HIPERSENSITIVITY

TISSUE DAMAGE
INAPROPRIATE IMMUNE RESPONSE DUE TO :
EXESSIVE AMOUNT OF ANTIGEN
HEIGHTENED LEVEL OF IMMUNE RESPONSE
 NK

Cytotoxic action

Mast-cell degranulation
Mediator release
Complement mediated lysis

I II
 IL-4,5

Th2

Th0
Th1

IFN-g

IFN-g, IL-2

CTL
CTL

Immune-complex deposition Cell-mediated hypersensitivity

III IV
 CLASSIFICATION :
GELL & COOMBS :

1. TYPE I : ANAPHYLACTIC REACTIONS

2. TYPE II : CYTOTOXIC REACTIONS
3. TYPE III : IMMUNE COMPLEX-MEDIATED REACTIONS
4. TYPE IV : CELL-MEDIATED REACTIONS

Characteristic Type I Type II Type III TypeIV

Antibody IgE IgG,IgM IgG, IgM None
Antigens Exogenous Cell surface Soluble Tis/Org
Transferred by Antibody Antibody Antibody T-cells
Histology Basophils. Antibody Complement Monocytes
Eosinophils Complement Neutrophils Lymphocytes

Back
 Anaphylactic reaction ( Type I )
Allergic reaction
IgE

Mast Cell
Histamin, Serotonin, Lekotrien,
Prostaglandin, TNF , etc…….

Back
 Allergic reaction Rhinitis
IgE
Asthma

Mast Cell
Histamin, Serotonin, Lekotrien,
Prostaglandin, TNF , etc…….
Urtica

Diarrhoea

Back
 Molecular events of histamine release
Allergens

Ca2+ IgE

cAMP

Phosphodiesterase

AMP
Adenylate
cyclase

cAMP

Histamine
Histamine Receptor Targert organs
Back
 SKIN TEST

ALERGENS

Back
 Mosmann 1986

Th1 Th2
IFN-g

IL- 4

IL-4
IFN-g IL-5
IL-2 IL-6
IL-10

Cellular dominant Humoral dominant

Back
 Peripheral Blood Mononuclear Cells

Cytokines

IFN-g IL-12

TYPE 1 TYPE 2
IL- 4 Il-10 IL-4
IFN-g
IL-5
IL-2
IL-6
IL-12
IL-10
IL-13

Cellular dominant Humoral dominant

Domination of Type II cytokines induces allergic reactions

Back
 Abbas 2000

Back
 Mast cell

PREFORMED NEWLY SYNTHESIZED

Histamine : vasodilation, increase Lipoxygenase pathway :
permeability, bronchoconstriction
Leukotriene C4 , D4 ( SRSA) , Leukotriene B4 :
Vasoactive, bronchoconstriction, chemotaxis
ECF : Eosinophil chemotaxis
NCF : Neutrophil chemotaxis
Cyclo-oxygenase pathway :
Prostaglandin , tromboxane :
PAF : Mediator release
Affect bronchial muscle, platelet aggregation ,
vasodilation
IL-3,4,5,6,
TNF : Ig E production, eosinophil
maturation, acute phase response

Back
 Mast cell activation
and granule release

Gastrointestinal Airways Blood vessels

Increased fluid Decreased diameter, Increased blood flow,
secretion, Increased increased mucus increased permeability
peristalsis secretion

Expulsion of Expulsion of airway Increased of :

gastrointestinal content content ( coughing,
Fluid, cells and protein
(diarrhea, vomiting) phlegm )
, effector respone in
tissues
Back
 PREFORMED :
MBP, ECP Toxic to helminths, bacteria, host cells
Eosinophil peroxidase
Lysosomal hydrolase Tissue damage, remodelling
Lysophospholipase

EOSINOPHIL NEWLY SYNTHESIZED

Leukotriene C4, D4, E4 Incr. Permeability, bronchoconstriction
mucus secretion
Lipoxin Promote inflammation

IL-3, 5, GM-CSF Eosinophil production and activation

IL-8, 10, RANTES
Eotaxin, MIP-1alpha Chemotaxis of leukocytes

Back
 Membrane
Phospholipid

Phospholipase

ARACHIDONIC ACID

cyclooxygenase lipoxygenase

Prostaglandin endoperoxide 5-H PETE

Leukotriene A4
Thromboxane
synthetase gluthathione

Thromboxane A2 Prostaglandines Leukotriene Leukotriene 5-HETE

C4, D4 , E4 B4

Vasoconstriction, Vasoactive agents SRS-A , Bronchial Leucocyte activation

Pletelet smooth muscle
aggregation contraction
Back
 Early phase ( 0 –1 ) Late phase ( 6-8 ) Very late phase (24-48)

MBP, ECP,
Macr EDN etc.
B
Il-3, Il-4
IL-5, IL-8
GMCSF
Mast cell
Th2 Eos
MBP, ECP,
IL-3, IL-4 EDN etc.
IL-5, IL-6
IL-13
TNF
Th2 RANTES
IL-4
IL-5
Histamine, IL-8
Leukotriene, GM-CSF IL-4, IL-13
Prostaglandin MIP-1 MIP-1
etc MCP-3
Bas
RANTES
Eotaxin,
GM-CSF

Adhesion
molecules
CYTOTOXIC REACTIONS ( TYPE II )

ANTIBODY-DEPENDENT CYTOTOXIC HYPERSENSITIVITY

INVOLVE PRIMARILY ANTIBODY (IgG OR IgM) REACTING WITH

CELL BOUND ANTIGENS THAT LEADS TO DESTRUCTIVE
PROCESSES

Mechanisms of destructive processes :

1. Lysis via Complement activation
2. Phagocytosis of target cells
3. ADCC through natural killer cells (NK)

Back
 C3

Fc receptor Complement C3 receptor

mediated lytic pathway mediated
CLINICAL FEATURES :

AlloimmuneReactions:
Red blood cells lysis : ABO blood group
Platelet transfusion : HLA antigen
Rhesus Incompatibility
Organ Transplantation

Autoimmune Reactions
Goodpasture’s syndrome
Granulocytopenia
Autoimmune hemolytic anemia
SLE
Idiophatic thrombocytopenic purpura
Transfusion Reactions
Occur when a recipient has antibodies that react against donor erythrocytes
Antibodies to ABO antigens usually IgM and cause agglutination, complement
activation and intravascular hemolysis.
Other blood group induces IgG. The IgG sensitized cells are usually taken up by
phagocytic cells in the liver or spleen, although severe reaction may cause
erythrocytes destruction by complement activation. These transfusion reaction may
occur in unsensitized individuals and develop over days or weeks after the transfusion
as antibodies against the foreign antigens are produced.

Five major blood group system involved in transfusion reaction

ABO A, B or O
Kell K or k
Duffy Fya, Fyb or Fy
Rhesus C or c; D or d; E or e
MN M or N
 NK

Cell lysis due to complement

activation, phagocytosis and NK
cell’s antibody-dependent cell-
Complement mediated cytotoxicity (ADCC)
mechanism
Hemolytic Disease of the Newborn (HDNB)

HDNB occurs when the mother has been previously sensitized to the infant’s erythrocytes
and makes IgG antibodies. These antibodies cross the placenta and react with the fetal
erythrocytes, causing cells destruction.
Rhesus D (RhD) is the most commonly involved antigen
The risk of HDNB due to Rh incompatibility will be reduced if the father is of different ABO
group to mother. Why ? ABO is more immunogenic than Rh antigens. The cells will be
destroyed before the Rh antigens sensitize the mother !

Hyperacute graft rejection

Occurs when preformed cytotoxic antibodies present in recipient’s blood. Te most severe
reactions in this type of rejection are due to ABOand HLA antigens.
Tissue matching is very important for donor selection.
Autoimmune haemolytic anaemias
Arise spontaneously as autoimmune diseases, or may be indirect as reactions to
drugs
AIHA can be devided into 3 types, depending upon whether they are due to :
Warm autoantibodies (react with antigens at 37 c)
Frequently found against Rhesus system antigens, The cause is unknown but
some are associated with other autoimmune diseases. The anaemia to be a result
of accelerated clearance of the sensitized erythrocytes by spleen macrophages as
well as complement-mediated lysis.
Cold-reactive autoantibodies
The antibodies are primarily IgM and fix complement strongly. In most cases
specific for Ii blood group. Some cases may follow infection with Mycoplasma
pneumoniae due to cross reacting antigens. Cells destruction occurs in the
peripheral circulation (particularly in winter) due to complement-mediated lysis.
Drug induced reaction to blood components
May occurs in three different ways:
The drug bind to red blood cells and antibodies are produced against the drug :
sedormid, penicillin, quinin, sulphoamide
Immune complex consists of drug-antibody absorbed on to the erythrocytes
The drug is absorbed on to cell membrane , induces an autoantibodies against cell
membrane.
REACTIONS AGAINST TISSUE ANTIGENS

Good pasture’s syndromes

Antibodies to collagen type IV, a major group component of basement membrane.
The antibody usually IgG fixing complement

Pemphigus
Autoantibodies against desmoglein 1 and 3 (component of desmosomes) which
form the junction between epidermal cells. The antibody is IgG4 against a different
part of the molecule.
Strongly associated with HLA-DR4 (DRB1*0402)

Myasthenia gravis
Autoantibody against Acetylecholine receptors located at the motor endplate where
the neuron contact the muscle.
Anti-glomerular basement membrane
(Immunofluorescence Test)
 IMMUNE COMPLEX MEDIATED REACTION (TYPE III)

INITIATED BY ANTIGEN-ANTIBODY (IMMUNE COMPLEX) THAT

EITHER ARE FORMED LOCALLY AT THE SITE OF TISSUE
DAMAGE OR DEPOSITED FROM THE CIRCULATION

MECHANISMS OF TISSUE DAMAGE:

1. Complement acivation
2. Attraction of PMN which release tissue-damaging mediators
3. Platelet aggregation causing microthrombi and vasoactive amine
release

Back
 CLINICAL FEATURES

ARTHUS REACTION: local IC formation :

Rheumatoid arthritis, Pigeon fancier’s disease,
farmer’s lung disease.

SERUM SICKNESS: soluble IC : systemic:

glomerulonephritis, vasculitis, chorioiditis,

Back
IMMUNOPATHOLOGY

Immune complex

Platelet
Immune-complex
Complement Proteolytic enzymes ,
Inflammatory mediators,
Macrophage etc

PMN Back
IMMUNOPATHOLOGY

Immune complex

Platelet

Complement Proteolytic enzymes ,

Inflammatory mediators, Immune-complex
Macrophage etc

PMN Back
IMMUNOPATHOLOGY

Immune complex
 CELL-MEDIATED REACTIONS (TYPE IV)
DELAYED HYPERSENSITIVITY AND CELL-MEDIATED
CYTOTOXICITY (TYPE IV)

Pathogenic mechanisms:
Effector cells :
CD4+Th1 cells that activate macrophages and other cells through
cytokines secretion

CD8+ ( T cytotoxic cells ) which are directly cytotoxic to target cells by

releasing perforin / granzyme.

Eosinophils mediated cells destruction

Back
 CELL-MEDIATED (TYPE IV) REACTIONS : DELAYED
HYPERSENSITIVITY AND CELL-MEDIATED CYTOXOXICITY

CELLS / MEDIATORS INVOLVED IN TYPE IV REACTIONS ;

LYMPHOCYTES ( TH1 CD4+ )

MACROPHAGES

CTL (T CYTOTOXIC CD8)

CYTOKINES (IFN-g, IL-2 also TNF, IL-1,6 and 8)

Back
 IL-4,5

Th2

Th0
Th1

IFN-g

IFN-g, IL-2

CTL
CTL
Back
 CLINICAL FEATURES :

INFECTIONS
BACTERIAL ( TUBERCULOSIS, LEPROSY)
FUNGAL ( BLASTOMYCOSIS AND HISTOPLASMOSIS)
VIRAL ( HERPES AND MUMPS )
PROTOZOAN ( LEISHMANIASIS )
WORMS ( SCHISTOSOMIASIS, TRICHINELLOSIS )
TUMORS
CONTACT DERMATITIS
GRAFT REJECTION
LATE PHASE OF ALLERGIC RHINITIS / ASTHMA
Back
 IFN-g Th1

Th1

Back
Granuloma

Back