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Overview of the Immune
Response
The Immune System Seen in the
Context of the Response to Infectious
Agents
Extracellular Bacteria
Bacteria that replicate outside of host cells
Circulation
Connective tissue
Tissues spaces such as airways and intestinal lumen
Extracellular Bacteria
Bacteria that replicate outside of host cells
Examples:
Streptococcus pneumoniae
E. coli
Staphylococcus aureus
Extracellular Bacteria
Induce Inflammation
Produce toxins
Endotoxins- products of bacterial cell walls such as LPS
Exotoxins which are actively secreted
cytotoxic
interfere with cell function without death
induce cytokine production
Extracellular Bacteria
Upon exposure to the infectious agent the innate immune system is
activated
Extracellular Bacteria
Upon exposure to the infectious agent the innate immune system is
activated
Complement can be directly activated
C1q binds directly to bacteria
Mannan binding lectin binds the pathogen
Alternative pathway
Cleavage products of complement function
as opsonins
C3a , C4a and C5a areanaphylatoxins
Small peptides that causes smooth muscle contraction,
increases vascular permeability and mast cell and
basophil degranulation.
C5a is also a chemoattractant and activator of WBC
Also amplify the inflammatory response by inducing
the synthesis of pro-inflammatory cytokines.
Their receptors are present on many cell types
including leukocytes, mast cells, macrophages,
endothelial cells, astrocytes and microglial cells
Form membrane attack complex: only Gram negative lyse
Phagocytes have receptors that directly recognize bacteria and
lead to phagocytosis, activation, microbicidal activity and cytokine
secretion
Macrophage Has Many
Activation
Receptors
Engulfment
LPS
receptor
(CD14)
Scavenger
receptos
Mannose
receptor
CD11b/
CD18
TLR
TLR
Fc receptors
Cytokine Secretion
TNF and IL-1: inflammation and leukocyte recruitment
IL-12: TH1 differentiation and IFN-g production
Antigen presentation
ADAPTIVE IMMUNITY
Adaptive immunity is triggered when an infection eludes the
innate defense mechanism and generates a threshold of antigen.
It becomes effective only after several days, the time required
to have antigen-specific T and B cells proliferate
and differentiate into effector cells.
The first step is the activation of T
cells in the draining lymphoid organ.
T cells do not become sensitized
in peripheral tissue.
Antigens in tissues are trapped in
draining lymph nodes; antigens in the
blood are taken to the spleen where the
immune response in initiated in the
white pulp.
Ag uptake by Langerhans' cells
Langerhans' cell leave skin, enter lymphatics and move to
lymph nodes to become dendritic cells expressing B7
=APCs
B7-positive dendritic cells
stimulate T cells
Naive T cells continually recirculate through
the lymphoid organs
If a naive T cell recognizes it antigen, LFA-1
is activated causing the T cell to adhere
strongly to the APC and cease migration
During the initial response of naïve CD4+ T cells to Ag,
differentiation into TH1 or TH2 occurs and has a critical
impact on the outcome of an adaptive immune.
This differentiation is influenced by the cytokines that
are present.
CD4 T cells develop into TH2 cells if
activated in the presence of IL-4,
especially if IL-6 is present . IL-4 and IL10 inhibit the differentiation of TH1. IL-4
from the early response may be from
NK1.1+ CD4 cells.
CD4 T cells develop into TH1 cells if
activated in the presence of IL-12 and
IFN-g. INF- g inhibits differentiation of
TH2 cells . IL-12 and INF- g are
produced by macrophages and NK
cells.
Activation of B cells takes place in secondary lymphoid organs
B cells specific for protein Ags cannot be activated until they encounter an activated
helper T cell. B cells migrate through peripheral lymphoid organs like T cells. If
they encounter Ag-specific helper T cells, they are activated to proliferate and
differentiate
Humoral immunity provides the principal
protective immune response against
extracellular bacteria
Humoral immunity provides the principal
protective immune response against
extracellular bacteria
Innate:
T independent response against polysaccharide Ags
Humoral immunity provides the principal
protective immune response against
extracellular bacteria
Innate:
T independent response against polysaccharide Ags
Adaptive:
T dependent response against protein Ags
Neutralization of toxins by high affinity IgG andIgA
Opsonization through Fc receptors
Complement activation by IgM and some subclasses
of IgG
Receptors for Fcs of IgG and for cleavage produces of complement are
important for the clearance of extracellular bacteria
Intracellular Bacteria
Eliminated by cell mediated immunity
Examples:
Mycobacterium tuberculosis
Listeria monocytogenes
Mycobacterium leprae
Intracellular Bacteria
Eliminated by cell mediated immunity
Innate immune response consists mainly of phagocytes
and NK cells
NK cells activated either directly or by IL-12
produced by macrophages
The major protective immune response is
cell mediated
Macrophage activation by T cells (IFN- g)
Lysis of infected cells by CTLs
If IL-12 and IFN-g are produced following the initial exposure to the
pathogens the response will be dominated by inflammatory T cells
Both IL-12 and IFN-g are critical for defense
against an intracellular bacterial infection
The differential capacity of a pathogen to interact with dendritic cells,
macrophages, NK and NK1.1+ T cells influences the overall balance
of the cytokines present early in the immune response and thus
determines whether TH1 or TH2 cells develop preferentially
Since inflammatory T cell cytokines make more inflammatory cells and
helper make more helper there tends to be amplification
TH1/TH2 decision can determine the
outcome of infection
For example, most mice mount a TH1 response
to Leishmania major and clear the infection.
However BALB/c mice mount a TH2 response
and die of disseminated disease.
However, note as pointed out in class Leismania
is a protozoan parasite, not a bacterium.
Nevertheless, the immune issues remain the
same.
Viruses
Replicate within cells
Cytopathic - cause cell lysis
Noncytopathic - latent
Innate Immunity to Viruses
Inhibition of infection by type 1 IFNs
double stranded RNAs engage Toll-like
receptors and trigger production
NK cell-mediated killing
Recognize stress-induced proteins
Viral infection frequently decreases class I
MHC expression
Adaptive Immunity to Viruses
Antibodies
block virus binding and entry into cell
CTLs
eliminate the infection by killing infected cells
Adaptive Immunity to Viruses
Antibodies- effective during extracellular stage
neutralizing Abs prevent virus attachment
and entry
opsonize viral particles and promote clearance
by phagocytes through Fc or C3b receptors
Adaptive Immunity to Viruses
Antibodies- effective during extracellular stage
effective in containing the spread of a virus
during acute infection and in protecting
against reinfection
sIgA in mucosal secretions plays an important
role by blocking viral attachment to mucosal
epithelial cells
complement activation may promote direct lysis
of viruses with lipid envelopes
Adaptive Immunity to Viruses
Antibodies- effective during extracellular stage
While antibodies block viral infection of cells
and spread of viruses from cell to cell, once
the virus enters the cell it is inaccessible to
antibodies and infected cells must be eliminated
by CTLs
Adaptive Immunity to Viruses
CTLs
CD8+ T cells recognize cytosolic, usually
endogenously synthesized viral Ags in
association with class I MHC
Adaptive Immunity to Viruses
CTLs
CTL activation requires co-stimulation.
If the virally infected cell is not a
professional APC, it may be
phagocytosed by one.
CD8+ T cells recognize cytosolic, usually
endogenously synthesized viral Ags in
association with class I MHC
Adaptive Immunity to Viruses
CTLs
CTL activation requires co-stimulation.
If the virally infected cell is not a
professional APC, it may be
phagocytosed by one
CD8+ T cells recognize cytosolic, usually
endogenously synthesized viral Ags in
association with class I MHC
full differentiation of CTLs requires
cytokines produced by CD4+ helper
cells
Activated CTLs differentiate
into effectors CTLs that can kill any infected
nucleated cell (Ag specific)
Adaptive Immunity to Viruses
CTLs
In some viral infections, especially with noncytopathic viruses, CTLs may be responsible
for tissue injury
T-cell deficient mice become chronic carriers of
LCMV
Normal mice develop meningitis because
virus-specific CTLs kill infected meningeal cells
Immunity to Parasites
There is a wide range of animal parasites
including protozoa (which are small) and the
helminths (large worms)
Immunity to Parasites
Parasites currently account for greater morbidity
and mortality than any other class of infectious
organism, particularly in developing countries
30% of the world’s population suffers from
parasitic infection
Malaria alone affects more than 100 million
people, killing 1 million annually
Innate Immunity to Parasites
Principal innate response is phagocytosis; however
many parasites are resistant to phagocytosis and
may even replicate within macrophages
Innate Immunity to Parasites
Phagocytes attack helminthic parasites and secrete
microbicidal substances to kill organisms too large
to be phagocytosed
Many helminths have thick teguments that make
them resistant to cytocidal mechanisms of
neutrophils and macrophages
Although some helminths activate the alternative
pathway of complement, many appear to have
developed resistance to complement-mediated lysis
Adaptive Immunity to Parasites
Different parasites elicit distinct adaptive immune
responses
Pathogenic protozoa have evolved to live within
host cells.
The principal defense mechanism against
protozoa that survive within macrophages
is cell mediated immunity, particularly macrophage
activation by TH1-derived cytokines
Mice resistant to Leishmania produce large amounts of IFN-g.
BALB/c, which are susceptible, respond to Leishmania infection
with the production of IL-4.
Immunity to trypanosomes is mediated by antibodies.
Trypanosomes have developed the ability to change the expression
of their surface antigen, thereby evading the immune response
Protozoa such as malaria that replicate
within host cells and lyse these cells
stimulate specific antibody and CTL
responses
The defense against many helminthic infections is mediated by the
activation of TH2 cells which results in the production of IL-4 and
IL-5 leading to IgE production and eosinophil activation
Eosinophils attached through Fce receptors are activated to secrete
granule enzymes that destroy the parasites
Protective Immunity
Immunity to re-infection
Immune reactants such as Ab
Armed effector T cells
Protective Immunity
Immunity to polio requires pre-existing Ab to
prevent neuron infection
Specific IgA on epithelial surfaces can
neutralize a virus before it enters the body
Concentration (gml-1)
Immunologic Memory
IgG
Affinity (M-1)
IgM
IgG
IgM
Immunization
Are slightly increased in number relative to what is seen before
Immunization
Express markers characteristic of activated cells such as CD44
The isoform of CD45 that is expressed changes
CD45RA is on naïve T cells
CD45RO is present on memory cells