Download Immunity to infection

Immunity to infection
involves a constant battle between
the host defenses and the mutant
microbes trying to evolve evasive
strategies. Specific acquired responses
amplify and enhance innate immune
mechanisms.
Inflammation revisited
• Inflammation is a major defensive
reaction initiated by
infection or tissue injury.
The acute inflammatory response
• The mediators released upregulate
adhesion molecules
such as P-selectin on endothelial cells.
These pair with
ligands on leukocytes, initially causing
rolling of leukocytes
along the vessel wall and then passage
across the
blood vessel up the chemotactic gradient
to the site of
inflammation.
• Under the influence of interleukin-1
(IL-1) and tumor
necrosis factor (TNF), ICAM-1
(intercellular adhesion
molecule-1) is induced on endothelial
cells and binds to integrins
on polymorphonuclear neutrophil
(PMN) surfaces
causing their arrest.
• Macrophages and mast cells present in
the inflamed
tissue are activated and release a variety
of mediators,
cytokines and chemokines. Endothelial
cells themselves
may release cytokines and chemokines.
• Activated granulocytes and
macrophages easily phagocytose
organisms coated with antibody and
complement
proteins.
• Cytokines such as transforming
growth factor-b (TGFb)
and IL-10 are powerful regulators of
inflammation and
endogenous glucocorticoids.
• When tissue is severely traumatized,
TGFb may stimulate
fibroblasts to lay down collagen forming
scar tissue,
which is the end result of many
inflammatory events.
• Inability to eliminate the initiating
agent leads to a
chronic inflammatory response
dominated by macrophages
and often forming granulomas.
Extracellular bacteria susceptible to
killing by phagocytosis
and complement
• Bacteria try to evade the immune
response by surrounding
themselves with capsules to avoid
phagocytosis,
secreting exotoxins which kill
phagocytes or impede
inflammatory reactions, resisting
insertion of the complement
membrane attack complex, or by
secreting enzymes
which destroy C5.
• Antibody combats these tricks by
neutralizing the toxins,
and by overcoming the antiphagocytic
nature of the
capsules by opsonizing them with
immunoglobulin G
(IgG) and C3b.
• Antigen-presenting cells (APCs) have
receptors for
microorganisms, such as the Toll-like
receptors (TLRs),
which when activated lead to the
production of proinflammatory
cytokines.
• Mannose binding lectin (MBL) binds
to mannose on
bacterial surfaces. In association with
MASP-1 and MASP2 it leads to a further pathway of
complement activation.
• Complement activation is controlled
by a number of inhibitory
proteins and by various complement
receptors.
Protection of mucosal surfaces
• Defensins are antimicrobial proteins
produced by
macrophages and mucosal cells. Their
production is upregulated
by proinflammatory cytokines.
• The secretory immune system protects
the external
mucosal surfaces. Immunoglobulin A
inhibits adherence
of bacteria and can opsonize them.
• Immunoglobulin E bound to mast cells
can be found
in mucosal tissue. In contact with
antigen it will cause
degranulation of the mast cells. This
initiates release of
mediators which generate a local
inflammatory reaction.
Bacteria which grow in an intracellular
habitat
• Intracellular bacteria such as tubercle
and leprosy
bacilli grow within macrophages.
• They are killed by cell-mediated
immunity (CMI):
specifically sensitized T-cells become
activated and release
interferon g (IFNg) which activates the
macrophage
to kill the organisms.
• When intracellular organisms are not
destroyed, a
chronic inflammatory reaction will lead
to the formation
of a macrophage rich granuloma.
Immunity to viral infection
• Infected cells release type 1 interferons
which have
antiviral activity.
• Natural killer (NK) cells are activated
by IFNg and IL-2.
They can now attack virally infected
cells which have
(continued)
126 PART 4—Immunity to infection
FURTHER READING
Bloom, B. & Zinkernagel, R. (1996)
Immunity to infection. Current
Opinion in Immunology, 8, 465–6.
Brandtzaeg, P. (1995) Basic mechanisms of
mucosal immunity: A
major adaptive defense system. The
Immunologist, 3, 89–96.
Finkelman, F.D. & Urban, J.F. (2001) The
other side of the coin: The
protective role of the Th2 cytokines. Journal
of Allergy and Clinical
Immunology, 107, 772–80.
Ley, K. (2002) Integration of inflammatory
signals by rolling
neutrophils. Immunological Reviews, 186, 8–
18.
Nathan, C. (2002) Points of control in
inflammation. Nature, 420,
846–52.
Price, D.A., Klenerman, P., Booth, B.L.,
Phillips, R.E. & Sewell, A.K.
(1999) Cytotoxic T lymphocytes,
chemokines and antiviral immunity.
Immunology Today, 20, 212–16.
Rappuoli, R., Pizza, M., Douce, G. &
Dougan, G. (1999) Structure and
mucosal adjuvanticity of cholera and
Escherichia coli heat-labile
enterotoxins. Immunology Today, 20, 493–
500.
downregulated major histocompatibility
complex (MHC)
class 1 expression.
• Antibody neutralizes free virus and is
particularly effective
when the virus has to travel through the
bloodstream
before reaching its final target.
• Antibody is important in preventing
reinfection.
• “Budding” viruses that can invade
lateral cells without
becoming exposed to antibody are
combated by CMI. Infected
cells express a processed viral antigen
peptide on
their surface in association with MHC
class I.
• Rapid killing of the cell by cytotoxic ab
T-cells prevents
viral multiplication.
• Cytokines produced by CD4+ and
CD8+ cells activate
APCs and control the replication of
virus particles.
• Natural infection generates specific
antibody and Tcytotoxic
(Tc) cells with subsequent long-term
protection
against reinfection.
Immunity to fungi
• Fungal infections are common in
individuals with neutrophil
dysfunction and in patients with
defective CMI.
Immunity to parasitic infections
• Chronic parasitic infection can cause
exaggerated immune
responses leading to severe tissue
injury.
• Antibodies are usually effective
against the bloodborne
t cells.
parasitic diseases.
• Most parasitic infections stimulate a
Th2 response, with
IgE production and eosinophilia. These
are important in
destruction of parasites such as
schistosomes, which when
coated with IgG or IgE are killed by
adherent eosinophils
through the mechanism of antibodydependent cellular
cytotoxicity (ADCC).
• Organisms such as Leishmania spp.,
Trypanosoma cruzi
and Toxoplasma gondii hide from
antibodies inside
macrophages and use the same
strategies as intracellular
parasitic bacteria to survive. Like them,
they are killed
when the macrophages are activated by
cytokines produced
during CMI responses.
• Cytokines produced by Th2 cells are
important in the
expulsion of gastrointestinal worms and
in destroying
larval forms. They may also protect
against ectoparasites