Immune system

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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 




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





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







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








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.

Mucosal Immunology (2010) 3, 361-373;
doi:10.1038/mi.2010.25

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


Recognition of molecules of microbial origin, pathogen associated
molecular patterns (PAMPS).



Best known of these are Toll like receptors (TLR).



First identified in Drosophila. Control of infections by Gram-positive
bacteria and fungi.



Plants, insects and mammals.



Ligand of TLR4 is LPS (Lipopolysaccharides) from Gram-negative
bacteria.



Best known and well characterised are the LPS signaling pathway.
The prototype.



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


10 TLR’s found in humans.



The first ligand was only identified relatively recently in 1998, LPS
binding to TLR4.



TLR7 and TLR8 recognise single stranded viral RNA.



TLR2 recognise lipoteichoic acid and lipoproteins.



TLR3 recognise double stranded viral RNA.



TLR5 recognise bacterial flagellin.



TLR9 recognise unmethylated CpG DNA common to bacterial and
viral DNA.

usually protein kinases

Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008)

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.


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/

Microbial disruption of host response.


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.


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.



Yersinia can deliver 6 different
Yop proteins into host cell.



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.



http://www.bbc.com/news/worldafrica-24461474




YopJ
Inhibition of the inflammatory
response and induction of
macrophage apoptosis.



Inhibits multiple MAPK and
NFkB pathways.



Suppression of cytokine
release and thus inhibits
recruitment of immune cells to
site of infection thereby
evading the inflammatory
response.



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.



Ser/Thr acetyl transferase
activity.

YopJ


Inhibition of the inflammatory response and induction of macrophage
apoptosis.



Inhibits multiple MAPK and NFkB pathways.



Suppression of cytokine release and thus inhibits recruitment of
immune cells to site of infection thereby evading the inflammatory
response.



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.



Ser/Thr acetyl transferase activity.



YopP in Yersinia enterocolitica (YopJ in Yersinia Pestis) also binds to TAB1 and
inhibits TAK1.



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).

AIDS

Nature Reviews Microbiology 6, 143‐155 (February 2008)




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.

Infection is major cause of death in AIDS

END

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