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

September 29, 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

1. Definition of type 1 hypersensitivity reaction
   This is also called immediate hypersensitivity that occurs when an IgE response is directed against the antigens like pollens and leads to the release of pharmacological mediators, such as histamine, by IgE-sensitized mast cells and produce an acute inflammatory reaction with S/S like asthma or rhinitis.
2. This type 1 reaction can range from the life-threatening anaphylactic reaction to milder forms associated with food allergies.
3. Atopic allergy including hay fever, asthma, and food allergy.

Type 1 Hypersensitivity reaction and the role of mast cell

4. This is also called anaphylactic reaction (anaphylaxis – harmful), or allergic reaction. It has two presentations:
5. Immediate reaction: This reaction starts within 5-30 minutes and subsides in 60 minutes.
6. Late phase reaction: This starts in 2-8 hours and lasts 2-3 days.
7. The term allergy was used by Von Pirquet in 1906 meaning changed reactivity of the host when encountering the antigen on a second or subsequent occasion.

Types of Antigens

1. Characteristic of antigen or allergins:
   1. Any substance which gives rise to the wheel and flare and symptoms of allergic diseases are from various sources.
   2. When these substances are purified, these have almost all found to be proteins.
   3. Their molecular weight varies from 10,000 to 40,000 daltons.
   4. These proteins all are freely soluble in the aqueous solution, but many different biological functions.
2. The most common examples of antigen (allergins) are:
   

   Source of the allergin	Type of airborne particles	Size of the airborne particle
   Grass	Pollen	30 µm
   Dust mite	Feces	10 to 40 µm
   Cats	Dander particles	2 to 15 µm
   Rat	urine	2 to 20
   German cockroach	Feces and saliva	≥5 µm
   Fungi	Spores	14 x 10 µm 2 µm

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

Type 1 Hypersensitivity reaction and Fc receptor for IgE on Mast/Basophils

The Fc-receptor are of two types:

1.  High affinity called IgεR1 (IgεRI).
2.  Low affinity is called IgεR2 (IgεRII)

 Formation of IgE

1. Antigen stimulates B-L with the help of antigen-presenting cells and Th2. These activated B-lymphocytes are transformed into plasma cells and produce IgE. 100 molecules of IgE are needed to initiate the reaction.
   

   Fig 89: Formation of IgE molecule by activation of B-lymphocyte

2. IgE is a local response occurring at the site of the entry of the allergins.
3. Locally produced IgE will first sensitize the local mast cells and the rest of the IgE enters the circulation and binds to the Fc-receptors on basophils and tissue fixed mast cells throughout the body.
4. The half-life of serum IgE is only 2.5 days while mast cells may remain sensitized up to 12 weeks.
   

   IgE structure and Fc receptor

5. IgE level is raised in allergic diseases and markedly raised in the parasitic infestation.
6. There is no transfer across the placenta. While IgG can cross the placental barrier.

Type 1 hypersensitivity reaction mechanism

Normal IgE level:

Serum of normal individual = <10 to 10,000 IU/mL (IU unit = 2.4 ng).

Most sera contain = <1 µg IgE/mL

Cord blood = <1 IU/mL (<2 ng/mL)

Types of mast cells:

1. Mast cells are found in:
   1. Around the blood vessels in most of the tissues (Connective tissue mast cells, CTMC).
   2. Mucosal mast cells are found in the gut and the lungs (Mucosal mast cells, MMC).
   3. CTMC from the peritoneum and the skin are different as the number of the histamine granules, the density of the staining, and the pharmacological functions.
   4. MMC is found more in the midgut and the lungs.
      1. In paracytic infestation, their number increases in the gut.
      2. Their number also increases in the Crohn’s disease and ulcerative colitis.
   5. Mast cells activation:
      1. Once the IgE binds to the Fc receptor on the mast cells and basophils, then degranulation takes place by the cross-linking of the IgE antibody.
         Difference between the connective tissue mast cells and the mucosal mast cells:

         Characteristics	Connective tissue mast cells	Mucosal mast cells
         Location in the body	Around the blood vessels Skin Intestinal submucosa	The mucosa of lungs. Nasal mucosa Intestinal mucosa
         Functions in the body		Parasitic worm infestation
         Morphology	larger in size	Smaller in size
         Life span in the body	>40 days	<40 days (smaller and short-lived)
         Intracytoplasmic IgE	Negative	Positive
         Histamine contents	Positive (++)	Positive (+)
         T-lymphocytes dependency	Negative	Positive (dependant)
         Number of Fc-receptors	3 x 104	2 x 105
         Cytoplasmic granules	Histamine and serotonin More granules	Histamine and serotonin
         Arachidonic acid metabolites	Prostaglandins and leukotrienes Leukotrienes (LTC4) : Prostaglandins (PGD2) = 1:40	Prostaglandins and leukotrienes Leukotrienes (LTC4) : Prostagaldins  (PGD2) = 25:1
         Effect of drugs (Theophylline, Na cromoglycate)	Inhibit histamine release	No inhibition of the histamine So not useful in the treatment of asthma

Mast cell structure and function

The cells with Fc^ε-receptor are:

1. Mast cells and basophils. These have IgE mediated reaction through Fc^ε-receptor.
2. T-lymphocytes have about 1% Fc^ε-receptor, increasing in the atopy during the pollen season.
3. B-lymphocytes about 30% have Fc^ε-receptor and increases during the pollen season.
4. Monocytes about 2% have Fc^ε-receptor and increasing up to 20% in allergic conditions.
5. Eosinophils have Fc^ε-receptor cause damage to the parasites.
6. Platelets have also Fc^ε-receptor.

Type of Cells which take part in type 1 hypersensitivity reaction:

1. These are mast cells in the tissue and basophil in the blood.
2. Mast cells are of two types:
   1. Mast cells in the connective tissue.
   2. Mast cells in the mucosa of the gut.

Role of T-lymphocytes in the activation of B-lymphocyte and formation of IgE and IgG4:

1. The production of IgE is dependant upon the T-lymphocytes which activate the B-lymphocytes and produce IgE and IgG4.
2. The T-cells can suppress the formation of IgE by the production of interferon-gamma (IFN-γ).
3. The production of IgE is dependent upon the Th-2 helper cells. While Th-1 cells will suppress IgE production.
   

   Type 1 hypersensitivity reaction and the Role of T-cells

Stages of Type 1 Hypersensitivity Reactions are:

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: Stages of type 1 hypersensitivity reaction

Basically, type 1 reaction has four stages:

1. Activation of the B-lymphocytes to produce IgE.
2. Antigen and IgE will sensitize mast cells.
3. Mast cells release chemical mediators.
4. The patient will have S/S like asthma, hay fever, or atopic eczema.

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 of IgE 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 of type 1 Hypersensitivity Reaction are:

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:

1. These cells recruit more inflammatory cells.
2. TNFa, IL1, IL3, IL4, IL5, IL6, GM-CSF
   

   Type 1 Hypersensitivity reaction and mediators

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 the 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 muscle 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 the 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 and effects of the mediators

Type 1 Hypersensitivity reaction and mediators

Type 1 Hypersensitivity reaction, Mast mediators and signs/symptoms

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 and stages

Mediators of the type 1 hypersensitivity reactions are:

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 a 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.

The 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.
Clinically types of the type 1 hypersensitivity reaction are:

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. This was described by Coca and Cooke in 1923, the term atopy described clinical features of type 1 hypersensitivity reaction, like asthma, eczema, hay fever, and urticaria in subjects with a family history of similar complaints and showing positive immediate wheal and flare skin reactions to common inhalant allergens.
2. It is a Greek word that means out of place. The patients give 50% family history. There is an association with HLA DR2 for ragweed.
3. If both parents have a history of allergy then 50% of children will develop an allergy. Even with one of the parents having an allergy, the chances are still 30% in the children.
4. 5% of the American population has asthma.
5. 10% suffers from Hay fever.
6. 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-γ Production down-regulate IgE production. So when there is a decrease in IFN-γ 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 the 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.
   1. The antigen is introduced subcutaneously, leading to the release of preformed mediators, which will increase vascular permeability, local edema, and itching.
   2. The late phase reaction is usually overlooked, and it will show with the appearance of a lump in the skin and is painful rather itchy.
      

      Type 1 hypersensitivity reaction, skin test interpretation

3. IgE level:- Total IgE level may be raised in the majority of the patients.
4. RAST: – This is a radioallergosorbent 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 at various stages of the reaction

Hypersensitivity reaction and their summary:

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