Page 66 - Review of Medical Microbiology and Immunology ( PDFDrive )

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CHAPTER 8 Host Defenses
55
As part of the inflammatory response, bacteria are
Poor
engulfed (phagocytized) by polymorphonuclear neutrophils
phagocytosis
nor C3b
(PMNs) and macrophages. PMNs make up approximately
60% of the leukocytes in the blood, and their numbers
bacterium
increase significantly during infection (leukocytosis). It
should be noted, however, that in certain bacterial infections
such as typhoid fever, a decrease in the number of leukocytes
+
Enhanced
Neutrophil
+
Antibody
and/or C3b
phagocytosis
(leukopenia) is found. The increase in PMNs is due to the
Encapsulated
production of granulocyte-stimulating factors (granulocyte FIGURE 8–3 Opsonization. Top: An encapsulated bacterium is
bacterium
colony-stimulating factor [G-CSF] and granulocyte-macro-
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phage colony-stimulating factor [GM-CSF]; see Chapter 58)
poorly phagocytized by a neutrophil in the absence of either immu-
by macrophages soon after infection.
Note that although both PMNs and macrophages
either IgG antibody or C3b or both, the bacterium is opsonized
phagocytose bacteria, PMNs do not present antigen to
(i.e., it is made more easily phagocytized by the neutrophil).
helper T lymphocytes, whereas macrophages (and den-
dritic cells) do (see Chapter 58). Dendritic cells are the
antibody, the C3b component of complement, which can
most important antigen-presenting cells. The phagocytic
be generated by the “alternative” pathway, can opsonize.
ability of dendritic cells is enhanced by the presence of
This is particularly important for bacterial and fungal
receptors for mannose-binding protein.
The process of phagocytosis can be divided into three
pathway of complement.
steps: migration, ingestion, and killing. Migration of
At the time of engulfment, a new metabolic pathway,
PMNs to the infection site is due to the production of che- organisms whose polysaccharides activate the alternative
known as the respiratory burst, is triggered. This results in
mokines, such as interleukin-8 and complement compo-
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the production of two microbicidal agents, the superoxide
nent C5a, at that location. Adhesion of PMNs to the
radical and hydrogen peroxide. These highly reactive com-
endothelium at the site of infection is mediated first by the
interaction of the PMNs with selectin proteins on the
synthesized by the following reactions:
endothelium and then by the interaction of integrin pro-
teins called “LFA proteins,” located on the PMN surface,
−
−
O + e → O
2
2
with intracellular adhesion molecule (ICAM) proteins on
+
−
1
the endothelial cell surface.
2O + 2H → H O + O
2
2
2
2
ICAM proteins on the endothelium are increased by
In the first reaction, molecular oxygen is reduced by an
inflammatory mediators, such as IL-1 and TNF (see
Chapter 58), which are produced by macrophages in
oxidase) to form the superoxide radical, which is weakly
response to the presence of bacteria. The increase in the
bactericidal. In the next step, the enzyme superoxide dis-
level of ICAM proteins ensures that PMNs selectively
mutase catalyzes the formation of hydrogen peroxide from
adhere to the site of infection. Increased permeability of electron by NADPH oxidase (also known as phagocyte
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two superoxide radicals. Hydrogen peroxide is more toxic
capillaries as a result of histamine, kinins, and prostaglan-
than superoxide but is not effective against catalase-pro-
2
dins allows PMNs to migrate through the capillary wall to
ducing organisms such as staphylococci. Hydrogen perox-
reach the bacteria. This migration is called diapedesis and
takes several minutes to occur.
most powerful of the microbicidal substances (see later).
The bacteria are ingested by the invagination of the
Nitric oxide (NO) is another important microbicidal
PMN cell membrane around the bacteria to form a vacuole
agent. It is a reactive nitrogen intermediate that is synthe-
(phagosome). This engulfment is enhanced by the binding
sized by an inducible enzyme called nitric oxide synthase in
of immunoglobulin G (IgG) antibodies (opsonins) to the
response to stimulators such as endotoxin. Overproduction
surface of the bacteria, a process called opsonization
(Figure 8–3). The C3b component of complement is
because it causes vasodilation of peripheral blood vessels.
another important opsonin. (The outer cell membranes of
The respiratory burst also results in the production of
both PMNs and macrophages have receptors both for the
the microbicidal agent–NO. NO contains a free radical that
Fc portion of IgG and for C3b.) Even in the absence of of NO contributes to the hypotension seen in septic shock
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participates in oxidative killing of ingested microbes phago-
cytosed by neutrophils and macrophages. Nitric oxide
synthase, the enzyme that produces NO, is induced in these
1
LFA proteins and ICAM proteins mediate adhesion between many types of
The killing of the organism within the phagosome is a
cells. These proteins are described in more detail in Chapter 58.
two-step process that consists of degranulation followed by
2
The anti-inflammatory action of aspirin is the result of its ability to inhibit
production of hypochlorite, which is probably the most
cyclooxygenase, thus reducing the synthesis of prostaglandins.
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