Department of Pathology,

Faculty of Veterinary Medicine,

Zagazig University, Egypt.

HypersensitivityBY

Prof. Dr. Mohamed Hamed Mohamedmohamedelariny@yahoo.com

+201224067373

2012

HypersensitivityAllergy

It is abnormal antigen-antibody reaction which damage the cells of the body (produced

by the normal immune system). Hypersensitivity requires a pre-sensitized (immune)

state of the hosts.

Allergens: They are antigens which produce a harmful effect and may be bacterial, non

bacterial or even simple chemical substance.

Mechanisms of hypersensitivity: There are four different mechanisms:

-Type I-hypersensitivity.

-Type II-hypersensitivity. Immediate Hypersensitivity

-Type III-hypersensitivity.

-Type IV-hypersensitivity. Delayed Hypersensitivity

-All forms of hypersensitivity, except type IV, are mediated by antibodies.

Type IV is mediated by T-lymphocytes and macrophages.

Immediate Delayed-Immediate onset (up to 12 hours). -Delayed onset (after 12 hours).

-Circulating antibodies (humoral). -Cellular immunity (no antibodies).

-Passive transfer by serum. -Passive transfer by cells.

-Affect smooth muscle, blood vessels and collagen. -Affect any tissue.

-Not affected by the rout of administration. - Almost through the skin.

-Types include: Type I,II and III. -Types include: Type IV.

Types of Immediate Hypersensitivity:1-Type-I Hypersensitivity (Cytotropic Anaphylaxis).

2-Type-II Hypersensitivity (Cytotoxic) Anaphylaxis.

3-Type-III Hypersensitivity (Aggregate) Anaphylaxis.

1-Type-I Hypersensitivity (Cytotropic Anaphylaxis)

Components and cells: i-Allergen:

pollen, dust, mite, insects etc

selectively activate CD4+Th2 cells and B cells

ii-IgE and its production:

IgE： mainly produced by mucosal B cells in the lamina propria. It has

special affinity to the same cells

IL-4: is essential to switch B cells to IgE production

iii-High affinity receptor of the IgE on mast cell and basophil.

iv-Eosinophil

Chemical Mediators:

A-Primary Mediators (Preformed mediators in granules):1-Histamine: dilated blood capillaries, increase the vascular permeability, increase

mucus secretion and smooth muscle contraction.

2-Serotinin: as histamine.

3-Eosinophil-chemotactic factor of anaphylaxis (ECF-A): attraction of

eosinophils to the site of hypersensitivity reaction.

4-Neutrophil-chemotactic factor of anaphylaxis (NCF-A): neutrophils

chemotaxis.

5-Proteases (Tryptase): increase the mucus secretion and ct. degradation

(proteolysis).

B-Secondary Mediators (Newly formed mediators):1-Leukotrienes (B4, C4, D4): similar to histamine but more potent. It induces

bronchial smooth muscles contraction (asthma).

2-Prostaglandins (D2): high concentration of PGE inhibits the secretion of

histamine. While the low concentration of PGE could promote the release of

histamine. Increase vascular permeability (edema), smooth muscles contraction and

platelet activation.

3-Platelet activating factor (PAF): platelet aggregations (Microthrombi) and

heparin release.

4-Bradykinin: similar to PGE and causes vasodilation.

5-Cytokines: They have numerous effects as

i-Activation of endothelium.

ii-Eosinophil recruitment.

NB; The complement is not necessary.

Anaphylactic Shock:In Guinea Pig:It dies within 10 minutes due to asphyxia caused by bronchial muscles contraction

(Mast cells concentrated around bronchioles) bronchostenosis (Partial).

Lesions: “Acute diffuse alveolar emphysema”.

IN Dog: It shows epileptiform fits, coma and death within 1-2 hours of restlessness,

diarrhea and vomiting due to falling of blood pressure

Lesions: pooling of blood in the liver and mesenteries due to contraction of venous

passages, especially the hepatic vein.

In Cattle: It shows cutaneous edema around the eyes, vulva and dyspnea.

In Rabbit: It shows constriction of pulmonary artery and dilation of the right heart.

In Rat: It shows increase vascular permeability and intestinal hemorrhage.

The lesions of anaphylactic shock can be summarized as1-Spasm of the smooth muscles of blood vessels and bronchioles.

2-Damaged endothelium of blood vessels with increase permeability.

3-Damaged connective tissue fibers

Atopy (Local anaphylaxis): It is a local anaphylactic reaction of type I hypersensitivity (atopic or

allergic dermatitis). It is common in dogs.

2-Type-II Hypersensitivity (Cytotoxic Anaphylaxis)

Mechanism of Type II hypersensitivityAntigen or hapten on cell

+

Antibody (IgG, IgM)

Activate complement Opsonic phagocytosis NK , phagocyte Stimulate / block

Lyse target cell Destroy target cell ADCC

Target cell injury Change the function

of Target cell

There are two mechanisms by which antibody and complement mediate

type II hypersensitivity: 1-Antibody reacts with the antigen present on the surface of the cells causing

activation of the complement system and resulting in formation of membrane

attack complex, resulting cell lysis.

2- The cells become susceptible to phagocytosis (opsonization) by fixation of

antibody or C3b fragment to the cell surface.

3-Type-III hypersensitivity (Aggregate Anaphylaxis)The hypersensitivity-III is immune complex-mediated reaction. This complex

is deposited either locally or systematically with activation of complement

and acute inflammation.

Pathogenesis:

Types of immune complex reaction:1-Local form: Arthus reaction :

2-Systemic or general form: Serum sickness :

Local Form:

Arthus reaction: It is immediate hypersensitivity characterized by vasculitis.

Pathogenesis: The subcutaneously injected antigen into sensitized animal diffuses away

from the site of injection into the small blood vessel-walls and formed

immune complex beneath the endothelial cells and leads to release

complement (C3a and C5a) attract the neutrophils to the site of

injection. The neutrophils release lysosomal enzymes causing

damage of the wall of b.vs. Edema, hemorrhages, thrombosis

and necrosis.

NB: If the neutrophil is blocked, the reaction does not occur.

Microscopic Lesions:i-Vasculitis with necrotic vessel-wall (small b.vs. and capillaries) and

massive aggregation of neutrophils with serofibrinous inflammation

(fibrinoid necrosis).

ii-Hemorrhage and edema (due to increase the permeability).

iii-Thrombosis and infarction.

Systemic or general form:

Serum sickness : It has two types.

i-Acute Serum Sickness

ii-Chronic Serum Sickness

Acute serum sickness: It develops without previous sensitization to the responsible antigen. A

large single dose of antigen is injected as horse serum. A part of this

antigen acts as preparatory dose and to produce specific antibodies and

the second part acts as eliciting to and combined with produced

antibodies forming Ag-Ab complex in the blood circulation.

Large blood vessels, endocardium and renal glomeruli are affected.

Chronic serum sickness: It results of repeated intravenous exposure to antigen which results in

immune complex formation in blood.

Delayed Hypersensitivity

Type-IV Hypersensitivity

Cell-mediated Hypersensitivity

Types of delayed hypersensitivity:1-Bacterial hypersensitivity. 2-Contact dermatitis hypersensitivity.

3-Transplant rejection. 4-Fleea-bite dermatitis.

5-Drug hypersensitivity.

Bacterial hypersensitivity:Numerous bacterial infection causes delayed hypersensitivity as tuberculosis,

brucellosis and glanders. It is manifested by erythema and edema to necrosis.

Koch phenomenonIt is the reaction caused by tubercle bacilli in normal and immunized

guinea pigs. The normal one develops hard nodules at the site of

injection within 2 weeks. These nodules are ulcerated and the animals

die from generalized tuberculosis within 2 months. The tuberculous

guinea pig develops inflammatory edema and necrosis at the site of

injection within 1-2 days. The necrotic area sloughs and heals with scar

formation, and the animal does not die. Microscopically, granulomatous

reaction is seen (Macrophages, lymphocytes and epithelioid cells besides

fibrous tissue capsule).

Transplant rejection:The immunologic reactivity against transplanted cells may be directed

against many antigens on the surface membrane of cells such as

i-Antigens on erythrocytes

ii-Antigens on surface of nucleated cells as MHC class I.

Graft rejection occurs when the recipient's immune system recognizes

the graft as foreign, and destroys it. There are several different kinds

of grafts:

Autograft: tissue transferred from one site in the body to another in

the same individual.

Isograft: tissue transferred between genetically identical individuals

Allograft: tissue transferred between genetically different individuals

of the same species

Xenograft: tissue transferred between different species

Autografts and isografts are usually accepted (because graft and host

are genetically identical). Allografts are often rejected as foreign. Xenografts

have the most genetic disparity, and are often vigorously rejected. "Graft

rejection" usually refers to allograft rejection (because autografts and

isografts don't induce rejection, and xenografts are rare events).

Mechanism of transplant rejection

i-Direct pathway of graft rejection (recognition): It is mediated by CD8 cytotoxic T lymphocytes which cause cell injury and

tissue damage

ii-Indirect pathway of graft rejection (recognition): It mediated by recipient's T lymphocytes that recognize antigen on the graft

presented by the antigen presenting cells of the recipient. It is depend on

the activation of CD4 lymphocytes and attracted by mediators (cytokines or

lymphokines) which released from T-cells (delayed hypersensitivity).

Major histocompatibility complex (HLA):It is a collection of genes on chromosome 6.

Class I genes: for recognition so it present on all nucleated cells.

Class II genes: for body defense so it present on macrophages, dendritic cells, T

and B lymphocytes.

Class III genes: encode products of complement protein and TNF.

Koch Phenomenon: It is the reaction caused by tubercle bacilli in normal and

immunized guinea pigs.

Koch blue bodies: It is lymphoid form of the theileria in lymph nodes and

spleen.

Koch Postulate: It is a diagnostic test for reappearance the symptoms of a

disease by experimental animals.

Types

Cla

ssif

icat

ion

s

Mechanis

m

Ig Mediators

Histamine

Compl

-ement

Target

tissue

Examples

Type I

Imm

edia

te

Cytotropic IgE + ve None Smooth

muscle

Collagen,

b. vs.

Anaphylactic

shock

Type II Cytotoxic IgG,

M

+ ve + ve RBCs,

WBCs.

Platelets

Eq inf anemia

B. transfusion

Type III Aggregate IgG,

M

None + ve b. vs.,

endocardiu

m,

glomeruli

Arthus ph,

Serum

sickness

Type IV Delaye

dCell

mediated

None None None All tissue Koch ph,

transplantati

on

Differences between types of hypersensitivity reactions