LearningObjective

Tcells,MHCandorgantransplantrejection
Immunosuppressivedrugs
Allergies

Twomainclassesofadaptiveimmuneresponse

Lymphocytes carry out both classes of

responses.B cells work by secreting
antibodies which neutralise the virus. T
cells work by cell-mediated killing.

Positiveandnegativeselectioninthethymus

Eliminationofself
reactivecells
98%ofTcellsdiein
thethymusby
programmedcell
death.
Positiveselection
selectforcells
capableofbinding
MHCmolecules
Negativeselection
eliminatescells
bindingtoMHC
moleculesaloneorto
selfantigenswhich
resultsinself
tolerance.

Thethymusismostactiveinthefetalandneonatal
period

Thethymusislargestandmostactiveduringtheneonatalandpreadolescentperiods.
Maximumsizebeforepubertyfollowedbyshrinkageofupto 80%inmassafterwards.
During embryonic lifeandimmediatelyafterbirth,cells graduallyacquiretheabilityto
distinguishbetweentheirown tissue substancesontheonehandandunwantedcells
andforeignmaterialontheother.

Organtransplants

About112,700solidorganstransplantedworldwidein2012
Atleast77,800kidneytransplantsdonein2012
About23,986livertransplantsdoneworldwide
http://www.transplant-observatory.org/

Transplantationinhistory
The Saints Cosmas and Damian
miraculously transplant the black leg of the
Ethiopian onto the white body of the
patient.

Frankensteins Monster

Tcellmediatedgraftrejection

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

Tcellmediatedgraftrejection

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.

HLAmatchingfororgantransplants
Many HLA groups including HLA-A, HLA-B, HLA-Cetc

HLA Class I
Gene

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

HLAmatchingfororgantransplants
Many general HLA groups including HLA-A, HLA-B, HLA-C
Minimal crossover

HLAmatchingfororgantransplants
Many general HLA groups including HLA-A, HLA-B, HLA-C

HLAmatchingfororgantransplants
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)

Graftversushostdisease
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
Allergiesareinappropriateimmuneattacks
againstharmlessenvironmentalsubstances.
Twotypes:
immediatehypersensitivitiesinvolvingthe
productionofIgE antibodiesbyBcells
delayedhypersensitivitiesinvolvingmore
slowlyrespondingTcellsresponseagainstthe
allergen

Table 12-5 p450

Allergy
Commonallergensincludepollengrains,
beestings,penicillin,certainfoods
(peanuts)molds,dust,feathersoranimal
fur,catsaliva,dustmites.
InducesBlymphocytestosynthesise IgE
ratherthanIgG(bacterialantigens).
IgE areleastplentifulinthebodyanddo
notfreelycirculate.
Tailportionsbindtomastcells(connective
tissueofskin,eyes,respiratoryand
digestivetract)andbasophils(circulating)
whichthenarestimulatedtorelease
histamine.
Onskin,theappearanceofhives
Vasodilationandincreasedcapillary
permeability.

Foodallergies

Peanutallergies
Commonandpotentiallylifethreatening.
Shock,suddendropinbloodpressureandtroublebreathing.
Immediatetreatmentwithepinephrineautoinjector (e.g.EpiPen)totreatanallergic
attack.
Toincreasebloodflowthroughveinsandtoreduceswellinginairways.
Antihistaminepillnotsufficient.

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

 Allergyepidemicinwesternworld.
Studiesshownthatpreviousgenerations
didnotsufferepidemic.
Why?
Manyfactorsgenetic,environmental
(pollution,reducedexposuretobacteria
andworms)

Allergyandtheparasiticwormconnection
Bothallergyandparasiticwormselicitthe
productionofIgE.
Verylittlecasesofallergyinpopulationinregions
whereparasiticinfectionareendemic.
Somewormsarecapableofdampingdownthe
immunesystem.
Wormtherapycurrentlyinclinicaltrials.
Suggestedthatmoleculessecretedbywormshave
antiinflammatorycharacteristics.
Antiwormdrugsledtoincreasedincidenceof
asthmaandallergysymptoms.
http://www.bbc.com/future/story/20130422feelingillswallowaparasite
http://news.sciencemag.org/biology/2011/02/whatdowormshavedoasthma

Allergyandtheparasiticwormconnection
Bothallergyandparasiticwormselicitthe
productionofIgE.
Ourancestorshavebeenconstantlyinhabitedby
parasiticwormsandtheimmunesystemhas
evolvedtonotmountanimmunereaction.

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 isthebodysabilitytoprotectitselfby
resistingoreliminatingpotentiallyharmfulforeign
invaders.
Twoimmuneresponses:
innateimmunity(nonspecific)responsesthat
nonselectivelydefendagainstforeignmaterial
firstlineofdefense.Recognisespathogens
throughTLR(TollLikeReceptors)onneutrophils
andmacrophages.
adaptiveimmunity(specificresponses)that
selectivelytargetparticularinvaders.

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 TLRs 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

NatureReviewsMicrobiology 6, 143155 (February2008)

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