Transcript Types of Hypersensitivity

Types of Hypersensitivity
Excessive immune response in a
sensitized individual leading to tissue
damage.
Types of Hypersensitivity:
 Types I,II,III------>Immediate, Abs.
 Type IV
------>Delayed, T cells.
Cooms and Gell (in the early 1960s)
Type I, II, III:
Ab mediated
Type IV: T cell mediated
TYPE I :IgE-mediated Reactions
Immediate hypersensitivity
TYPE II: ANTIBODY-MEDIATED CYTOTOXIC
Reactions
TYPE III: IMMUNE COMPLEX REACTIONS
TYPE IV: T-CELL-MEDIATED, DELAYED-TYPE
HYPERSENSITIVITY (DTH)
1. Basic concepts
Hypersensitivity reactions are harmful antigen-specific immune responses ,
occur when an individual who has been primed by an innocuous antigen
subsequently encounters the same antigen , produce tissue injury and
dysfuntion.
Allergen：the antigens that give rise to immediate hypersensitivity
Atopy：the genetic predisposition to synthesize inappropriate levels of IgE
specific for external allergens
Types of hypersensitivity：I、II、III、IV
2. Type I hypersensitivity
1)、Characteristics
2)、Components and cells
3)、The process and mechanism
4)、Commen diseases of type I Hypersensitivity
5)、Therapy for type I Hypersensitivity
Type I Hypersensitivity
•Known as:
•Immediate
hypersensitivity
•Anaphylaxis
•IgE-associated
immune responses
Immunreaktionen der Haut
5
1) Characteristics
Occur and resolve quickly
Mediated by serum IgE
Systemic and regional tissue dysfuntion
Genetic predisposition
2) Components and cells in Type I hypersensitivity
Allergen ：
pollen、dust mite、insects etc
selectively activate CD4+Th2 cells and B cells
Allergin（IgE）and its production
IgE： mainly produced by mucosal B cells
IL-4 is essential to switch B cells to IgE production
Only Ab that can bind mast cells.
Cross linking of IgE Fc receptors leads to Mast cell
degranulation.
High affinity receptor of the IgE on mast cell and basophil
Eosinophil
Pathogenic mechanisms
* First exposure to allergen
Allergen stimulates formation of antibody (Ig E type) Ig E fixes, by its Fc portion
to mast cells and basophiles
* Second exposure to the same allergen
It bridges between Ig E molecules fixed to mast cells leading to activation and
degranulation of mast cells and release of mediators
Three classes of mediators derived from mast cells:
1) Preformed mediators stored in granules (histamine)
2) Newly sensitized mediators:
leukotrienes, prostaglandins, platelets activating factor
3) Cytokines produced by activated mast cells, basophils
e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines
* These mediators cause: smooth muscle contraction,
mucous secretion and bronchial spasm, vasodilatation,
vascular permeability and edema
Type-I Hypersensitivity: Animation I
Production of IgE in Response to an Allergen
10
Type-I Hypersensitivity: Animation II
Allergen Interaction with IgE on the Surface of Mast
Cells triggers the Release of Inflammatory Mediators
11
Summary of Mast cell activation
Y
IgE
Fc Receptor
Mast cells
Histamine
granule release
activated phospholipase A2
arachidonic acid
cyclo-oxygenase lipoxygenase
histamine,proteolytic enzymes, pathway
pathway
heparin, chemotactic factors prostaglandins
leukotrienes
Preformed Mediators
Newly Synthesized
Physiological Effects of mast cell mediators
Y
IgE
Fc Receptor
Mast cells
Histamine
and other
mediators
NCF
ECF
LTB4
Chemo-attractants
Attract neutrophils,
eosinophils,
monocytes and
basophils
Activators
Histamine
vasodilatation &
vascular permeability
Microthrombi
PAF
Activation of C
Tryptase
Kininogenase Kinins-->vasodilatation
spasmogens
Bronchial smooth muscle
Histamine
contraction, mucosal
Prostaglandins
oedema, mucus
Leukotrienes secretion
Type I Hypersensitivity Reaction
Anaphylaxis
* Systemic form of Type I hypersensitivity
* Exposure to allergen to which a person is previously sensitized
* Allergens:
Drugs: penicillin
Serum injection : anti-diphtheritic or ant-tetanic serum,
anesthesia or insect venom
* Clinical picture:
Shock due to sudden decrease of blood pressure, respiratory distress due to
bronhospasm, cyanosis, edema, urticaria
* Treatment: corticosteroids injection, epinephrine, antihistamines
Atopy
* Local form of type I hypersensitivity
* Exposure to certain allergens that induce production of specific Ig E
* Allergens :
Inhalants:dust mite faeces, tree or pollens, mould spor.
Ingestants: milk, egg, fish, choclate
Contactants: wool, nylon, animal fur
Drugs: penicillin, salicylates, anesthesia insect venom
* There is a strong familial predisposition to atopic allergy
* The predisposition is genetically determined
Type I Hypersensitivity:
Systemic or Localized
• Systemic (Anaphylaxis shock)
• Symptoms include: labored breathing, drop in blood pressure, smooth
muscle contraction, bronchiole constriction (suffocation)
• Localized
• Examples: Hay fever (allergic rhinitis), asthma (allergic or intrinsic), food
allergies, atopic dermatitis (eczema)
Anaphylaxis to bee venom
Bee venom has Mellitin which can directly
trigger mast cells
Mechanism of type I hypersensitivity
Allergen
Primary
Individual
Generation
IgE
Adhesion
Secondary
IgE binds to the FceRI on mast cell and basophil
Allergen binds to the IgE on primed target cell
Crosslikage of FceRI
Degranulate and release the biological mediators
Preformed granule mediators
Histamine
Bradykinin
New generated mediators
Leukotrienes
PAF
Prostaglandin D2
Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle
Systemic anaphylaxis
Skin
Respiratory tract
Degist tract
Treatment for Type I
Pharmacotherapy
•Drugs.
•Non-steroidal anti-inflammatories
•Antihistamines block histamine
receptors.
•Steroids
•Theophylline OR epinephrine prolongs or increases cAMP levels in
mast cells which inhibits
degranulation.
Treatment for Type I
•Immunotherapy
•Desensitization
(hyposensitization)
also known as allergy shots.
•Repeated injections of allergen to
reduce the IgE on Mast cells and
produce IgG.
Type II Hypersensitivity
Cytotoxic or Cytolytic Reactions
1. Characteristic features
2. Mechanism of Type II Hypersensitivity
3. Common diseases of Type II Hypersensitivity
1. Characteristic features
Primed IgG or IgM
+
Antigen or hapten on membrane
Injury and dysfunction of target cells
Type II: Cytotoxic or Cytolytic Reactions
• An antibody (Ig G or Ig M) reacts with antigen on the cell
surface
* This antigen may be part of cell membrane or
circulating antigen (or hapten) that attaches to cell
membrane
Mechanism of Cytolysis
* Cell lysis
results due to :
1) Complement fixation to antigen antibody complex on
cell surface. The activated complement will lead to
cell lysis
2) Phagocytosis is enhanced by the antibody (opsinin)
bound to cell antigen leading to opsonization of the
target cell
Mechanism of cytolysis
3) Antibody depended cellular cytotoxicity (ADCC):
- Antibody coated cells e.g. tumour cells, graft cells or infected
cells can be killed by cells possess Fc receptors
- The process different from phagocytosis and independent of
complement
- Cells most active in ADCC are:
NK, macrophages, neutrophils and eosinophils
Type II Hypersensitivity
Antibody-Complement Dependent Mediated Lysis
Animation: IgG or IgM reacts with epitopes on the host cell membrane and
activates the classical complement pathway. Membrane attack complex (MAC)
then causes lysis of the cell.
Immunreaktionen der Haut
30
Allergen
Stimulate
Antibody
Cell
A. Opsonic phagocytosis
Combined opsonic activities
D. ADCC of NK
C. Effect of complement
Cell injury ways of type II hypersensitivity
Type II Hypersensitivity
Antibody-Complement Dependent Mediated Lysis
Example: Autoimmune Hemolytic Anemia
32
Type II Hypersensitivity
Antibody Dependent Cell Mediated Cytotoxicity
Animation: Antibodies react with epitopes on the host cell membrane and NK cells
bind to the Fc of the antibodies. The NK cells then lyse the cell with pore-forming
perforins and cytotoxic granzymes
33
Drug-Induced Reactions:
Adherence to Blood Components
blood cell adsorbed drug
or antigen drug metabolite
antibody to drug
complement
lysis
Antigen or hapten on cell
Antibody (IgG, IgM)
Activate complement
Lyse target cell
Opsonic phagocytosis
Destroy target cell
Target cell injury
NK , phagocyte
Stimulate / block
ADCC
Change the function ofTarget cell
Mechanism of Type II hypersensitivity
Clinical Conditions
1) Transfusion reaction due to ABO incompatibility
2) Rh-incompatability (Haemolytic disease of the newborn)
3) Autoimmune diseases
The mechanism of tissue damage is cytotoxic reactions
e.g. SLE, autoimmune haemolytic anaemia, idiopathic thrombocytopenic
purpura, myasthenia gravis, nephrotoxic nephritis, Hashimoto’s thyroiditis
4) A non-cytotoxic Type II hypersensitivity is Graves’s disease
It is a form of thyroditits in which antibodies are produced against TSH surface
receptor. This lead to mimic the effect of TSH and stimulate cells to overproduce thyroid hormones
Clinical Conditions
5- Graft rejection cytotoxic reactions:
In hyperacute rejection the recipient already has performed
antibody against the graft
6- Drug reaction:
Penicillin may attach as haptens to RBCs and induce antibodies
which are cytotoxic for the cell-drug complex leading to haemolysis
Quinine may attach to platelets and the antibodies cause platelets
destruction and thrombocytopenic purpura
Examples of drug-induced
type II hypersensitivity
Red cells:
Penicillin, chloropromazine, phenacetin
Granulocytes:
Quinidine, amidopyridine
Platelets:
sulphonamides, thiazides
TYPE III HYPERSENSITIVITY
Antigen antibody immune complexes. IgG
mediated
1. Characteristics
2. Mechanism of type III hepersensitivity
3. Common disease of type III hepersensitivity
1、characteristics
Free Ag + Primed Ab
Larger immune complex
Deposit in tissue or blood vessel wall
Inflammation
Types of immune complex disease
cause
antigen
site of deposition
persistent
infection
bacterial, viral,
parasitic, etc.
infected organ,
kidney
inhaled antigens
mold, plant or animal
antigen
lung
injected material
serum
kidney, skin, arteries, joint
autoimmunity
self antigen
kidney, joint, arteries, skin
2、Mechanism of type III hypersensitivity
Formation of the intermediate immune complex
Deposition of the intermediate immune complex
Tissue injury by the immune complex
•Large amount of antigen and antibodies
form complexes in blood.
•If not eliminated can deposit in capillaries
or joints and trigger inflammation.
•PMNs and macrophages bind to immune
complexes via FcR and phagocytize the
complexes.
BUT
•If unable to phagocytize the immune
complexes can cause inflammation via C’
activation ---> C3a C4a, C5a and
"frustrated phagocytes".
"Frustrated Phagocytes"
•If neutrophils and macrophages are unable
to phagocytize the immune complexes
these cells will degranulate in the area of
immune complex deposition and trigger
inflammation.
•Unable to eat -------try to digest outside cell.
•Complexing of antigen plus antibody
facilitates phagocytosis and clearing of
antigen
•Large amounts of these complexes can lead
to tissue damage
• “Immune complex
disease”
• Soluble Ag/IgG or IgM
• high titers of each required
• Immune processes
involved:
• classical complement
pathway
• phagocytic cells
45
Immune complexes not cleared
Activation of Complement
C3a & C5a
Inflammation
Mast cells
Type III hypersensitivity mechanism
Type III hypersensitivity mechanism
Type II Hypersensitivity
Antibody-Mediated Cell Disfunction
Example: Myasthenia Gravis
Immunreaktionen der Haut
49
TYPE III
Immune Complex Disease
Localized disease
•Deposited in joints causing local
inflammation = arthritis.
•Deposited in kidneys = glomerulonephritis.
Arthus Reaction
Serum sickness
•Serum sickness from large amounts of
antigen such as injection of foreign serum.
•Serum sickness is usually transient immune
complex disease with removal of antigen
source.
 Occurs when antigen enters bloodstream, circulating immune complexes
form
 Symptoms include:
•
•
•
•
Fever
Weakness
Rashes
And many others
1.
Complement initiates mast
cell degranulation
2.
Neutrophils are
chemotactically attracted to
the site
3.
Neutrophils release lytic
enzyme after failed attempts
to endocytose the immune
complex
Soluble antigen
Body
Antibody
Immune complex
Small molecular soluble
Immune complex
intermediate molecular soluble
Immune complex
Large molecular insoluble
Immune complex
Deposit on the basement of capillaries
Eliminate by phogacytosis
Combine and activate complement system
Basophils and mast cells
C3a,C5a,C3b
Platelets
Infiltration of neutrophils
Blood Clotting Mechanisms
Release of vasoactive amine
Phagocytose complex
Release of vasoactive amine
Aggregation of platlets
Increase vascular permeability
Edema
Release the enzymes in lysosome
Thrombus
Tissue injury
Bleeding
Increase vascular permeability
Edema
Local or systemic immune complex diseases
common disease of type III hypersensitivity
1. Local immune complex disease
Arthus reaction ：Experimental local reaction,
Necrotic vasculitis vasculitis, Ulcer
Human local reaction: insulin-dependent diabetes mellitus (IDDM)
2. Acute systemic immune complex disease
serum sickness
Anti-serum
Ab+Ag
Pinicillin、Sulfanilamide
systemic tissue injury ,fever, arthritis, skin rash
Acute immune complex glomerulonephritis :
Streptococcus infection
3. Chronic immune complex disease
SLE
Rheumatoid arthritis ：RF+IgG
Deposit on synovial membrane
5. Type IV hypersensitivity
1、characteristics of type IV hepersensitivity
2、 mechanism of type IV hepersensitivity
3、common diseases of type IV hepersensitivity
1. Characteristics
Interaction of primed T cells and associated antigen
Infiltration of Mononuclear Cells, Inflammatory response
2. Mechanism of type IV hypersensitivity
Formation of effector and memory T cells
Inflammation and cytotoxicity caused by effector T cells
1) Inflammation and tissue injury mediated by CD4+Th1
Release chemokines and cytokines
Immune injury mainly caused by infiltration of mononuclear cells and lymphocytes
2) Cytotoxicity of CD8+CTL
Delayed type hypersensitivity
Th1 cells and macrophages
• DTH response is from:
• Th1 cells release cytokines to activate macrophages causing inflammation and tissue
damage.
• Continued macrophage activation can cause chronic inflammation resulting in tissue
lesions, scarring, and granuloma formation.
• Delayed is relative because DTH response arise 24-72
hours after exposure rather than within minutes.
Stages of Type IV DTH
Sensitization stage
•Memory Th1 cells against DTH antigens
are generated by dendritic cells during
the sensitization stage.
•These Th1 cells can activate
macrophages and trigger inflammatory
response.
Stages of Type IV DTH
Effector stage
•Secondary contact yields what we call DTH.
•Th1 memory cells are activated and produce
cytokines.
•IFN-g, TNF-a, and TNF-b which cause
tissue destruction, inflammation.
•IL-2 that activates T cells and CTLs.
•Chemokines- for macrophage recruitment.
•IL-3, GM-CSF for increased
monocyte/macrophage
Stages of Type IV DTH
Effector stage
Secondary exposure to antigen
•Inflamed area becomes red and fluid filled
can form lesion.
•From tissue damage there is activation of
clotting cascades and tissue repair.
•Continued exposure to antigen can cause
chronic inflammation and result in granuloma
formation.
Antigen
Induce
T cell
(CD4+,CD8+)
CD4+
T cell
Release
Secondary
contact
Primed T cell
CD8+
T cell
Cytokines
IL-2
TNF-b
INF-g
TF
MCF
MIF
MAF
SRF
Infiltration of
monocyte and Mf
Proliferation of T cell
Exudation and edema
Cytotoxicity
Directly kill target cells
Inflammation characterized by infiltration of Mf , monocyte,
And tissue injury
Mechanism of type IV hypersensitivity
Figure 16.1
The DTH reaction
3. Common disease of type IV hypersensitivity
1) Infectious delayed type hypersensitivity
OT( Old Tuberculin ) test
2) Contact dermatitis :
Paint, drug
red rash, papula, water blister, dermatitis
3) Acute rejection of allogenic transplantation and
immune response in local tumor mass
Same disease (SLE), multiple immune injury ,hypersensitivity involved
Same drug (penicillin), several types of hypersensitivity
Tuberculin-type Hypersensitivity
 Tuberculosis Patient
 PPD(Ag derived from M.tuberculosis)
 Erythema & Induration
 Used as a diagnostic Test
 Not accurate.
Type IV DTH
Contact dermatitis
•The response to poison oak is a classic Type IV.
•Small molecules act as haptens and complex
with skin proteins to be taken up by APCs and
presented to Th1 cells to get sensitization.
•During secondary exposure Th1 memory cells
become activated to cause DTH.
Four types of Hypersensitivity Reactions
Type I
Type II
Ag
Y
IgE
Y
Target cell
IgG
Target
Fc receptor cell
Complement
Ab
Neutrophils
Endothelial cells
Fc recepKiller cell
Mast cells
tor
Ab
Histamine
Complement
Type III
Type IV
Ag
Ag
Th
Macrophage
Th
cell
Cytokines
Activated Macrophage
THANK YOU
-PHARMA STREET