Page 327 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 307

Complement-dependent opsonization is of greatest importance
in infections with encapsulated extracellular bacteria, and Complement or protease activation
individuals with deficiencies in Ab production, neutrophil func-
tion, or C3 share increased susceptibility to these organisms,
including Streptococcus pneumoniae and Haemophilus influenzae. Limited local release of C5a
MBL deficiency is also associated with recurrent pyogenic infec-
tions in young children. In general, activation of complement
by natural Ab or MBL results in C3b and iC3b deposition on Neutrophil Macrophage Endothelial cell
these pathogens, overcoming the antiphagocytic effects of the
capsule. Phagocytic cells ingest and kill the organisms using Priming ↑ of activating Expression of
CD35, CD11b/CD18, and CD11c/CD18 receptors in conjunction ↓ of inhibitory FcγR P-selectin
with other innate and Fc receptors. C5aR signaling activates
Chemokine (IL-8)
these receptors, leading to increased phagocytosis. Gram-negative Activation of C receptors and cytokine (IL-6)
Assembly of oxidase
bacteria are susceptible to complement-dependent lysis. This is synthesis
evident in the increased incidence of disseminated neisserial
infection in individuals deficient in C3, any of the MAC com-
ponents, or P, as discussed below. Effective control of infection
transmigration, phagocytosis, killing
Complement in Inflammation
An essential function of complement in host defense is the FIG 21.6 C5a in Local Host Defense. Note that C5a can also
be released by a direct protease event, such as by thrombin.
coordination of the local inflammatory response. C5a is the most IL-8, Interleukin 8.
39
potent complement product in this activity. Sublytic deposition
of the MAC on endothelial cells and platelets and C3a interaction
with the C3aR also contribute to the proinflammatory effects defense against viruses is suggested by the multiple strategies
of complement activation. As discussed below, these potent used by viruses to evade complement. 21,42 Several viruses produce
inflammatory fragments of complement, when generated in complement regulatory proteins, including vaccinia virus comple-
high amounts or targeted inappropriately, result in many of ment control protein and herpes virus glycoprotein C, which
the disease-related deleterious effects of complement. Local facilitate breakdown of C3b and C4b. Some viruses, such as
production of C5a at a site of infection occurs either through human immunodeficiency virus (HIV), incorporate complement
local complement activation or through direct cleavage of C5 regulatory proteins into the viral envelope, a strategy that is also
by tissue macrophages or thrombin. 37,38 This C5a is released used by other pathogens, such as Schistosoma. 21,42,43
and sets up a chemotactic gradient for neutrophils and mac- There are also many examples of complement receptors and
rophages. In addition, C5a activates endothelial cells to express membrane regulatory proteins being exploited as receptors for
P-selectin and synthesize chemokines, including interleukin-8 pathogens to invade cells. Examples of these include strategies
(IL-8). Interaction of C5a with mast cells releases vasoactive of direct pathogen binding to receptors as well as deposition of
amines, increasing endothelial permeability. Neutrophils and C3 fragments followed by invasion through host C3 receptors. 21
macrophages are “primed” by interaction of C5a with its recep-
tor. Priming includes enhancement of chemotaxis, activation Role of Complement in Adaptive Immunity
of complement receptors for phagocytosis increased expression Over the past 10 years there has been renewed interest in the
1,8
of activating FcγR, and assembly of the nicotinamide adenine role of the innate immune system in adaptive immune responses.
dinucleotide phosphate (NADPH)–oxidase that is required for The importance of complement in humoral immunity has been
effective killing of microbes after phagocytosis. C5a also prevents recognized since the observation that complement depletion of
neutrophil apoptosis, prolonging survival and contributing to mice before immunization decreased Ab responses to thymus-
local accumulation. Together, these actions result in the attraction dependent antigens. Further studies have shown that complement
and activation of potent antimicrobial cells and resolution of receptors CR1 (CD35) and CR2 (CD21) are also required. 33,34
infection (Fig. 21.6). In humans, these receptors are found together on B cells and
FDCs. CD35 is also expressed on a number of other cell types
Pathogen Evasion of Complement (described above), including erythrocytes and phagocytic cells.
Further evidence of the host defense function of complement is
the association of complement evasion strategies with virulence. Effects of Complement on the Humoral Immune Response
Pathogenic gram-negative bacteria, such as Salmonella, have Results obtained by experimental manipulation of C3, C4, and
lipopolysaccharides with long O-polysaccharide side chains that their receptors in mouse models indicate roles for these comple-
promote rapid shedding of the MAC and prevent its insertion ment components at multiple levels in the humoral immune
into the cell membrane. Neisseria species have several FH-binding response. 33,34 One caveat regarding these studies is that in the
components that help restrict AP activation and protect against mouse CD35 and CD21 are alternative splice products of the
lysis. Group A and B streptococci and S. pneumoniae have cell same gene, and genetically deficient animals lack both recep-
surface components (M protein, Bac or beta, PspC, Hic) that bind tors. 34,44 In humans, CD35 and CD21 are encoded by separate
to FH and/or C4bp, restricting complement activation. Other genes. The first role of CD35/CD21 is in B-cell development,
organisms, including type 3 group B streptococci, elaborate sialic indicated by a pronounced defect in B-1-cell development in
acid–containing capsules or cell walls to limit AP activation. CD35/CD21–deficient mice. B-1 cells are generally found outside
Although complement deficiencies are not generally associated lymphoid follicles, have a restricted repertoire, and are essential
with viral infections, the importance of complement in host in the production of natural Ab to pathogens, such as S.