Transcript ImmunLec21-2010 - 81-493

The role of the thymus in T
cell differentiation
T cell with
CD8
Binds to
MHC1
TCR interrogates
MHC1 peptide
binding site
looking for 8-10
aa peptide
placed there via
endogenous
pathway
T cells with CD3
T cell
with CD4
Binds to
MHCII
TCR
interrogates
MHCII peptide
binding site
looking for 1834 aa peptide
placed there
via exogenous
pathway
T cells are MHC restricted. They only help
or kill cells with whom they share MHC.
Zinkernagel
1994.
This work indicated that T cells recognize both
MHC and specific antigen fragments.
Does one receptor recognize the MHC and
another receptor recognize the antigen fragment
embedded in the binding site on the MHC ? Or is
there one receptor with specificity for MHC in
combination with a specific antigen fragment ?
Dual Receptor Theory
Experiment demonstrating the thymus selects this MHC specificity.
T cell differentiation in the
thymus
T cell
differentiation :
How to explain
MHC restriction
and double the
number of T
helper cells
compared to
cytotoxic cells.
 T lymphocytes spend three weeks in the thymus.
 T cells leaving the thymus circulate in blood and lymphatics
and enter secondary immune tissues.
 The thymus involutes following puberty and shrinks. In a
human infant the thymus weighs 70 gms by age 40-50 it is
only 3 gms.
In cortex, thymic epithelial cells presents 2X the
amount of MHC2 molecules as MHC1 molecules.
They present all the alleles in the persons genome: 6
MHC class 1 molecules and 12 different MHC class 2
molecules. This determines the ratio of Th to Tc as
2:1. This determines that only T cells with a TCR
receptor that recognizes the persons own MHC
survives the cortex.
Now those T cells that survive the cortex
move to the medulla,
they upregulate the number and affinity of
their TCRs and become committed as either
CD4 or CD8 positive.
Present day
Present day
Present day
Present day
Present day
Emerging
Pathogens
Emerging areas of concern :
• New virulent organisms that develop
spontaneously
• Antibiotic resistant strains of bacteria
• Epidemic spread in a global economy
• New virulent organisms engineered for
Bioterrorism
Hypersensitivity Reactions
antibody mediated
Ig E
antibody mediated
antibody mediated
Ig M or IgG
Ig M or IgG
Immediate
Immediate
Fastest (sec)
4-6 hrs
Immediate
w/i 4-6 hrs
cell mediated
T lymphocyte
Delayed
48-72 hrs.
Type 1 hypersensitivity
• All hypersensitivity reactions require a first
asymptomatic exposure to antigen
• Second exposure manifests a exaggerated and
extensive reaction
• In type one reactions, these are very fast
within secs and usually but not always can
resolve not causing permanent damage. They
can during the reactive phase however cause
death.
Type 1 hypersensitivity
• A. Systemic anaphylaxis
• B. Local Anaphylaxis-atopic allergies
– 1.
– 2.
– 3.
– 4.
Allergic rhinitis 20% of the population
Asthma
Food allergies
Atopic dermatitis
First exposure
All type 1 Rxs.
Second exposure
HS1
A. Systemic anaphylaxis
• Portier and
Richet Nobel
1913
• Dogs with jelly
fish toxins
• Guinea pigs
with penicillin
Systemic Analyphaxis-Shock
• Within secs of second exposure to drugs, venoms or
specific foods (peanuts).
• Mast cells degranulate.
• GI tract –increased fluid (edema), increased peristalsis
= severe diarrhea and vomiting.
• Lungs- this is life threatening . Every time the person
exhales, SMC constrict causing further decreased
diameter of bronchi, increased mucous secretion and
swelling of connective tissue closes airways
completely. Within minutes they cant take a breathe
in = asphyxiation.
Upper and lower respiratory
At multiple sites
Tract,
GI tract, skin reaction.
simultaneouslyGI tract, upper and lower
respiratory tract, skin
Severe
constriction
Severe
permeability
Severe
secretion
Severe
Histamine release
1. Processing of antigen
2. T help that produces a Ig E response
3. 2- 10 X more mast cells
4. Mast cells with 10 x higher affinity
receptors
What is different about an allergic individual and a non-allergic individual.
5. Mast cells with 10-100 x more histamine per cell
6. More and higher histamine receptors on SMC
7. Mast cells with 10 x higher affinity
receptors
If you suspect that you or someone you are with is having an
anaphylactic reaction, inject epinephrine immediately. The shot is given
into the outer thigh and can be administered through light fabric. Rub the
site to improve absorption of the drug. An Epi Pen kit is shown.
Epinephrine antagonist of histamine and causes EC tight junction to reformation and SMC relaxation.
Type 1 hypersensitivity
Systemic anaphylaxis-severe.
• Local Anaphylaxis-mild-severe
– Allergic rhinitis 20% of the population.
hay fever, animal dander.
– Asthma (Extrinsic not Intrinsic)-pollen, dust
mites, fumes, insect products.
– Food allergies-hives, anaphylaxis.
– Atopic dermatitis-fabric softeners, wool.