Learning Objective
• T cells, MHC and organ transplant rejection
• Immunosuppressive drugs
• Allergies
Two main classes of adaptive immune response
Lymphocytes carry out both classes of
responses.B cells work by secreting
antibodies which neutralise the virus. T
cells work by cell-mediated killing.
Positive and negative selection in the thymus
Elimination of self‐
reactive cells
98% of T cells die in
the thymus by
programmed cell
death.
Positive selection‐
select for cells
capable of binding
MHC molecules
Negative selection‐
eliminates cells
binding to MHC
molecules alone or to
self antigens which
results in self
tolerance.
The thymus is most active in the fetal and neonatal
period
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The thymus is largest and most active during the neonatal and pre‐adolescent periods.
Maximum size before puberty followed by shrinkage of upto 80% in mass afterwards.
During embryonic life and immediately after birth,cells gradually acquire the ability to
distinguish between their own tissue substances on the one hand and unwanted cells
and foreign material on the other.
Organ transplants
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About 112,700 solid organs transplanted worldwide in 2012
At least 77,800 kidney transplants done in 2012
About 23,986 liver transplants done worldwide
http://www.transplant-observatory.org/
Transplantation in history
The Saints Cosmas and Damian
miraculously transplant the black leg of the
Ethiopian onto the white body of the
patient.
Frankenstein’s Monster
T cell mediated graft rejection
Peter Medawar had discovered that skin grafts given to patients with severe burns
survived if derived from the patient's own body, but withered away if taken from a donor. A
second graft from the same donor was rejected more quickly than the first.
Each individual has a unique combination of HLA (human MHC) molecules on the surface
of their cells, a biological identification system.
Textbook of Immunology
By Arvind Kumar
T cell mediated graft rejection
As recently as the 1940s, immunologists thought lymphocytes served no
purpose. T cells are involved in organ rejection response by recognising the
cells bearing HLA (human MHC) molecules which are foreign.
Thymus deficient mice , devoid of functional T cells unable to reject allograft.
HLA matching for organ transplants
Many HLA groups including HLA-A, HLA-B, HLA-C…etc
HLA Class I
Gene
A
B
C
E
F
G
Alleles
Proteins
3,192
2,245
3,977
2,938
2,740
1,941
17
6
22
4
50
16
Major HLA class I for matching
HLA Class II
Gene
DRA
DRB
DQA1
DQB1
DPA1
DPB1
DMA
DMB
DOA
DOB
Alleles
Proteins
7
2
1,868
1,364
54
32
807
539
40
20
550
447
7
4
13
7
12
3
13
5
Major HLA class II for matching
http://hla.alleles.org/nomenclature/stats.html
HLA matching for organ transplants
Many general HLA groups including HLA-A, HLA-B, HLA-C
Minimal crossover
HLA matching for organ transplants
Many general HLA groups including HLA-A, HLA-B, HLA-C
HLA matching for organ transplants
Many general HLA groups including HLA-A, HLA-B, HLA-C
Immunosupression
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Although major HLA are matched between organ donor and recipient,
not complete.
Previous studies have estimated the rate of graft loss for patients with
HLA mismatches was twice that of those with zero HLA-A, -B, or -DR
mismatches.
Still requires immunosuppressive (anti-rejection) drugs taken everyday to
reduce organ rejection. All act on T cells.
Unwanted side effect of immunosuppression is increased risk of
infection!!!!!!
And higher risk for cancer because the immune system also protects
against cancer.
•Calcineurin Inhibitors: Tacrolimus and Cyclosporine (no T cell activation)
•Antiproliferative agents: Mycophenolate Mofetil, Mycophenolate Sodium and Azathioprine (causes T
cells to undergo programmed cell death (apoptosis) or undergo ‘suicide’)
•mTOR inhibitor: Sirolimus (stops T cells dividiing and proliferating)
•Steroids: Prednisone (causes T cells and other immune cells to undergo programmed cell death
(apoptosis) or undergo ‘suicide’)
Graft versus host disease
Overcame ‘graft versus host’
reaction in transplants.
Developed techniques such as use
of immunosuppressive drugs.
Transplanted organ is X-rayed to
kill lymphocytes from donor.
Murray successfully transplanted a
kidney between homozygous twins
for the first time in 1954, Boston
USA.
Thomas was successful in
transplanting bone marrow cells
from one individual to another as a
treatment for leukemia.
Allergies
• Allergies are inappropriate immune attacks
against harmless environmental substances.
• Two types:
• immediate hypersensitivities involving the
production of IgE antibodies by B cells
• delayed hypersensitivities involving more
slowly responding T cells response against the
allergen
Table 12-5 p450
Allergy
Common allergens include pollen grains,
bee stings, penicillin, certain foods
(peanuts) molds, dust, feathers or animal
fur, cat saliva, dust mites.
Induces B lymphocytes to synthesise IgE
rather than IgG (bacterial antigens).
IgE are least plentiful in the body and do
not freely circulate.
Tail portions bind to mast cells (connective
tissue of skin, eyes, respiratory and
digestive tract) and basophils (circulating)
which then are stimulated to release
histamine.
On skin, the appearance of hives
Vasodilation and increased capillary
permeability.
Food allergies
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Peanut allergies
Common and potentially life threatening.
Shock, sudden drop in blood pressure and trouble breathing.
Immediate treatment with epinephrine autoinjector (e.g. EpiPen) to treat an allergic
attack.
To increase blood flow through veins and to reduce swelling in airways.
Antihistamine pill not sufficient.
Minimizing development of allergies in new born by breast feeding
Food and
environmental
antigens are passed
to the infant in
brestmilk to educate
the adaptive
immune system.
Health hazards from recent trend of buying human breast milk online
• Allergy epidemic in western world.
• Studies shown that previous generations
did not suffer epidemic.
• Why?
• Many factors‐genetic, environmental
(pollution, reduced exposure to bacteria
and worms)
Allergy and the parasitic worm connection
Both allergy and parasitic worms elicit the
production of IgE.
Very little cases of allergy in population in regions
where parasitic infection are endemic.
Some worms are capable of damping down the
immune system.
Worm therapy currently in clinical trials.
Suggested that molecules secreted by worms have
anti‐inflammatory characteristics.
Anti‐worm drugs led to increased incidence of
asthma and allergy symptoms.
http://www.bbc.com/future/story/20130422‐feeling‐ill‐swallow‐a‐parasite
http://news.sciencemag.org/biology/2011/02/what‐do‐worms‐have‐do‐asthma
Allergy and the parasitic worm connection
Both allergy and parasitic worms elicit the
production of IgE.
Our ancestors have been constantly inhabited by
parasitic worms and the immune system has
evolved to not mount an immune reaction.
BREAK
Learning Objective
• Introduction to signaling pathways in the immune response
• Dysregulation of these signaling pathways causes disease
• Signaling molecules have potential as drug targets to combat
immune disease
• Modulation of signaling pathways by pathogens can increase
their virulence.
Immunity
• Immunity is the body’s ability to protect itself by
resisting or eliminating potentially harmful foreign
invaders.
• Two immune responses:
• innate immunity (nonspecific) responses that
nonselectively defend against foreign material
“first line of defense”. Recognises pathogens
through TLR (Toll‐Like Receptors) on neutrophils
and macrophages.
• adaptive immunity (specific responses) that
selectively target particular invaders.
“for your discovery that in his case Toll, and your case the Toll-like receptors
were the eyes of the immune system – the sensors of innate immunity. The
immune system in flies and in mammals is so similar?
Toll Like Receptors
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Recognition of molecules of microbial origin, pathogen associated
molecular patterns (PAMPS).
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Best known of these are Toll like receptors (TLR).
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First identified in Drosophila. Control of infections by Gram-positive
bacteria and fungi.
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Plants, insects and mammals.
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Ligand of TLR4 is LPS (Lipopolysaccharides) from Gram-negative
bacteria.
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Best known and well characterised are the LPS signaling pathway.
The prototype.
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LPS signaling can trigger off a battery of gene expression that
activates immune response.
Domain structure of IL1R/TLR
PolyIC
Single stranded RNA
Toll Like Receptors
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10 TLR’s found in humans.
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The first ligand was only identified relatively recently in 1998, LPS
binding to TLR4.
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TLR7 and TLR8 recognise single stranded viral RNA.
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TLR2 recognise lipoteichoic acid and lipoproteins.
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TLR3 recognise double stranded viral RNA.
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TLR5 recognise bacterial flagellin.
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TLR9 recognise unmethylated CpG DNA common to bacterial and
viral DNA.
Sepsis
TNF and IL-1
Aspirin inhibits IKK,
and therefore also
COX.
MKK4/7 or MKK3/6
Paracetamol inhibits
COX-3
JNK
p38
MAPKAPK-2
Immune activation genes, e.g.TNF
Cox-3, IL-18.
“Sepsis occurs when chemicals released into the bloodstream to fight
the infection trigger inflammatory responses throughout the body. This
inflammation can trigger a cascade of changes that can damage
multiple organ systems, causing them to fail”-From Mayo Clinic
Microbial disruption of host response.
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Why is the plague
interesting? The Black
Death.
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The Yersinia bacterium
killed several million people
in Europe in the 14-15th
century. Fleas on rats were
carriers.
Now treated with antibiotics. If untreated, mortality rate is
60-90%
http://edition.cnn.com/2015/09/11/health/plaguesurvivors/
Microbial disruption of host response.
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Why is the plague
interesting? The Black
Death.
•
The Yersinia bacterium
killed several million people
in Europe in the 14-15th
century. Fleas on rats were
carriers.
Now treated with antibiotics. If untreated, mortality rate is
60-90%
http://edition.cnn.com/2015/09/11/health/plaguesurvivors/
Yersinia bacterium
Microbial disruption of host response.
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TTSS (Type Three Secretion
System) is a translocation
apparatus highly conserved
amongst some Gram-negative
pathogens and is used to inject
effector proteins from the
bacterial cytoplasm into the host
control.
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Yersinia can deliver 6 different
Yop proteins into host cell.
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Once inside the Yops (Yersinia
outer proteins) interfere with
signaling pathways involved in
regulation of actin cytoskeleton,
phagocytosis, apoptosis and the
inflammatory response, thus
favouring survival of bacteria.
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http://www.bbc.com/news/worldafrica-24461474
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YopJ
Inhibition of the inflammatory
response and induction of
macrophage apoptosis.
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Inhibits multiple MAPK and
NFkB pathways.
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Suppression of cytokine
release and thus inhibits
recruitment of immune cells to
site of infection thereby
evading the inflammatory
response.
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Originally thought to be a
ubiquitin protease but now
has acetylase activity
modifying the residues on
MKK6 and IKK thus
preventing their activation by
phosphorylation.
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Ser/Thr acetyl transferase
activity.
YopJ
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Inhibition of the inflammatory response and induction of macrophage
apoptosis.
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Inhibits multiple MAPK and NFkB pathways.
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Suppression of cytokine release and thus inhibits recruitment of
immune cells to site of infection thereby evading the inflammatory
response.
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Originally thought to be a ubiquitin protease but now has acetylase
activity modifying the residues on MKK6 and IKK thus preventing
their activation by phosphorylation.
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Ser/Thr acetyl transferase activity.
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YopP in Yersinia enterocolitica (YopJ in Yersinia Pestis) also binds to TAB1 and
inhibits TAK1.
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Alternative mechanism is that YopP may inhibit assembly of TAK1-TAB1-TAB2
complex or TAK1-TAB1-TAB3 complex (see Thiefes et al, EMBO Rep, 2006).
HIV (human immunodeficiency virus ) virus targets and destroys helper T cells
(CD4+ T cells) thus sabotaging the immune system.
HIV virus binds to CD4 receptor, is internalised and destroys the helper T cells
resulting in a compromised immune system.