hypersensitivity final.ppt

Introduction
• What is hypersensitivity?
• It is excessive immune response which
leads to undesirable consequences, i.e.
tissue or organ damage/ dysfunction.

Hypersensivity
Reactions
Allergies Greek = altered reactivity
1906 – von Pirquet coined term: hypersensitivity
Hypersensitivity reactions – ‘over reaction’ of
the immune system to harmless environmental
antigens

• Hypersensitivity refers to undesirable
(damaging, discomfort-producing and
sometimes fatal) reactions produced by
the normal immune system
• Hypersensitivity reactions require a pre-
sensitized (immune) state of the host
• Hypersensitivity (Allergy): An
abnormal response to antigens.

Classification
Four Types of Hypersensitivity Reactions:
• Type I (Anaphylactic) Reactions
• Type II (Cytotoxic) Reactions
• Type III (Immune Complex) Reactions
• Type IV (Cell-Mediated) Reactions/Delayed

Four Types of Hypersensitivity Reactions:
• Type I (Anaphylactic) Reactions
• Type II (Cytotoxic) Reactions
• Type III (Immune Complex) Reactions
• Type IV (Cell-Mediated) Reactions
• Type V Stimulatory hypersensitivity

• Anibody mediated – I, II, III
• Cell mediated – IV

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

Type I hypersensitivity
• IgE mediated, immediate hypersensitivity/
allergy
• Major features:
React and disappear quickly on re-
exposure to Ag
Dysfunction rather than severe tissue and
cell damage occurs
Obvious individual difference and genetic
correlation

1) Characteristics
Occur and resolve quickly
Mediated by serum IgE
Systemic and regional tissue dysfuntion
Genetic predisposition

•Allergens are small Ags, usually
inocuous
•B cells produced IgE
• Occur within minutes of exposure
to antigen
•Anaphylactic shock: Massive drop
in blood pressure. Can be fatal in
minutes.

Type I Hypersensitivity
• Mechanism
– Allergen is recognized by naïve B cell
– B cell stimulated by T helper cell through IL4
– IgE specific for allergen is recognized by mast
cell
– Cross linkage of IgE on mast cells
– Mast cell degranulates

Increase in Atopic Allergy
• Environmental factors
– Exposure to pathogens in childhood
• Measles, HepA, tuberculosis exposure beneficial?
– Environmental pollution
• Eg. Children in Hale, East Germany
– Allergen levels
• No evidence of rise
– Dietary changes
• No evidence of effect

• Genetics factors and Allergies
– Cytokines and their receptors
– MHC II genes
– Other polymorphisms

What are mast cells and basophils?
Basophil- rare blood cell
Mast cells- found in connective tissue
Granules contain active mediators

Events in an allergic reaction:
First exposure
B cells produce allergen-specific IgE Ab
Tail of IgE Ab reacts with Fc receptors on
mast cells, leaving Fab’s directed away
from the cell surface
Second exposure
Allergen enters body, cross-links IgE on
mast cell in mucous membranes, skin, and
triggers release of chemicals  symptoms

Mast Cells and the Allergic
Response

EFFECTS OF MAST CELL
DEGRANULATION

Mast Cell Degranulation
• Leukotrienes
– Smooth muscle contraction; vascular permeability
• Platelet activating factor
– Activates platelets
• Histamine
– Vascular permeability; smooth muscle contraction
• Cytokines
– IL4- Stimulates T helper response
– IL3- Activates eosinophils
– TNF- Promotes inflammation
• Chemokines
– MIP- Attracts macrophages

Effects of type I reactions
Systemic anaphylaxis
Respiration becomes difficult
Blood pressure drops
Smooth muscles of bladder and GI tract
contract
Bronchoconstriction
Countered by epinephrine
relaxes smooth muscles
decreases vascular permeability
improves cardiac output

Localized anaphylaxis
Allergic rhinitis (hay fever)- nasal mucosa
Asthma- lower respiratory tract
bronchoconstriction,
edema
mucus
inflammation

Early phase response: short-lived,
resolve within 1 hr. Increase of
vasopermeability, smooth muscle
contraction, gland hypersecretion and
vasodilation
Late phase response: inflammation,
peak at around 5 hrs, last for several
days. Eosinophils, mast cells, basophils,
T-cells and neutrophils infiltration.

Early response - histamine, leukotrienes,
prostaglandins
bronchoconstriction, vasodilation,
smooth muscle contraction
Late response - IL-4, TNF-, etc.
endothelial cell adhesion
Also leukocyte migration, leukocyte
activation factors
Neutrophils (also eosinophils) cause a lot of
tissue damage

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 in the lamina prapria
special affinity to the same cell
IL-4 is essential to switch B cells to IgE production
High affinity receptor of the IgE on mast cell and basophil
Eosinophil
2) Components and cells in Type I hypersensitivity

3 The process and mechanism of Type I hypersensitivity
1) Priming stage： last more than half a year
2) Activating stage：
Crosslinkage Enzyme reaction Degranulation of mast cell , basophil
3) Effect stage：
Immediate/early phase response: Mediated by histamine
Start within seconds
Last several hours
Late-phase response ： Mediated by new-synthesized lipid mediators
Take up 8-12hours to develop
Last several days

4. Skin allergy:
4. Common disease of type I hypersensitivity
1. Systemic anaphylaxis: a very dangerous syndrome
1) Anaphylactic drug allergy ：penicillin
2) Anaphylactic serum allergy ：
2. Respiratory allergic diseases :
1) Allergic asthma：acute response, chronic response
2) Allergic rhinitis
3. Gastrointestinal allergic diseases :
The lack of SIgA protein hydrolase Undigested protein
Allergen

Atopy
• Allergic rhinitis: Hay fever, airborn
allergens, symptoms include shedding
tears, sneezing, coughing, etc.
• Asthma: airborn/blood-born allergens.
Occur in lower respiratory tract
Cardinal clinic and physiological
features: variable airflow obstruction,
bronchial hyper-responsiveness.

• Food allergies: diarrhea, vomiting, wheal
and flare reaction
• Atopic dermatitis: eczema, urticaria. itch,
desquamation, pachyderma

DIAGNOSTIC TESTS FOR IMMEDIATE
HYPERSENSITIVITY INCLUDE
• skin (prick and intradermal) tests
• measurement of total IgE and specific IgE
antibodies against the suspected allergens
• Total IgE and specific IgE antibodies are
measured by a modification of enzyme
immunoassay (ELISA)
• Increased IgE levels are indicative of
an atopic condition, although IgE may be
elevated in some non-atopic diseases (e.g.,
myelomas, helminthic infection, etc.)

5. Therapy of type I hypersensitivity
1. Allergen avoidance : Atopy patch test
2. Desensitivity therapy / Hyposensitization :
1) Allogenic serum desensitivity therapy:
2) Specific allergen desensitivity therapy
Repeated injection small amounts of allergen, Temporality
IgG+allergen Neutralizing antibody, Blocking antibody
3. Drug therapy：
1) Stabilization of triggering cells
sodium cromoglycate stabilize the membrane, inhibit mast cell degranulation
2) Mediator antagonism
Chlor-Trimeton Antihistamine
Acetylsalicylic acid Bradykinin antagonism
3) Improve the responsibility of target organs
4. New immunotherapy ：

TYPE II (CYTOTOXIC) REACTIONS
– Involve activation of complement by IgG or IgM
binding to an antigenic cell.
– Antigenic cell is lysed.
– Transfusion reactions:

• Mediated by IgG and/or IgM
• Mechanism:
Ag present on the surface of cells→ im-
munity activation→Ab→tissue damage/
dysfunction
Tissue damage caused by:
Opsonic adherence: phagocytosis
Complement: membrane damage
ADCC: cell destruction
Type II hypersensitivity

Mechanism of tissue damage of typeⅡ
hypersensitivity

Type II Hypersensitivity
• Cell associated antigens
– Transfusion reactions
– Hemagglutinins
– Complement mediated
– Clinical symptoms include fever, chills,
nausea

Characteristic features
Primed IgG or IgM + Antigen or hapten on membrane
Injury and dysfunction of target cells

Type II associated diseases
• Transfusion reaction: mismatched blood
transfusion cause complement-mediated
hemolysis.
ABO blood group: isohemagglutinins(IgM)
Prevention: cross-matching between
donor and recipient blood

Heamolytic diseases of newborn
• Rh incompatibility: Rh blood groups
Rh- mother has the first Rh+ baby→
mother sensitized by baby’s erythrocy-tes
→anti-Rh IgG
Mother has the second Rh+ baby→ IgG
enter the fetus through placenta→
destruction of fetal RBC

Hemolytic disease of the newborn due to
rhesus incompatibility

Drug-induced hemolytic anemia
• Drug adsorb RBC proteins→Anti-RBC
IgG/IgM→complement, opsonization,
ADCC →RBC lysis, anemia

Grave’s disease and myasthenia
gravis
• Special class of type V hypersensitivity,
Autoimmune diseases, tissue/organ
dysfunction
• Grave’s disease: anti-TSH receptor
• Myasthenia gravis: anti-acetylcholine
receptors

Myasthenia gravis
Grave’s disease

Allergen
Stimulate
Antibody
A. Opsonic phagocytosis
D. ADCC of NK
C. Effect of complement
Combined opsonic activities
Cell injury ways of type II hypersensitivity
Cell

2. Mechanism of Type II hypersentivity
1. Surface antigen on target cells
Target cells: Normal tissue cell, changed or modified self tissue cells
2. Antibody, complement and modified self-cell
Antigen : Blood group antigen, Common antigen,
Self-antigen modified by physical factors or infection
Drug antigen,
Antigen-antibody complex
Activate complement Lyse target cells
Opsonic phogacytosis Destroy target cells
ADCC
Mf、NK、 T
Stimulating or blocking effect Promote /surpress the target cell funcion

Antigen or hapten on cell
Antibody (IgG, IgM)
Activate complement
Lyse target cell
Opsonic phagocytosis NK , phagocyte Stimulate / block
Destroy target cell ADCC
Target cell injury Change the function ofTarget cell
Mechanism of Type II hypersensitivity

3. Common disease of type II hypersensitivity
1)Transfusion reaction
hemolysis : mismatch of ABO blood group, severely destroy RBC
nonhemolysis : repeat transfusion of allogenic HLA
drug anaphylactic shock：penicilline
2) Hemolytic disease of newborn
Mother Rh- : first baby Rh+(Ab), second baby Rh+,
fetal RBC destroyed
3) Autoimmune hemolytic anemia and type II drug reaction
i. Foreign antigen or hapten
Penicillin RBC hemolytic anemia
Quinin Platlet thrombocytopenic purpura
Pyramidone Granulocyte agranulocytosis
ii. Self-antigen
Drug conversion from a hapten to a full antigen
induce self antibody autoimmune hemolytic anemia

4.Anti -glomerular basement membrane nephritis
β-Hemolytic streptococcus and human glomerular basement membrane
----
cross
reaction
Common antigen ---nephrotoxic nephritis
5. Super acute rejection in allogenic organ
transplantation
6. Goodpasture syndrome
7.Hyperthyroidism or hypothyroidism—receptor
diseases

• Diagnostic tests include detection
of circulating antibody against the
tissues involved and the
presence of antibody and
complement in the lesion (biopsy)
by immunofluorescence.

Typical diseases of
anaphylaxis
• Systemic anaphylaxis(anaphylactic
shock): fatal, venom from bee, wasp;
drugs such as penicillin, antitoxins, etc.
• Localized anaphylaxis(atopy): the tend-
ency to manifest localized anaphylaxis is
inherited and called atopy. typical
diseases: asthma, hayfever, eczema,
food allergy, etc.

hypersensitivity final.ppt

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