial cells, and fibroblasts. IL-6 is another to a microbe becomes a binding site for factor B. Bound factor
potent inducer of acute phase reactants, including CRP and B is cleaved by factor D, generating factor Bb that binds covalently
fibrinogen. CRP, SAA, and SAP function as opsonins and can to C3b, forming the AP C3 convertase, which activates the late
bind phosphorylcholine and phosphatidylethanolamine expressed steps of complement activation, as in the CP.
on bacteria and apoptotic cells, enhancing phagocytosis of bacteria The lectin pathway is activated by MBL or ficolins binding
and apoptotic cells by macrophages. to microbial surfaces. MBL then binds to MBL-associated serine
Lipopolysaccharide-binding protein (LBP) is an acute phase proteases (MASPs)-1, -2, and -3. MASP-2 cleaves C4 and C2 to
reactant synthesized by the liver in response to gram-negative activate the complement cascade, as in the CP (Fig. 3.1).
bacterial infections. LBP binds to LPS and subsequently forms Complement components also function as opsonins.
a complex with CD14, TLR4, and MD-2, which functions as a Complement-coated microbes can be phagocytosed via comple-
high-affinity receptor for LPS. 15 ment receptors on phagocytes. Complement receptor type 1
Mannose-binding lectin (MBL) is a member of the calcium- (CR1) is a high-affinity receptor for the C3b and C4b fragments
dependent (C-type) lectins (collectins) produced by the liver in of complement and mediates the internalization of C3b- and
response to infection. MBL binds to carbohydrates with terminal C4b-coated particles. On erythrocytes, it mediates clearance of
mannose and fucose residues that are expressed on microbial immune complexes from the circulation. Complement type 2
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cell surfaces. MBL can bind to the C1q receptor on macrophages receptor (CR2, also known as CD21) is expressed on B cells and
to enhance phagocytosis and can activate the complement system follicular dendritic cells (FDCs). It binds C3 proteolytic fragments,
via the lectin pathway (discussed below). including C3d, C3dg, and iC3b. CR2 augments humoral immune
Surfactant protein-A and surfactant protein-D are collectins responses by enhancing B-cell activation by antigen and by
expressed in the lung and can bind a variety of microbes and promoting trapping of antigen–antibody complexes in germinal
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inhibit their growth. 13,17 They also function as opsonins that centers. CR2 is also the receptor for Epstein-Barr virus (EBV),
promote ingestion by alveolar macrophages. allowing EBV to enter B cells. Complement receptor 3 (CR3) is
Finally, ficolins are plasma proteins capable of binding to composed of a heterodimer of CD18 and CD11b and is expressed
several types of bacteria and can activate complement. in polymorphonuclear neutrophils (PMNs) and monocytes or
macrophages. CR3 binds to iC3b bound to the surface of microbes,
leading to phagocytosis and destruction of the pathogen. Activa-
CLINICaL PEarLS tion of complement via the AP can greatly enhance monocyte-
Complement generated TNF-α elicited by gram-positive bacteria, such as group
B Streptococcus. 20
• Deficiency of early components of the complement cascade create There are multiple regulatory proteins within the complement
susceptibility to invasive infections with encapsulated bacteria and pathways. C1-inhibitor (C1-INH) binds to, and inhibits, the
development of a lupus-like syndrome. enzymatic functions of C1r and C1s within the CP (21). Properdin
• Deficiency of late components of the complement cascade (C5–9) stabilizes C3bBb complex, increasing the life span of the AP C3
result in susceptibility to meningitis caused by Neisseria meningitis.
• Deficiency of C1-inhibitor protein (or function) results in hereditary convertase. Conversely, factor H inhibits the formation of, and
angioedema. degrades, C3bBb complex. Factor I inactivates C3b. CD55 (decay
• Deficiency of factor H is associated with development of membrano- accelerating factor) and CD59 are cell surface, GPI-linked proteins
proliferative glomerulonephritis, hemolytic–uremic syndrome, and that block complement-mediated cytolysis by inhibiting formation
age-related macular degeneration. of C3bBb complex and binding of C9 to C5b678 complex,
• Deficiency of mannose-binding lectin can result in susceptibility to respectively. Paroxysmal nocturnal hemoglobinuria, an acquired
bacterial infection in individuals with comorbid conditions (e.g., cystic
fibrosis). defect in the PIGA gene that causes a deficiency of GPI-linked
proteins, is the result of absent cell surface expression of CD55