How does a T cell know that a pathogen is inside a cell?

Receptors and ligands

The receptor is the T cell receptor

The ligandis a molecular complex

that the infected cell puts on it’s
cell surface -
A complex of a MHC molecule and
a peptide from the pathogen.

Engagement of the TCR by MHC

and peptide results in stimulation
of the T cell, cytokine production
and stimulation of the macrophage
to become more cytotoxic.
 Major Histocompatibility Complex (MHC)
Molecules
Human MHC – HLA (Human Leukocyte Antigens)

Stimulation of immune system

- Transplanted tissue or against host (GVH)
- Autoimmunity
- Against pathogens
Steer the immune system to most effective response
- Humoral – extracellular microorganisms
- Cellular – intracellular microorganisms
Education of T cells in thymus
- Self from non-self
- Elimination of self-reactive T cells
 Ig vs. TCR

Similarities

Constant region

Variable region

Part of the same multigene

family

Differences

Abs can be soluble

TCR – Cell-associated

Ligands recognized
 Linear
epitopes

Whole
virus

Disco ntinuous o r
confo rmational epitopes
In In In
ER ER ER
 MHC class I expression
is induced by type I
interferons

MHC CLASS II
TRANSACTIVATOR
BARE
LYMPHOCYTE
SYNDROME

Plasmodium
 JUST REMEMBER THE NUMBER “8”


 MHC I x CD8 = 8


 MHC II x CD4 = 8
 TAP

I
I
I

I
 MHC and Transplantation

The immune system (T cells) responds to “non-self MHC” on transplanted donor

cells the same way that it responds to self-MHC with foreign peptide.
Polymorphism in 120
MHC 250
70
MHC alleles differ from each other by 1-50 amino acids – mostly in
antigen binding cleft
 Allergy/Type I
Hypersensitivity
 Hypersensitivity
• Defined by two immunologists called
Coombs and Gell
• They originally classified
hypersensitivity into Types I-IV
• These can occur in isolation but
diseases may present with a
mixture of hypersensitivity
responses
 Hypersensitivity
• Type I Hypersensitivity: IgE mediated
activation of mast cells
• Type II Hypersensitivity: antibody
mediated binding of cell or tissue
bound antigens
• Type III Hypersensitivity: antibody
mediated immune complexes
• Type IV Hypersensitivity: T cell
mediated DTH
 TYPES OF HYPERSENSITIVITY
Gells and Coombs classification
• Type 1 - Immediate reaction - Ig E
antibodies
• Type 2 - Cytotoxicreaction - IgG &
IgM
• Type 3 – Immune complexes – IgG &
IgM
• Type 4 – Delayed reaction 48 hrs – T-
cell mediated
•
 Type I Hypersensitivity
Reactions
• This is the immunological process
which brings about
– Anaphylaxis
– Allergies
• The most common disorder of
immunity
• About 20% of individuals in the US
have some type of allergy
 Type I (Immediate)
Hypersensitivity
It is the typical response that occurs in


• Hay fever (allergic rhinitis) : Edema,

irritation, mucus in nasal
mucosa
• Asthma: bronchial constriction ,edema,
mucus prod.
• Atopic dermatitis (eczema)
– Hives (urticaria) is usually associated with
Type I Hypersensitivity
• Can be caused by other mechanisms
An individual who has an allergy is atopic


(out of place)
• Systemic anaphylaxis: bronchial
constriction, vasodilation
Eczema
 Type I Hypersensitivity
Mechanism
• Production of IgE by B cells
– Under Th2 control
• IgE binds to Fcε RI on mast cells and
basophils
• Re-introduced antigen binds (cross-
links) to IgE
• Mast cell/basophil degranulation
occurs
 Type I Hypersensitivity
• If the above reaction takes place in the
skin the response is a wheal and flare
reaction
– This is seen in urticaria (hives)
• The reaction is called immediate
– It takes about 5' to occur and
subsides within an hour
• Sometimes there is a further late phase
reaction that occurs about 2 hours later
and peaks at about 24 hours
Wheal and Flare
Urticaria
• A vascular
reaction of the
skin
characterized
by erythema
(flare) and
wheal formation
due to localized
increase of
vascular
permeability
Urticaria
 IgE
• Some diseases are characterized by very
high IgE levels
– Atopic eczema
• Levels up to 30,000 IU
• In many cases it is IgE specificity which is
important
– i.e., what is the allergen
• Measure by a skin prick test
• Measure by a RAST
(radioallergosorbent test)
 Skin prick test
• This involves placing a small drop of
a solution of the allergen to be
tested onto the patients skin
– Usually the back or arms
• Then inserting this into the intra-
epidermis
– Using a hypodermic needle
• A wheal and flare response would be
a positive result
Skin prick test
 Regulation of IgE Synthesis
• This is induced by cytokines acting
upon B cells to induce antibody
class switching
– Secondary immune response
• IL-4 and IL-13 appear to induce the
production of IgE
 Common Allergens
• Airborne • Foods
– Grass Pollen – Fish/shellfish
– Tree Pollen – Eggs
– Mold Spores – Peanuts
– Animal Dander – Milk
– House Dust – Gluten
Mite
 A patient is stung by a bee for the first time and
presents with a wheal and flare response. What will
your course of action be?

A. Give immediate
epinephrine to prevent
anaphylactic shock
B. Give the patient a
prescription for
epinephrine in case
they are stung again
C. Give the patient a
prescription for anti-
histamines
D.Admit the patient to ER
and monitor the 0
patients vital signs
E. Prescribe a topical
 Mast Cells and Basophils
• Mast cells are tissue bound cells that
are found throughout the body
• There are differing types of mast
cells in humans
– They vary morphologically,
biochemically, and in their tissue
distribution
Mast Cell
Eosinophil
 Eosinophils

• Regulation of eosinophils appears to

be partially controlled by IL-5
• Evidence suggests a major role for
eotaxin
– A chemokine
• During an acute helminth infection
– Numbers of circulating and local
eosinophils increase
 Mast Cell Activation
• Activation of mast cells and basophils
results in
– Exocytosis of granules containing pre-
formed mediators
– Synthesis of new mediators
– Secretion of cytokines, such as:
• IL-4
• IL-5
• IL-13
 Mast Cell Activation

• Preformed mediators include

biogenic amines
• Histamine
• Heparin
• Chemotactic factors, serotonin
• Tryptase and chymase
 Histamine
• Binds to target cell receptors called H1 - H4
and causes a number of effects such as
– Smooth muscle contraction resulting in, for
example
–Increased peristalsis
 - Bronchospasms
• Vasodilation
– Large blood vessels are constricted and
small ones are dilated
• Can give a blushing effect
• Effects upon the patient include
– Vascular endothelial cell retraction, plasma
leakage, the wheal and flare response
–
 Newly Synthesized
Mediators
Newly synthesised from Arachdonic


acid
• PGE-2 : Increases the pain response
• PGD-2 : increases the smooth muscle
contraction
• Leukotrienes C4, D4 , E4 : same as
PGD2
• Leukotriene B4 : chemotactic for
neutrophils
 Physical effects of mast-cell
degranulation vary by tissue
• Airways
– Decreased diameter, increased mucus secretion
– Expulsion of airway contents (phlegm, coughing)
• Skin
– Edema and erythema, “wheal and flare” response
• GI tract
– Increased fluid secretion, increased peristalsis
– Expulsion of GI contents (diarrhea, vomiting)
• Blood vessels
– Systemic anaphylaxis
– Increased blood flow and permeability
– Edema, inflammation, increased lymph flow
 Prevention of Immediate
Hypersensitivity
Treatment is by:
A) blocking the events leading to the

clinical condition
– Anti-histamines
– Corticosteroids to inhibit PG and LT
B) by reversing the physical changes


that occur because of the reaction

– E.g., with epinephrine
 Allergen Avoidance
• One needs to identify the allergen
– Many are common and may be
avoided somewhat
• House dust mite
• Animal dander
– Many are common but are not easily
avoided
• Peanuts
 Anaphylactic Shock
Pathophysiologic Effects Clinical Anaphylaxis

Vascular dilation Hypotension

Cardiac arrhythmia Syncope

Bronchoconstriction Laryngeal/respiratory
Laryngeal edema obstruction
Smooth muscle Abdominal cramping,
contraction vomiting diarrhea
 Type II Hypersensitivity
• This is where antibody (IgG or IgM) binds
to an antigen on a cell surface
• The cell is frequently part of an organ
– The kidney and lung
• in Goodpasture's syndrome
– The thyroid gland
• Graves or Hashimoto's diseases
– Or just an individual cell
• Immune thrombocytopenic
purpura (ITP)
 Type II Hypersensitivity
Mechanisms
Once bound, the antibodies can:


1.Activate complement leading to cell

damage
– Immune thrombocytopenic purpura
(ITP)
– Hemolytic anemia
2.Activate ADCC for cytotoxic cell
attack
– Autoimmune thyroiditis
 Type II Hypersensitivity
Mechanisms
3.Antibodies can induce phagocytosis
of target cells when they act as
opsonins
– Extravascular autoimmune hemolytic
anemia
4.Bind to hormone receptors to
activate the function of a cell or
organ
– Hyperthyroidism
 Type II Hypersensitivity
• The consequences of Type II
Hypersensitivity are frequently
severe and progressive unless
treated
• In some cases removal of the
antibody can be of value
– Plasmapheresis for Goodpasture's
syndrome
 Type III Hypersensitivity

• This is the classic immune complex

(IC) disease situation and occurs
where:
– A large amount of both antigen and
specific antibody accumulate
– If either antibody or antigen is in
great XS large IC do not occur
• As seen in serum sickness and the
Arthus reaction
 Type III Hypersensitivity
• They also occur when the
antibody/antigen complexes do not
activate the classical complement
cascade
• Can occur during a complement
deficiency (C1, C4, C2)
– Can result in a disease similar to
lupus

 Type III Hypersensitivity
• This situation can also occur when
immune complexes evade
activation of the classical
Complement pathway
– IgA
• e.g., Henoch-Schonlein purpura
Henoch-Schonlein Purpura
• IgA immune
complexes are
deposited
• Two syndromes
– Henoch
purpura
• affects
the skin
and GI
tract
– Schonlein
purpura
 Immune Complexes
• The antibody forming IC is usually
IgM, IgG or IgA
• The antigen can be: a drug, from a
pathogen, a vaccine, host tissue, or
antibody as in rheumatoid factor
(Rf)
– IgM antibody bound to the Fc of IgG
(usually)
 Immune Complexes
• Immune complexes will circulate
throughout the body and may be
deposited in various sites
– The kidney
– The joints
– The peripheral vasculature (skin)
 Immune Complexes
• Activated C’ will release
anaphylatoxins
• Phagocytes will release inflammatory
and toxic molecules that will cause
tissue damage and platelet
recruitment
• The results can be inflammation and,
if appropriate, purpura
Systemic lupus erythematosus
(SLE)
• A systemic autoimmune disorder affecting
– The vasculature
– Kidneys
– Skin
– Joints
– CNS
– Serous tissue (serositis)
• Heart, spleen, lungs
Systemic lupus erythematosus
(SLE)
• Characterized by numerous
autoantibodies
– Especially anti-nuclear antibodies
(ANA)
• Is often described as the typical Type
III Hypersensitivity disease
– But also has elements of Type II
Hypersensitivity
• May have positive Coombs test
Lupus
Systemic lupus erythematosus
(SLE)
 Arthus reaction
• This is a local tissue bound Type III
Hypersensitivity reaction
• It usually occurs after repeated
intramuscular (IM) injections of
antigens
• It can induce pain and even necrosis
Type III Hypersensitivity
• Arthus reaction
– Local
immune
complex
deposition
due to
immunizati
on
Arthus Reaction
 Immune Complex Mediated
Disease
• Serum sickness
– This is due to the development of
Type III Hypersensitivity
– It is a problem when administering
equine antiserum for bacterial
toxins such as:
• Diphtheria
• Tetanus
 Serum sickness
• After repeated administration of horse
antiserum individuals developed
– Arthritis
– Myalgia
– Vomiting
– Malaise
– Rashes
– Fever
 Contrasts Between
Hypersensitivity Types II and III

• Although both can affect the

kidneys the mechanism are
different
• For example, both immune
complexes and anti-GBM
antibodies can accumulate in the
kidneys but the effects are
dissimilar
 Goodpasture’s Syndrome
• Rapid progressive glomerulonephritis
due to anti-glomerular basement
membrane antibody, plus
pulmonary hemorrhage
• Antibody cross reacts with the GBM
and alveolar basement membrane
(Type II Hypersensitivity)
•
 Goodpasture’s Syndrome
• Both lupus and Goodpasture’s will
activate complement by the
classical pathways (C1, C2 and C4
levels my be lower than NR)
• Both diseases will cause renal
disease
• The actual effects caused by
antibodies are different
 Goodpasture’s Syndrome
• Goodpasture’s syndrome IF
microscopy will reveal linear
deposition of IgG along the GBM
• Lupus however shows clumps of
immune complexes deposited on
the GBM that have a “lumpy-
bumpy” appearance
 Type IV (Delayed Type)
Hypersensitivity (DTH)
• This was originally defined as
– A hypersensitivity reaction that took
more than 12 hours to develop
• This is typified by the classical skin
reaction which occurs in response
to
– Nickel, poison ivy, latex, for example
 Type IV (Delayed Type)
Hypersensitivity (DTH)
• It can also take place in internal
organs
– The liver, gut
• The reaction is often chronic if
internal and can last for years
• It occurs in conditions where the
antigen is unknown or disputed, for
example sarcoidosis and perhaps
Crohn's disease
 Type IV (Delayed Type)
Hypersensitivity (DTH)

• It occurs in response to some

chronic infections, particularly
intracellular ones, e.g.,
Mycobacterium tuberculosis (TB)
• It can also occur during graft
rejection against solid organ
transplants
– Liver, kidneys, heart
• It is a major mechanism for
attacking solid tumors
 Delayed Type
Hypersensitivity
• It is an immune response mediated
mostly by CD4+ T cells
tTh1
– Also CD8+ T cells can contribute
• The effector cells are largely MΦ
 DTH
• Many of the substances inducing
contact hypersensitivity are
haptens
– Small molecules which are not
antigenic until bound to a larger
protein, e.g., nickel
• They can complex with skin
molecules
– Internalized by Langerhan's cells in
the epidermis
 DTH
• This complex is then presented with MHC
Class II
– To CD4+ T cells
• Release cytokines (TNF-β , IL-2,
IFN-γ )
• Approximately 24-48 hours after exposure,
MΦ accumulate
• The MΦ release lysozomal enzymes
– Redness and pustules result
 DTH
• The MΦ can also release
– TNF-α
– Active oxygen species
• The cytokines released from the T
cells will also have severe effects
upon the skin
– TNF-β
 Chronic DTH
• The MΦ change morphology
– They fuse to form giant cells
• These become focused around sites
of stimulation
– To form granulomas
• The tissue at the site of chronic DTH
is eventually replaced by fibrous
tissue
– Fibrosis
 Hypersensitivity and Drugs
• Type IV responses are frequently due
to topical medications
• A suspected sensitivity can be
confirmed by applying a weak
solution to the skin in a patch test.
Contact Hypersensitivity