PATHOGENESIS OF ALLERGY

Immunologic Diseases
Allergy
Autoimmunity
Immunodeficiency
 What is Allergy ?
Disease(s) in which immune responses to
environmental antigens cause tissue
inflammation and organ dysfunction.

Synonim : Hypersensitivity, sensitivity

 Allergen
Allergen is antigen that causes allergy.
The allergen can be inhalan, contactan or
ingestan, injectant
Is processed by the dendritic cell, an antigen-
presenting cell.
It can be complete protein antigens or low
molecular weight proteins capable of eliciting
an IgE response.
Pollen and animal dander represent complete
protein antigens.
 Atopy

Atopy is the inherited propensity to

respond immunologically to such common
naturally occurring allergens with
continuous production of IgE antibodies.
 Allergic diseases
Classification :
Type of immune response
Effector mechanism responsible for cells
and tissue injury
Two basic of allergic reactions:
Antibody mediated
T-cell mediated
 Types of Allergic Reaction

Allergic reactions require a pre-sensitized

(immune) state of the host.
Allergic reactions can be divided into four
types: type I, type II, type III and type IV
Frequently, a particular clinical condition
(disease) may involve more than one type of
reaction.
The four types of hypersensitivity reaction
type l type ll
allergen
cell surface antigen
lgG

target
K cell
lgE
cytotoxic action

Fc receptor antibody

complement target
mast cell degranulation complement cell
mediator release mediated lysis
type lll type lV
immune-complex
deposition antigens

complement T

inflammatory lymphokines
mediators

tissue
blood basement
membrane activated macrophage
vessel
 Classification of Allergic Diseases
Type of Allergic Pathologic immune Mechanisms of tissue injury and disease
Reaction mechanisms

Immediate IgE antibody Mast cells and their mediators (vasoactive amines,
hypersensitivity: lipid mediators, cytokines)
Type I
Antibody IgM, IgG antibodies against cell Opsonization and phagocytosis of cells
mediated: Type II surface or extracellular matrix Complement- and Fc receptor-mediated
antigens recruitment and activation of leukocytes
(neutrophils, macrophages)
Abnormalities in cellular functions, e.g., hormone
receptor signaling

Immune complex Immune complexes of circulating Complement- and Fc receptor-mediated

mediated: Type III antigens and IgM or IgG
antibodies
T cell mediated: 1. CD4+ T cells (delayed-type
Type IV hypersensitivity)
2. 2. CD8+ CTLs (T cell-
mediated cytolysis)
recruitment and activation of leukocytes
1. Macrophage activation, cytokine-mediated
inflammation
2. Direct target cell killing, cytokine-mediated
inflammation
 Type I Reaction
(Anaphylactic Type)
Prototype Disorders Immune Mechanisms
Anaphylaxis IgE-Mast cells
Allergic rhinnitis Vascular
Allergic asthma permeability
Allergic urticaria Eosinophils
Atopic dermatitis
 Pathophysiology
Induction and effector mechanisms in Type l Hypersensitivity

antigen

pharmacological effects
blood vessels
processing airways etc.
APC
and presentation cell infiltration
(see Fig. 19.22)

lgE Ca2+ l preformed

and newly
clinical effects
formed
asthma
mediators
TH Be eczema
IL-4 hay fever
lL-3, lL-4
cytokines (see Fig. 19.23)

lL-4, lL-5, lL-6 GM-CSF, TNFa feedback effects

IFNy on the immune
lL-8/9, inflammatory
cell activation system (see FSig. 19.23)

mast cell
antigen presentation lgE production mediator release clinical effects
activation
non IgE mediated
13
 Type I Reaction
Type I reactions are usually the result of
exposure to environmental allergens in
genetically susceptible individuals
1/10 persons in Indonesia affected to varying
degrees
Atopy: a genetic predisposition for
developing IgE responses to many antigens
Local or systemic symptoms
Type I Reaction (cont.)
Most common form :
Brochial asthma
Atopic dermatitis (eczema)
Allergic Rhinitis
Some food allergies
Allergens
Pollens, molds, house dust mite, animal
dander, certain foods,
 Resting mast cell Activated mast cell

Fce receptor lgE antibody

Resting mast cell shows Multivalent antigen crosslinks

granules containing serotonin bound lgE antibody causing release
and histamine of granule contents
 MAST CELLS MEDIATORS
Preformed Newly Synthesized
Histamine
Chemotaxin Leukotrien
-eosinophil Prostaglandins
-neutrophil PAF
Proteases Cytokine
-tryptase -IL-4, 5, 6, 8
-khimase -TNF-
 Histamine
Present in most tissues of the body, particularly high
concentration in lungs, skin, & GI tract.
Stored in mast cells and basophils
Receptors
H1, H2, H3
 Histamine
Main actions in humans:
Stimulation of gastric secretion H1
Contraction of most smooth muscle (except for blood
vessels) H1
Vasodilatation H1
Increased vascular permeability H1
 Histamine Receptors
Acts on H1 receptors to cause
Smooth muscle contraction
Increased vascular permeability
Prostaglandin generation
 Histamine Receptors
Acts on H2 receptors to cause
Increased vascular permeability
Gastric acid secretion
Stimulation of suppressor lymphocytes
Decreased PMN enzyme release
Release of more histamine from mast cells and
basophils
 Histamine Receptors
Acts on H3 receptors to cause
Inhibition of central, peripheral nervous system
neurotransmitter release
Inhibition of further histamine formation, release
Additional mediators of Inflammation
 Summary: Type I
Reaction

Antibody: IgE
Effector Cells: Mast Cell & Eosinophil
Complement: No
Reaction: Minutes
 Type II
(Cytotoxic reaction)
Cytotoxic or Type II Reactions: Binding of Antibody
(IgG or IgM) with cell membrane or tissue antigens
Red blood cell membrane antigens - hemolytic anemias
Platelet antigens - thrombocytopenia cell membrane -
petechial hemorrhage
Nuclear antigens (ds-DNA, RNA) -- LE
Basement Membrane - Goodpastures syndrome
Kidney - proteinuria
Lung - hemorrhage
 Type II
(Cytotoxic Reaction)
Prototype Disorders Immune
Hemolytic reactions Mechanisms
Goodpastures IgG
Syndrome Complement
Myasthenia Gravis Phagocytic cells
Graves Disease ADCC
(hyperthyroidism)
Lupus
erythematosus
 Mechanisms
Opsonin dependent phagocytosis
Complement-dependent Ab lysis
Antibody-dependent cell cytotoxicity
 Rh Incompatibility in Newborn:
Hemolytic Anemia

Sensitized during birth of

Rh+ First child

Pregnant woman
Rh-

2nd pregnancy forms circulating

Rh+ child lgG antibody (Anti-D)

IgG crosses placenta

RBC hemolysis

Preventative Therapy: Block sensitization by giving mother

anti-D (Rho) Immunoglobulin within 72
hours after first birth or abortion
 Type III, Immune Complex
Disease
Prototype Disorders Immune Mechanisms
Post-streptococcal Ab-Ag reactions
glomerulonephritis Complement
Vasculitis Neutrophils
Polyarteritis nodosa Fibrin, hemorrhage
Pemphigus vulgaris
Pemphigoid bulosa
The four types of hypersensitivity reaction
type l type ll
allergen
cell surface antigen
lgG

target
K cell
lgE
cytotoxic action

Fc receptor antibody

complement target
mast cell degranulation complement cell
mediator release mediated lysis
type lll type lV
immune-complex
deposition antigens

complement T

inflammatory lymphokines
mediators

tissue
blood basement
membrane activated macrophage
vessel
Type III: Immune Complex Mediated Tissue Injury

antibody antigen

Ag-Ab complex

Complement Monocyte/macrophage
activation activation

Cytokines
C5a
(e.g. TNF, chemokines)

Neutrophil influx
J. Fantone
Summary: Immune Complex Mediated Tissue Injury

Neutrophil influx

Phagocytosis of immune complexes

Oxygen metabolites Lysosomal enzymes

O2-, H2O2 etc. Proteases etc.

Tissue injury

J. Fantone
Pathology of Immune Complex Injury

Fibrinoid necrosis
Hemorrhage
Neutrophils
Antibody + Complement deposition
EM: Electron dense depositis
Granular immunofluorescence
 Immune Complex-Mediated
Hypersensitivity (Type III) (cont.)

Pathology
Light microscopy: neutrophils, hemorrhage,
edema
Electron microscopy: electron dense
deposits
Immunofluorescence: immunoglobulin and
complement deposition, granular
immunoflouresence pattern
 Immune Complex-Mediated
Hypersensitivity (Type III) (cont.)

Clinical - depends on target organ and/or site of

immune complex deposition
Synovium - rheumatoid arthritis
Kidney - glomerulus
Post-streptococcal glomerulonephritis
Systemic lupus erythematosus
Blood vessel walls - vasculitis
Polyarteritis nodosa
Early transplant rejection
Lung - hypersensitivity pneumonitis
 Immune Complex-Mediated
Hypersensitivity (Type III) (cont.)
Diagnosis
Skin tests for Type III reactions

Therapy
Elimination of antigen - as in transfusion
reactions, hypersensitivity lung reactions to
foreign antigens, and certain drug reactions
Corticosteroid and immunosuppressive therapy
(cytoxan, cylosporin)
Plasmapheresis
Summary: Type II/III Reaction

Antibody: IgM & IgG

Effector Cells: Phagocytic
Complement: Yes
Reaction: 6-24 hours
 Type IV, Cell-Mediated
(Delayed) Hypersensitivity
Prototype Disorders Immune Mechanisms
Contact Dermatitis T-lymphocytes
Leprosy Monocyte/macro-
(granulomatous
inflammation)
phage
Cytotoxic T-cell
Dr. Kings lectures
The four types of hypersensitivity reaction
type l type ll
allergen
cell surface antigen
lgG

target
K cell
lgE
cytotoxic action

Fc receptor antibody

complement target
mast cell degranulation complement cell
mediator release mediated lysis
type lll type lV
immune-complex
deposition antigens

complement T

inflammatory lymphokines
mediators

tissue
blood basement
membrane activated macrophage
vessel
type IV
antigens

inflammatory
mediators
lymphokines

activated macrophage
Source Undetermined
J. Fantone
Summary: Type IV Reaction

Antibody: No
Effector Cells: T-lymphocytes,
Monocyte/Macrophage
Complement: No
Reaction: 48-72 hours (skin test)