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Immunological memory
Antigen-antibody complex can be retained on FDC
for long periods of time and cause periodic
activation of B cells.
Memory T and B cells.
The death of activated T effector cells.
Involves FAS and FasL. Defects in Fas and FasL
cause lymphoproliferative and autoimune phenotype
(lpr and gld) in mice.
In humans, this defect causes ALPS (autoimmune
lymphoproliferative syndrome).
The patients are characterized with enlarged
spleen and lymph nodes with no overt signs of
infection. Have elevated levels of
immunoglobulin in serum and develop
autoantibodies.
FasL
Predisposed to develop lymphomas.
The genetic defect is in Fas gene. The mutation
is dominant negative. Activaeted T and B cells do
not undergo Fas-mediated apoptosis.
Fas is a trimer
One mutant copy renders the receptor inactive
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Immune Response to Virus
Innate immunity
Virus
Infected cells
M?, DC
MHC I
IFN-???
IL12, IL18
Stimulatory ligand
IL15
Inhibit protein sythesis Apoptosis of infected
cell
NK cells
IFN-?
Lysis of infected cell
Activate antigen presentation Promote TH1 response
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Adaptive Immunity
Virus
DC
B cell
CD4 T cell
CD8 T cell
IL12 IFN-?
CTL
TH1
Activated B cells
IL2
Lysis of infected cell
IFN-?
antibodies
neutralization
complement
T cell proliferation
Antigen Presentation IgG2a
ADCC
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Superantigen
Viral superantigen mouse mammary tumor virus,
rabies virus, Epstein-Barr virus
Bacteria superantigen staphylococcal
enterotoxins (SEs, foodpoisoning) toxic shock
syndrome toxin-1 (TSST-1, toxic shock syndrome)
Superantigens crosslink class II MHC with TCR V?
chain.
The interaction is independent of Peptide
sequence.
Each superantigen can bind 2-20 of all T cells.
Superantigens are not processed and presented by
MHC.
Superantigens can cause massive activation of CD4
T cells, which release cytokines (IFN-?, TNF-?)
and activate macrophages to release inflammatory
cytokines (IL1, TNF-?) These cytokines cause the
toxic shock syndrome (similar to septic
shock). The massive activation of CD4 T cells
eventually lead to their death, and cause
immunol suppression, which aid the propagation of
pathogens.
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Latent viral infection
Latent viruses do not replicate, do not cause
disease, and are not detected by the immune
system. These laten viruses are activated when
immune system is weakened.
Herpes simplex viruses establish latency in
sensory neuron. environmental stress or decrease
in immune function reactivate the virus to cause
cold sores.
Epstein-Barr virus (EBV, herpes virus) establish
latency in B cells. It produces EBNA-1, which is
needed for replication. But EBNA-1 inhibits
proteasome processing and antigen
presentation. Some of these infected cells can be
transformed. When T cell function is
compromised, they could develop into B cell
lymphomas (Burkitts lymphoma).
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Mutation as evasion strategy
Influenza virus
H5N1, H1N1, etc
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Evasion by hiding
Neurons produce very low levels of class I
MHC. Viruses (Rabies virus) are not effectively
recognized by T cells
Destruction of Immune Cells
HIV destroyes CD4 T cells. HBV kills CD8 effector
T cells that are specific for HBV infected
hepatocytes.
Interference with cytokine function
EBV, HCMV produces IL-10 like molecules to
inhibit TH1 resposne. Some viruses express
mimetics of IFN, IL2.
Downregulation of class I MHC
Inhibition of transcription, intererence with
peptide transport by TAP, targeting of Newly
synthesized class I MHC for degradation, and
rapid turnover of surface expressed MHC.
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Immune Response to Parasite
Protozoa
Protozoa infection generally has both
extracellular and intracellular stages.
Plasmodium (malaria)
Travel through blood circulation Infect
hepatocytes and RBC.
Trypanosoma (African sleeping sickness)
Multiply in blood. Establish infection in
central Nervous system.
Leishmania (Leishmaniasis)
Infect macrophages.
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Complements represent the first line of defense
during the extracellular stage of infection.
Protozoa evolved many evasion strategies for
complement.
Trypanosoma cruzi expresses gp160, which is
homologous to host DAF.
Bb
Decay accelerating factor (DAF)
Bb
C3b
Human cell
Leishmanias plasma membrane contains long
lipophosphoglycans that prevent the insertion of
MAC
Entamaeba histolytica produces a lectin
(Gal.GalNAc) that is similar to CD59.
Homologous restriction factor (HRF) and CD59
C9
C5b,6,7,8
Human cell
Prevents the recruitment of C9
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Leshmania utilize complement activation to
infect macrophage.
Leishmania expresses gp63 (protease) that cleaves
C3b into iC3b.
gp63
C3b
iC3b
No further complement activation
Leishmania
Phagocytosis through complement receptors (CR1
and CR3)
Phagocytosis through complement receptor does not
activate respiratory burst to produce ROI and
RNI. Leishmania survive and establish infection.
Macrophage
T. cruzi expresses a homolog of C9 that disrupt
the phagosome membrane and escape into the
cytoplasm.
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Recognition of protozoa GPI by M? and DCs induce
the production of cytokines (IL12, IL18, TNF-?).
protein
Different carbohydrates and lipids have
Different potency in eliciting cytokine
synthesis.
p
carbohydrates
inositol
p
lipids
membrane
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NK cells can be activated by IL12, IL18, TNF-?
from macrophages and DCs.
Activated NK cells secret IFN-?, which activates
macrophages to kill infected parasite.
Parasite infection tends to induce polarized TH1
or TH2 response
Leishmania major infection
TH1 response is critical for controlling the
infection by producing IFN-? to
activate macrophage. Activated macrophage produce
high levels of RNI (induction of iNOS). The
production of IL12 and IFN-? promotes the TH1
differentiation.
Some strains of mouse (Balb/c) tends to develop
TH2 response. IL4, IL10, IL13, TGF-g (Th2
cytokines) inhibit iNOS. These mice suffer severe
disseminated infection.
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Similarity to immune response to intracellular
bacteria
TH1 mediated immune response is critical for
controlling intracellular bacteria.
Mycobacterium leprae (leprosy)
Lepromatous leprosy TH2 response (IL4, IL5,
IL10) Cell-mediated immunity is depressed and M.
leprae infected cells are abundant. Bacteria
are widely disseminated. Tuberculoid
leprosy TH1 response (IL2, IFN-?,
TNF) Cell-mediated immunity with macrophage
activation controls the infection. Infection is
contained within granuloma with local damage.
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IFN-? can induce other effector functions.
IFN-? induce IGTP family of GTP binding proteins.
Mice deficient in IGTP are highly susceptible
to infection with T. gondii, while developing a
normal IFN-g response. The mechanism of these
proteins are unclear.
IFN-? induce indolamine 2,3 dioxygenase that
catabolizes tryptophan, an essential amino acid
for the growth of protozoan.
CTL mediate lysis of infected cells.
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Antibodies are more important when the
parasite have more extended extracellular stages
in their life cycle (e.g. Tranpanosoma in blood).
Neutralization complement opsonin
Antibodies are also important when the infected
cells are nonphagocytic and low in Antigen
presenting ability (e.g. RBC in plasmodium
infection)
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Plasmodium sp (malaria)
30 minutes in blood stream most accessible for
immune attack.
Plasmodium goes through a series of maturation
stages in their life cycle. They keep on changing
their host cells and surface antigens during the
different maturation stages. This makes it
difficult for immune recognition. It infects
nonphagocytic cells. RBC does not Express class
I, II MHC for antigen presentation.
Plasmodium undergoes clonal variation. Infected
RBCs express erythrocyte membrane protein-1
(PfEMP-1), which is encoded by members of the
var family of genes. These proteins allow the
infected cell to adhere to vascular endothelium
via host receptors. Brain and placenta are
preferred. These give rise to servere cerebral
and pregnancy malaria. Cytoadherence prevents
the passage of infected RBC through the spleen
and recognized as damaged or foreign and removed
from circulation.
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Trypanosoma sp. (African sleeping sickness)
Strong B cell response during growth in blood
stream
Effective antibody response control the
multiplication. (complement activation and
opsonizaton For phagocytosis) New variants arise
to escape the recognition by the antibodies. This
generates successive waves of parasitemia.
Trypanosoma brucei contains more than 1000 VSG
genes.
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Immune response to helminth
Schistosoma infection
Free swimming infectious larvae
Enter through skin
schistosomules
Blood circulation
snail
Primary infection sites
Intestinal veins, bladder veins, etc
Mature male and female worms
eggs
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Eosinophils may contribute to defense against
helminth.
Bilobed nucleus Granulated cytoplasm Stains with
acid dye (eosin red)
1-3 of leukocytes in blood Found mostly in
tissues (respiratory, intestinal, Genitourinary
tracts)
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Mast cells and basophils
Mast cell
The precursor is not clear.
Contain cytoplasmic granules.
Found in vasularized connetive Tissues.
basophil
Cytoplasmic granules that stain with Basic
dye. Circulate in blood (lt1 of leukocyte)
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IgE
Helminth infection induces strong TH2 response
IL4 IL10 IL13 TGF-?
?
IgE, IgA, IgG1
B cell
TH2
CD4 T cells
Helminth
DCs
IL-4
TGF-?
IFN-?
IL-4
Mouse IgH
V(D)J
?2a
??
?3
?1
?2b
??
?
?
Elevated IgE levels are associated with infection
by helminth.
Mast cells, basophils, eosinophils have high
affinity receptors (Fc?RI) for IgE.
When IgEs bound to Fc?RI are crosslinked by
multivalent antigens, they induce the Activation
and degranulation of mast cells, basophils and
eosinophils.
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Crosslinking of IgE induces degranulation of mast
cells.
Mast cell activation induces the Release of many
inflammatory Mediators (TNF-a,
histamines, Prostaglandins, leukotrienes). Mast
cell also produces IL-4, IL5, IL13, which
stimulates TH2 response..
Similar process for basophils
The inflammatory mediators recruit Other immune
functions and induce Muscular contraction to
physically expel the parasite from gut.
Mast cells accumulate at the site of helminth
infection (mastocytosis).
Mice deficient in mast cells, basophils are more
susceptible to intestinal nematode infection.
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Crosslinking of IgE, IgG, IgA bound to Fc
receptors of eosinophils induce activation and
degranulation.
Major basic proteins Eosinophil cationic
proteins Eosinophil-derived neurotoxic proteins
These proteins are highly toxic to helminth.
Eosinophils can efficiently kill schistosome
larva coated with antibodies (IgE, IgG or IgA).
Helminth infection leads to the accumulation of
eosinophils in blood and tissues
(eosinophilia). Infected tissues contain
degranulated eosinophils. Depletion of
eosinophils by antisera or IL5 deficiency
decreases immune response to certain helminth
infection.
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IgE and eosinophls may not be involved in the
immune response to some helminth infections.
Trichuris muris a parasite in mouse (related to
human whipworm).
TH2 response are important for immunity against
the infection.
Resistant mouse strains generate TH2
response. Susceptible mouse strains generate TH1
response.
IL4 can cure primary infection. Deficiency in
IL4, IL10, IL13 severely compromise immune
response to the infection.
IgE is not required for the immune response in
mice, but appears to play a role in rat.
Eosinophils are not required for the immune
response.
It is not clear what the role TH2 cytokines play.
IL4 affects intestinal physiology, causing
increased muscle contraction and mucous secretion.
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Immune response to cancer
Localized (benign)
mutation
Tumor cells
Normal cell
Loss of growth control
(transformation)
Invasive (malignant)
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Tumor rejection in mouse
Irradiated tumor cells induce immune
response toward the tumor.
Mouse
carcinogen
tumor
Mouse (inbred, same MHC allotype)
Tumor
The protection can be transferred by T cells,
not by serum.
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Tumor antigens
Tumor specific transplantation antigens (TSTAs)
Mutations alters the normal cellular protein to
create new antigenic peptide.
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Idiotypic sequence of antigen receptor is TSTA
for B and T cell tumors.
Difference of the same IgC region
between different alleles in a population.
Difference between different antigen binding
sites Antigen receptors may remain expressed by
the B and T cell tumors. The antigen binding
site is a unique feature (antigen) for the
tumor.
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Tumor associated transplantation antigens (TATAs)
Tumor cells can express proteins of male germ
cells.
Male germ cells do not express MHC and do not
normally present these antigens.
Reactivation of genes normally expressed during
embryonic development.
Oncofetal tumor antigens (alpha-fetoprotein, AFP
carcinoembryonic antigen, CEA)
Overexpression of normal self antigen.
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Immune surveillance?
Tumors may not present tumor antigen/MHC.
Tumors tend to be genetically unstable and may
lose the Expression of MHC or the tumor
antigen. Such variants would have selective
advantage.
Brown staining HLA
Many cells in the prostate cancer section have
lost MHC expression.
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MHC-loss variants could become a target for NK
cells.
Nude mice are deficient In T cells. They have
higher levels of NK cells.
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Antibodies can modulate tumor antigens.
Antibody binding to tumor antigens could induce
endocytosis and degradation of the antigen.
Antigen presentation in the absence of
co-stimulation may cause T cell anergy.
Tumors do not induce inflammation. Inflammatory
cytokines are needed to activate APCs to express
co-stimulatory molecules.
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Tumors may suppress immune response.
Many tumors produce immunosuppressive cytokines
such as TGF-b, IL10, which inhibits TH1 and
cell-mediated immune responses.
Tumors may be inaccessible to immune system.
Tumors may grow in nodules surrounded by
collagens and fibrin.
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Relevant part in book
Immune response to parasite p401-406
Immune response to cancer p499-515