HYPERSENSITIVITY REACTIONS

Francis Ian L. Salaver, RMT

HYPERSENSITIVITY
-Hypersensitivity (allergy) is an inappropriate immune response that may develop in the humoral or cell-mediated responses -Was first termed anaphylaxis -can be systematic, which often leads to shock and can be fatal, or localized, which is various atopic reactions

Types of Reactions
There are four types of reactions: Type I-IgE mediated Type II-AntibodyMediated Type III-Immune ComplexMediated Type IV-DelayedType Hypersensitivity (DTH)

Hypersensitivity Reaction
Hypersensitivity or allergy
* An immune response results in exaggerated reactions harmful to the host * There are four types of hypersensitivity reactions:
Type I, Type II, Type III, Type IV * Types I, II and III are antibody mediated * Type IV is cell mediated

TYPE I. IMMEDIATE OR ANAPHYLACTIC HYPERSENSITIVITY

- Antibody involved:

IgE

- effector cells : tissue mast cells and circulating basophils - mediators: histamine, Eosinophil Chemotactic Factor (ECF)

- Clinical States: Hay fever, asthma, eczema, anaphylactic shock

Type I: IgE-Mediated Hypersensitivity

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 cellsleading to activation and degranulation of mast cells and release of mediators

Pathogenic mechanisms
* 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

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 anti-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

Methods of diagnosis
1) History taking for determining the allergen involved 2) Skin tests: Intradermal injection of battery of different allergens A wheal and flare (erythema) develop at the site of allergen to which the person is allergic 3) Determination of total serum IgE level 4) Determination of specific Ig E levels to the different allergens

TYPE II. CYTOTOXIC HYPERSENSITIVITY

- Antibody involved:

IgG and IgM

- Reactions involved antibodies directed to antigen on surface of specific cells or tissues resulting to cytolysis

Clinical states: HTR, HDN, rxns to plt. transfusions, Goodpastures syndrome, Myasthenia gravis

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

Transfusion reactions:

Antibodies of the A,B, and O antigens are usually of the IgM class (these antigens are call isohemagglutinins) For example an A individual produce isohemagglutinins to B-like epitopes but not to A epitopes because they are self Person who are transfused with the wrong blood type will produce anti-hemmagglutinins causing complement mediated lysis Antibodies are usually of the IgG class

Transfusion reactions can be delayed or immediate but have different Ig isohemagglutinins Immediate reactions has a complement-mediated lysis triggered by IgM isohemagglutinins

Hemolytic Disease of the Newborn

This is where maternal IgG antibodies specific for fetal blood group antigens cross the placenta and destroy fetal RBCs Erythroblastosis fetalis-severe hemolytic disease of newborns

Most commonly develops when an Rh+ fetus expresses an Rh antigen on its blood that and Rh- mother doesnt recognize

Erythroblastosis fetalis

During the 1st pregnancy small amounts of fetal blood pass through the placenta but not enough to induce a responses During delivery larger amounts of fetal blood cross the placenta causing an activation of B-cells that are Rh specific thus leading to memory B-cells (anti-Rh antibodies) The IgM antibody clears the Rh+ cells from the mother In subsequent pregnancies with an Rh+ fetus, the Rh+ RBC cross the placenta activating the memory B-cells These in turn cross the placenta and damage the fetal RBC because they are seen as foreign

This type of reaction can be prevented by administering antibodies against the Rh antigen within 25-48 hours after the 1st delivery Rhogam-is the antibody that is injected it will bind to the fetal RBC that enter the mothers circulation and facilitate the clearance of them before Bcell activation In subsequent pregnancies the mother is unlikely to produce IgG anti-Rh antibodies If the mother doesnt receive this injection there are other ways to treat this, depending on the severity

Drug-Induced Hemolytic Anemia

This is where certain antibiotics can absorb nonspecifically to the proteins on RBC membranes Examples: penicillin, streptomycin Sometimes antibodies form inducing complement-mediated lysis and thus progressive anemia When drug is withdrawn the hemolytic anemia disappears

TYPE III. IMMUNE COMPLEX HYPERSENSITIVITY

- Antibody involved:

IgG and IgM

- Affects organs where antigen-antibody reactions are deposited

Clinical states: Arthus reaction, Rheumatoid arthritis, SLE, Glomerulonephritis, serum sickness

Type III-Immune Complex-Mediated Hypersensitivity

Reaction with antibodies create immune complexes These generally facilitate the clearance of antigen by phagocytosis Large amounts of immune complexes can lead to tissue damage (Type III reaction) The magnitude depends on the quantity of immune complexes and their distribution

Type III-Immune Complex-Mediated Hypersensitivity

The complexes get deposited in tissues:

Localized reaction is when they are deposited near the site of antigen entry When formed in the blood reaction can develop where ever they are deposited

Deposition of these complexes initiates a reaction that results in the recruitment of neutrophils Tissue is injured by the granular release from the neutrophil (attempted phagocytosis release lytic enzymes that cause the damage)

Localized Type III Reactions:

Injection of an Antigen:

Can lead to an acute Arthus reaction within 4-8 hours Localized tissue and vascular damage result from accumulation of fluid (edema) and RBC (erythema) Severity can vary from mild swelling to redness to tissue necrosis

Generalized Type III Reactions:

Large amounts of antigens enter the blood stream and bind to antibody, circulation immune complexes can form These cant be cleared by phagocytosis and can cause tissue damaging Type III reactions

Serum Sickness-type III hypersensitivity reaction that develops when antigen is intravenously administered resulting in formation of large amounts antigen-antibody complexes and the deposition in tissue Other conditions caused by Type IIIAutoimmune Diseases

Systematic lupus erythematosus Rheumatoid arthritis

1- Arthus Reaction
* This is a local immune complex deposition phenomenon e.g. diabetic patients receiving insulin subcutaneously

* Local reactions in the form of

edema erythema necrosis

deposited in small blood vessels vasculitis microthrombi vascular occlusion

* Immune complexes

leading to formation

2- Serum Sickness
* A systemic immune complex phenomenon * Injection of large doses of foreign serum * Antigen is slowly cleared from circulation * Immune complexes are deposited in various sites fever urticaria arthralgia lymphadenopathy splenomegaly glomerulonephritis antidiphtheritic serum penicillin sulphonamides

* 10 days after injection

e.g. treatment with

TYPE IV. CELL-MEDIATED/DELAYED-TYPED HYPERSENSITIVITY

- Reaction involves and release of its lymphokines as mediators and amplifiers

sensitized T cells

- Mediated by cells rather than antibodies

-

Clinical states: Contact dermatitis, GVHD reactions, Transplant rejection, PPD (Tuberculin Test for MTB)

Type IV Hypersensitivity
a.k.a. cell mediated hypersensitivity or delayed type hypersensitivity

A hypersensitive response mediated by sensitized TDTH cells, which release various cytokines and chemokines Generally occurs 2-3 days after TDTH cells interact with antigen An important part of host defense against intracellular parasites and bacteria

Phases of the DTH Response

Sensitization phase: occurs 1-2 weeks after primary contact with Ag What happens during this phase? TH cells are activated and clonally expanded by Ag presented together with class II MHC on an appropriate APC, such as macrophages or Langerhan cell (dendritic epidermal cell) Generally CD4+ cells of the TH1 subtype are activated during sensitization and designated as TDTH cells

Phases of the DTH Response

Effector phase: occurs upon subsequent exposure to the Ag What happens during this phase? TDTH cells secrete a variety of cytokines and chemokines, which recruit and activate macrophages Macrophage activation promotes phagocytic activity and increased concentration of lytic enzymes for more effective killing Activated macrophages are also more effective in presenting Ag and function as the primary effector cell

What happens if the DTH response is prolonged?

A granuloma develops Continuous activation of macrophages induces the macrophages to adhere closely to one another, assuming an epithelioid shape and sometimes fusing together to form giant, multinucleated cells.

Detrimental Effects of DTH Response

The initial response of the DTH is nonspecific and often results in significant damage to healthy tissue In some cases, a DTH response can cause such extensive tissue damage that the response itself is pathogenic Example: Mycobacterium tuberculosis an accumulation of activated macrophages whose lysosomal enzymes destroy healthy lung tissue In this case, tissue damage far outweighs any beneficial effects.

How Important is the DTH Response?

The AIDS virus illustrates the vitally important role of the DTH response in protecting against various intracellular pathogens. The disease cause severe depletion of CD4+ T cells, which results in a loss of the DTH response. AIDS patients develop life-threatening infections from intracellular pathogens that normally would not occur in individuals with intact DTH responses.