Chapter 11: Hypersensitivity Reactions, Type 1 Hypersensitivity reaction, Anaphylaxis

April 15, 2020Elementary Immunology

HYPERSENSITIVITY REACTIONS

Definition

Hypersensivity reactions are defined as any of the following:

• Hypersensitivity reactions are excessive immune responses leading to damage in the host.
• These are inappropriate immune responses resulting in pathological changes in the host.
• Inappropriate responses to innocuous foreign substances called allergy or hypersensitivity reactions.

Classification

1. Historically these are divided on the time bases:

1. 1. Immediate reaction: Reaction develops in less than 24 hours.
   2. Delayed reaction: When reaction develops within 24-48 hours.

2. Coomb’s and Gell classification: This was given in 1963.

• Ab-dependant reactions (B-L dependant)

1. 1. Type I        =          Anaphylactic and immediate reaction.
   2. Type II      =          Cytotoxic reaction.
   3. Type III     =          Immune – complex disease.

• Ab-independent reaction (T- L dependant)

1. 1. Type IV     =          Delayed or cell-mediated immunity
2. Kirk Patrick classification: This was given in 1987

• 1. Class-I =          Reagin dependant injury
  2. Class-II =          Cytotoxic reaction
  3. Class-III =          Immune complex disease
  4. Class-IV =          Anti-receptor Ab-reaction
  5. Class-V =          Delayed and cell-mediated

Among these three classifications, the Coombs and Gell classification is more popular and is commonly used.

TYPE-I HYPERSENSITIVITY REACTION

This is called anaphylactic reaction (anaphylaxis – harmful), or allergic reaction. It has two presentations:

1. Immediate reaction: This reaction starts within 5-30 minutes and subsides in 60 minutes.
2. Late phase reaction: This starts in 2-8 hours and lasts 2-3 days.

Types of Antigens

1. Heterologous proteins: e.g. antisera, hormones, enzymes, venom, and pollen.
2. Polysaccharide: e.g. Iron-dextran gives severe reaction and some other diagnostic agents like iodide and bromosulphophthalin etc.
3. Therapeutic agents: e.g. drugs like antibiotics (Penicillin gives severe reaction) and vitamins.
4. Food: e.g. milk, wheat, fish Nuts, and chocolate.
5. Insects venoms like bees and wasp.

Type of Antibodies

IgE is the main Ab and called as reagin. It is cytotoxic Ab. It has love and affinity once produced, attach to high-affinity receptors (IgεR) present on Mast cells and basophils.

IgE receptor (IgεR) consists of 2-α (molecular weight of 45,000) and 2-β (molecular weight of 30,000) chains.

Fig 88: IgE Receptor

This receptor is high affinity so also called IgεR1 while low affinity is called IgεR2.

 Formation of IgE

Antigen stimulates B-L which transform into plasma cells and produce IgE. 100 molecules of IgE are needed to initiate the reaction.

Fig 89: Formation of IgE molecule

Type 1 hypersensitivity reaction

Tissue Cells

These are mast cells in the tissue and basophil in the blood.

Stages of Reactions

This reaction takes place in two stages:

1. First Stage: This is the stage where there is sensitization of the host and formation of IgE Ab which once formed attach to the receptors on mast cells or basophil.
2. Second Stage: This is the stage of reaction or shocking-dose. In this stage where patients will have histamine effects and also called histamine poisoning.
   

   Fig 90: Combination of IgE with antigen site

Ag and Ab (Ag +IgE) bridging leads to degranulation, where Ag makes bridging between two IgE-Ab molecules present on the mast cell or basophils.

Fig 91: Mast cell and Basophil bridging with antigen

Degranulation is an active process, where:

1. There is an influx of calcium.
2. Initially, there is a rise in cAMP and later on, it decreases.

Degranulation leads to the release of:

1. Primary mediators
2. Secondary mediators
3. Cytokines

Chemical Mediators

Primary or Preformed Mediators

These are as follows:

1. Histamine
2. ECF-A (Eosinophilic chemotactic factor of anaphylaxis).
3. Neutrophil chemotactic factors (NCF).
4. Serotonin.

Secondary Mediators (Arachidonic Acid Metabolites)

These are:

1. Slow releasing substances of anaphylaxis (SRS-A) and now called leukotrienes e.g. LTB4, LTC4, LTD4, LTE4.
2. Platelet-activating factor (PAF).
3. Prostaglandin D2 (PGD2).

Mast Cell Associated Cytokines: These cells recruit more inflammatory cells.

TNFa, IL1, IL3, IL4, IL5, IL6, GM-CSF

Histamine

It is 10% of the weight of cells. It has the highest level in the morning and the lowest level in the late afternoon.

Histamine acts through separate receptors and these are named as:-

H1 – present on smooth muscles of bronchi and action stops by the antihistamine.

H2 – Present in stomach and action stops by cimetidine.

H3 – Present in CNS. It is under research.

Histamine clinically leads to:-

1. Wheal and flare.
2. Broncho-constriction.
3. Increase mucous secretions.
4. Hypotension due to vasodilatation and increased vascular permeability.
5. Cardiac arrhythmia.

Histamine target areas show:-

1. Skin – edema, and hives.
2. Trachea and bronchi due to broncho-constriction lead to asthma and increased mucous secretions.
3. Eyes and nose – increase secretion and red eyes.
4. Uterus – smooth muscles contraction leads to abortion and pain.
5. Gastrointestinal tract. There is nausea, vomiting, abdominal pain and diarrhea.

Secondary Mediators

1. Leukotrienes:
   1. These are the metabolites of arachidonic acid metabolism. These have the same action as histamine but more potent and strong, almost several thousands time more active than histamine.
   2. These are vasoactive and spasmogenic leads to contraction of smooth muscles and increase vascular permeability.
   3. LTB4 – It is chemotactic for eosinophils, ploys, and monocytes.
   4. Other leukotriene LTC4 (Previously) called as SRS-A.
2. Platelet Activating Factors (PAF)
   1. It is generated from complex -lipids stored in the cell membrane. It leads to:-
   2. Platelet aggregation and their lysis leading to histamine release.
   3. It activates neutrophils and eosinophil.
   4. It is the most potent eosinophil chemotactic factor.
3. Prostaglandin (PGD2)

1. 1. It is produced by human mast cells and leads to an increase in secretion, edema and smooth muscle contraction.
   2. Bridging of antigen and antibody over the surface of mast cell or basophil leads to the release of mediators.
      

      Fig 92: Type 1 Hypersensitivity reaction
      

Type 1 reaction and mediators

Type 1 Hypersensitivity reaction depends upon the production of  IgE by the activation of B-L with the help of the Th2 helper cell.

Fig 93:Summary of the Type 1 Hypersensitivity reaction

Clinically  Anaphylactic Reaction may be:

1. Localized reaction.
2. Systemic reaction.

Localized Reaction gives skin allergies (wheel), Hay fever, allergic rhinitis, asthma, atopic conjunctivitis and urticaria.

Systemic Anaphylactic Reaction: It is generalized phenomenon and leads to:-

1. Pallor, Nausea, vomiting, asthma, laryngeal edema,  and Hoarseness.
2. Abdominal pain, diarrhea, low blood pressure and ultimately patient goes into shock (anaphylactic shock).

Immediate Reactions starts within a few seconds to 30 minutes and may subside in 60 minutes.

Late Phase Reaction starts in 2-8 hours and may last for 2-3 days and is normally due to secondary mediators and inflammatory cell reaction.

Late Phase  produced by the activated mast cells and there is:-

1. Profound inflammatory response

2. Cells attracted to the site and activate other cells like Eosinophil, Neutrophils, Basophils, Lymphocytes, and Macrophages.

Table XVIII – IgE associated diseases

In late-phase activation of Mast Cells and its mediators ultimately leading to tissue damage, elaborated as follows:

Fig 94: Tissue damage in Type 1 Hypersensitivity reaction 

ATOPY

1. It is a Greek word means out of place. The patients give 50% family history. There is an association with HLA DR2 for ragweed.
2. 5% of the American population has asthma.
3. 10% suffers from Hay fever.
4. 1-2% has atopic dermatitis.

If there is a history of sensitivity to any antigen or some allergic diseases in a family and present in both parents then offsprings will have 75% if one of the parents then 50%. If none of these have sensitivity, then only 15% will develop atopy.

The tendency for allergic reactions has a strong heritability and such a tendency is called Atopy.

Atopy may be due to:

1. Genetic abnormality: One researcher group showed increased IgE response and gene on chromosome II.
2. It is seen in immune deficiency diseases like IgA-deficiency leading to eczema and asthma.
3. A high level of IgE in cord blood of infants predicts the future development of atopy.
4. Immune responsiveness: IFN-g Production down-regulate IgE production. So when there is a decrease in IFN-g then there will be an increase in IgE production. Also there is the role of T-suppressor cells.
5. Environmental factors like environmental allergen exposure in fetal life also influence such diseases.
   

   Fig 95: Atopy possible mechanism

Nature Check Mechanism

Nature has a check mechanism; otherwise, a small dose of Ag might have lead to death. There is the production of some enzymes which inactivate the mediators of type-I reaction.

Fig 96: Nature check mechanism of Type 1 Hypersensitivity reaction

Histaminase          = inactivate histamine

Aryl sulphatase     = inactivate SRS – A

Phospholipase D   = inactivate PAF 

Diagnosis

The diagnosis may be done by:

1. A detailed history of patient and guess may be made for the allergen.
2. Skin testing with a wide panel of Ag. This is done by injecting Ag subcutaneously or by patch test where you will see wheal and flare response.
3. IgE level:- Total IgE level may be raised in majority of the patients.
4. RAST: – This is radio-allergosorbent test, which detects allergen-specific IgE. It is a costly test and not as good as skin tests.
5. Eosinophil Count:-Blood eosinophilia may be found in allergic diseases.

Treatment
Types I reaction can be treated at different stages of reaction. The best treatment is the avoidance of the source (Ag). Treatment is shown diagrammatically with the phases of an allergic reaction.

Fig 97: Treatment of Type 1 Hypersensitivity