Overview of the Immune Response

1
Overview of the Immune Response

• The Immune System Seen in the Context of the
  Response to Infectious Agents

2
Extracellular Bacteria
Bacteria that replicate outside of host cells
Circulation Connective tissue Tissues spaces such
as airways and intestinal lumen
3
Extracellular Bacteria
Bacteria that replicate outside of host cells
Examples Streptococcus pneumoniae E.
coli Staphylococcus aureus
4
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
5
Extracellular Bacteria
Upon exposure to the infectious agent the innate
immune system is activated
6
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
7
(No Transcript)
8
Cleavage products of complement function as
opsonins
9
(No Transcript)
10
Form membrane attack complex only Gram negative
lyse
11
Phagocytes have receptors that directly recognize
bacteria and lead to phagocytosis, activation,
microbicidal activity and cytokine secretion
TNF and IL-1 inflammation and leukocyte
recruitment
IL-12 TH1 differentiation and IFN-g production
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
APCs
16
(No Transcript)
17
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.
18
(No Transcript)
19
(No Transcript)
20
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
21
Humoral immunity provides the principal
protective immune response against
extracellular bacteria
22
Humoral immunity provides the principal
protective immune response against
extracellular bacteria
Innate T independent response against
polysaccharide Ags
23
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
24
Effector mechanisms of Abs
Neutralization of toxins by high affinity IgG
andIgA
Opsonization through Fc receptors
Complement activation by IgM and some subclasses
of IgG
25
Receptors for Fcs of IgG and for cleavage
produces of complement are important
for the clearance of extracellular bacteria
26
Intracellular Bacteria
Eliminated by cell mediated immunity
Examples Mycobacterium tuberculosis Listeria
monocytogenes Mycobacterium leprae
27
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
28
(No Transcript)
29
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
30
Both IL-12 and IFN-g are critical for defense
against an intracellular bacterial infection
31
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
32
Since inflammatory T cell cytokines make more
inflammatory cells and helper make
more helper there tends to be amplification
33
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.
34
Viruses
Replicate within cells
Cytopathic - cause cell lysis
Noncytopathic - latent
35
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
36
Adaptive Immunity to Viruses
Antibodies
block virus binding and entry into cell
CTLs
eliminate the infection by killing infected cells
37
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
38
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
39
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
40
Adaptive Immunity to Viruses
CTLs
CD8 T cells recognize cytosolic, usually
endogenously synthesized viral Ags in
association with class I MHC
41
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
42
Adaptive Immunity to Viruses
CTLs
full differentiation of CTLs requires cytokines
produced by CD4 helper cells
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
43
Activated CTLs differentiate into effectors CTLs
that can kill any infected nucleated cell (Ag
specific)
44
Adaptive Immunity to Viruses
CTLs
In some viral infections, especially with
non- cytopathic 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
45
Immunity to Parasites
There is a wide range of animal parasites
including protozoa (which are small) and the
helminths (large worms)
46
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 worlds population suffers from
parasitic infection
Malaria alone affects more than 100 million
people, killing 1 million annually
47
Innate Immunity to Parasites
Principal innate response is phagocytosis
however many parasites are resistant to
phagocytosis and may even replicate within
macrophages
48
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
49
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
50
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.
51
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
52
Protozoa such as malaria that replicate within
host cells and lyse these cells stimulate
specific antibody and CTL responses
53
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
54
Eosinophils attached through Fce receptors are
activated to secrete granule enzymes that
destroy the parasites
55
(No Transcript)
56
(No Transcript)
57
(No Transcript)
58
(No Transcript)
59
Memory T cells

• 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

60
(No Transcript)
61
(No Transcript)