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U N I T 4
Infection and Immunity
and the coating materials are called
opsonins.
Once
the opsonin-coated microbe attaches to a complemen-
tary receptor on a phagocytic cell, phagocytosis is acti-
vated. Opsonins important in innate immunity and
acute inflammation include acute-phase proteins, lec-
tins (carbohydrate-binding proteins such as MBL), and
complement. With the activation of adaptive humoral
immunity, IgG and IgM antibodies can coat microbes
and act as opsonins by binding to receptors on neutro-
phils and macrophages. The adaptive immune response
can thus enhance the phagocytic function of innate cells.
Inflammatory Cytokines
The cytokines involved in innate immunity include
TNF-
α
; the interleukins IL-1, IL-6, and IL-12; interfer-
ons (IFN-
γ
, IFN-
α
, IFN-
β
); and chemokines (see Table
15-1). These cytokines serve various functions. They
influence the events of inflammation and innate immu-
nity by producing chemotaxis of leukocytes, stimulating
acute-phase protein production, inhibiting viral replica-
tion, and affecting the development of cells of the innate
and adaptive immune systems. A leukocyte exposed to
an external stimulus (e.g., bacteria) can be activated
through appropriately triggered receptors (e.g., TLRs)
and can respond by secreting small amounts of cyto-
kines and other soluble mediators. If many cells are acti-
vated, the concentration of cytokines may be sufficient
to influence the function of tissues distant from the site
of infection, a true endocrine action. The short half-life
of cytokines ensures that an excessive immune response
and systemic activation do not usually occur.
Other cytokines important in innate immunity are
the interferons, so named because of their ability to
interfere with virus infections. Although macrophages
and NK cells are the major producers of these cytokines,
they can also be secreted by tissue cells. Interferon-
α
and interferon-
β
are classified as type I IFNs and are
made by fibroblasts and macrophages. They func-
tion to inhibit the replication of viruses and improve
the recognition of a virally infected cell by cells of the
adaptive immune response. Type I IFNs interact with
receptors on neighboring cells to stimulate the transla-
tion of an antiviral protein that affects viral synthesis
and its spread to uninfected cells. The actions of type
I IFNs are effective against different types of viruses
and intracellular parasites and are thus considered part
of innate immunity. Interferon-
γ
can activate macro-
phages in innate immunity and regulate lymphocytes
in adaptive immunity. Interferon-
γ
is the most impor-
tant cytokine produced by the T-helper 1 subclass of
T lymphocytes. It is a potent activator of macrophages
and enables them to destroy pathogens that prolifer-
ate in their vesicles. Interferon-
γ
also stimulates the
production of antibodies that promote phagocytosis of
microbes through the complement system.
In addition to their local effects, several of the inflam-
matory cytokines (e.g., TNF-
α
, IL-1, and IL-6) have
important long-range effects that contribute to host
defense. One of the most important of these is the ini-
tiation of the acute-phase response. This involves a shift
in the proteins synthesized by the liver into the plasma.
Two of these, MBL and C-reactive protein (CRP), are of
particular interest because they mimic the action of anti-
bodies of the adaptive immune response, but unlike anti-
bodies, these proteins have broad specificity for PAMPs
and depend only on the presence of cytokines for their
production. Mannose-binding lectin and CRP function as
opsonins as well as activators of the complement system.
The Complement System
The complement system is an important effector of both
innate and humoral immunity that enables the body to
localize and destroy infectious pathogens. The comple-
ment system, like the blood coagulation system, consists
of a group of proteins that are present in the circulation
as functionally inactive precursors. These proteins, mainly
proteolytic enzymes, make up 10% to 15% of the plasma
proteins. For a complement reaction to occur, the comple-
ment components must be activated in the proper sequence.
Uncontrolled activation of the complement system is pre-
vented by inhibitor proteins and the instability of the acti-
vated complement proteins at each step of the process.
There are three parallel but independent pathways
for recognizing microorganisms that result in activa-
tion of the complement system: the classical, the lectin,
and the alternative pathways. The
classical pathway
recognizes complement-fixing antibodies (IgG, IgM) of
adaptive immunity bound to the surface of a microbe
or other structure. The
lectin pathway
uses a plasma
protein called the
mannose-binding ligand
(MBL) that
binds to mannose residues on microbial glycoproteins
or glycolipids. It is a component of innate immunity,
as is the
alternative pathway
, which recognizes certain
microbial molecules in the absence of antibody.
The reactions of the complement systems can be
divided into three phases: (1) initial activation, (2)
amplification of inflammation, and (3) membrane attack
response (See Understanding the Complement System).
Although the classical, lectin, and alternative path-
ways differ slightly in the proteins they use in the initial
activation phase, all converge in the process by acting
on the key complement protein C3, essential for the
amplification phase. All generate a series of enzymatic
reactions that prompt enzymatic cleavage of C3 into
two fragments. The larger C3b fragment is a key opso-
nin that coats microbes and allows them to be phagocy-
tized after binding to the type 1 complement receptor on
leukocytes. The smaller C3a fragment triggers an influx
of neutrophils to enhance the inflammatory response.
Production of C3a and C5a also leads to the activation
of basophils and mast cells and the release of inflam-
matory mediators that produce smooth muscle contrac-
tion, increased vascular permeability, and changes in
endothelial cells to enhance migration of phagocytes.
The late phase of the complement cascade triggers the
assembly of a membrane attack complex (MAC) made
up of complement proteins C5 to C9. As its name sug-
gests, the membrane attack complex leads to the lytic
destruction of many kinds of cells, including bacteria
and altered blood cells. The multiple functions of the
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