Chapter 13
Innate and Adaptive Immunity
287
There are three parallel but independent pathways that
result in activation of the complement system during the innate
immune response: the classical, the lectin, and the alternative
pathways. The reactions of the complement systems can be
divided into three phases:
1. Initiation or activation
2. Amplification of inflammation
3. Membrane attack response
The three pathways differ in the proteins used in the early stage
of activation, but all ultimately converge on the key comple-
ment protein C3, which is essential for the amplification stage.
Activated C3 then activates all subsequent complement mol-
ecules (C5 through C9) resulting in the ultimate lysis of cells.
The classic pathway is initiated by an antigen–antibody
complex (either IgG or IgM mediated), which causes a specific
reactive site on the antibody to be “uncovered” so that it can bind
directly to the C1 molecule in the complement system. Once C1
is activated, a “cascade” of sequential reactions is set in motion.
Initially a small amount of enzyme is produced, but with activa-
tion of successive complement proteins successively increas-
ing, concentrations of proteolytic enzymes are produced. This
process is known as
amplification
. In the lectin or alternative
complement pathway, inactive circulating complement proteins
are activated when they are exposed to microbial surface poly-
saccharides, MBL, CRP, and other soluble mediators that are
integral to innate immunity. Like the classic pathway, the lectin
and alternative pathways create a series of enzymatic reactions
that cleave successive complement proteins in the pathway.
During the activation phase of the complement cascade,
cleavage of C3 produces C3a and C3b. C3b is a key opsonin
that coats bacteria and allows them to be phagocytized after
binding to type I complement receptor on leukocytes. The
presence of C3a triggers the migration of neutrophils into the
tissues to enhance the inflammatory response. Production of
C3a, C4a, and C5a also leads to activation of mast cells and
basophils causing them to release histamine, heparin, and other
substances. These mediators of the inflammatory response
increase tissue blood flow and increase localized capillary per-
meability allowing increased leakage of fluids and protein into
the area. In addition, they stimulate changes in the endothelial
cells in order to stimulate chemotaxis of neutrophils and mac-
rophages to the site of inflammation. During the late phase of
the complement cascade, cleavage of C5 triggers the assembly
of a membrane attack complex from the C5 to C9 proteins.
The resulting complex creates a tubelike structure, which pen-
etrates the microbial cell membrane allowing the passage of
ions, small molecules, and water into the cell, causing the cell
to ultimately burst. The multiple and complementary func-
tions of the complement system make it an integral compo-
nent of innate immunity and inflammation. It also serves as
an essential bridge between the innate and humoral responses.
Pathophysiological manifestations associated with deficiencies
of complement range from increased susceptibility to infection
to inflammatory tissue and autoimmune disorders that are the
result of impaired activated complement clearance.
TNF-
α
and lymphotoxins are cytokines that are structur-
ally related and that have similar cytotoxic activities.
23
The two
cytokines differ in that TNF-
α
can be secreted by a variety of
immune cells, but the lymphotoxins are predominantly secreted
by activated lymphocytes and NK cells. These cytokines regu-
late development of the lymphoid tissues and the inflammatory
process through induction of adhesion molecules and other
cytokines/chemokines.
23
The IFNs are another family of cyto-
kines that are critically involved in initiating and enhancing
the cellular immune response to viral infection of host cells. In
addition, they play a key role in amplifying the presentation of
antigens to specific T cells. Type I interferon (IFN-
α
and IFN-
β
)
is secreted by virus-infected cells, while type II, immune or
gamma interferon (IFN-
γ
), is mainly secreted by T cells, NK
cells, and macrophages.
23,24
When activated IFNs interact with
specific cellular receptors, causing the expression of antiviral
and immune modulatory genes. IFNs activate macrophages,
induce B cells to switch Ig type, alter T-helper response, inhibit
cell growth, promote apoptosis, and induce an antiviral state
in uninfected cells. Finally, ILs help to regulate the immune
response by increasing the expression of adhesion molecules
on endothelial cells, stimulating migration of leukocytes into
infected tissues, and by stimulating the production of antibod-
ies by the cells of the adaptive immune response.
Acute-Phase Proteins
Two acute-phase proteins that are involved in the defense
against infections are the mannose-binding ligand (MBL) and
C-reactive protein (CRP). MBL and CRP are produced in the
liver in response to activation of proinflammatory cytokines.
MBL binds specifically to mannose residues, and CRP binds
to both phospholipids and sugars that are found on the surface
of microbes. These substances act as “costimulatory” opso-
nins and enhance the binding of phagocytic cells to subopti-
mally opsonized invading microorganisms.
25
They also act as
activators of the alternative complement pathway.
The Complement System
The complement system is a powerful effector mechanism of
both innate and adaptive immunity that allows the body to local-
ize infection and destroy invading microorganisms. The com-
plement system is composed of group of proteins found in the
circulation and in various extracellular fluids. The proteins of
the complement system normally circulate as inactive precur-
sors. When activated a series of proteolytic and protein–protein
interactions is initiated that ultimately culminates in opsoniza-
tion of invading pathogens, migration of leukocytes to the site
of invasion, initiation of a localized inflammatory reaction, and
ultimate lysis of the pathogen.
25
The proteins of the complement
system are mainly proteolytic enzymes and make up approxi-
mately 10% to 15% of the plasma proteins. For a complement
reaction to occur, the complement components must be activated
in the proper sequence. Inhibitor proteins and the instability of
the activated complement proteins at each step of the process
prevent uncontrolled activation of the complement system.
