• Type-I hypersensitivity reaction is an immediate type of reaction mediated by IgE.
• It is also known as anaphylactic reaction or allergy. It is induced by certain types of antigen called allergens such as pollengrains, dandruff, dusts, food components etc.
• Allergens induces humoral antibody response by the same mechanism as other soluble antigens in the generation of antibody secreting plasma cells and memory cells but the difference is that the plasma cell secretes IgE class of antibody.
• This IgE class of antibodies have high binding affinity to Fc receptor on the surface of tissue mast cells and blood basophils. Mast cells and basophils bound by IgE are said to be sensitized.
• A latter exposure to the same allergens cross links the membrane bound IgE on sensitized mast cell and basophils causing degranulation of these cells.
• Degranulation causes release of pharmacological active mediators which act on surrounding tissue causing vasodilation and smooth muscle contraction which may be either systemic or localized. This effect is also termed as Allergy.

Mechanism of Type I hypersesnsitivity reaction:

Development of allergy or anaphylactic reaction requires two dose of antigen. 1^st dose is known as sensitizing dose and 2^nd dose is known as shocking dose.

1. Production of IgE antibody:

• When antigen (allergen) enters into host production of antibody begins.
• At first allergen is processed and presented by antigen presenting cells (APCs) to CD4 T cells.
• Activated CD4 t cells divides to form T helper cell and memory cell. T helper produces IL4.
• At the same time B cell bind to antigen in presence of APC and IL4 and gets activated.
• Activated B cells divide to form plasma cells and memory cells.
• Up to this step, mechanism is similar to that of normal humoral immune response. The difference between Type I hypersensitivity and normal immune response is that the plasma cell produces IgE antibody instead of Ig M or IgG.

2. Sensitization:

• Fc region of IgE antibody has receptor on the surface of tissue mast cells and blood basophils. So the IgE antibody binds to FcRI of mast cells and basophils.
• This binding of IgE to mast cell and basophil is known as Sensitization and the mast cells and basophils are said to be sensitized.

3. Shocking dose of antigen:

• When the same antigen (allergen) enter into same host for second time in life, antigen cross linked with Fab region of IgE molecules on the surface of mast cell or basophils.

4. Degranulation of mast cell:

• The cross-linking of antigen (allergen) to IgE antibody  causes degradation of mast cell and basophils releasing various pharmacological active chemicals such as histamine, heparin, serotonin, cytokines, leucotriene, prostaglandin etc.

5. Anaphylatic reaction:

• These active chemical mediators acts on surrounding tissue producing various symptoms of allergy such as vasodylation, smooth muscle contraction, mucus production, sneezing, etc.
• The allergic reaction may be localized or systemic depending upon types of allergen.

Mechanism of Activation and Degranulation of mast cell:

The intracellular signelling events that ultimately results in mast cell degranulation are manifested involving cooperation among various protein and lipid kinase and phosphatase and rearrangement of cytoskeleton.

The biochemical events in mast cell activation and degranulation can be divided into 3 steps.

1. Phosphorylation
2. Methylation
3. Adenylation

Phosphorylation:

• Binding of alleging on FcERI bounded antibody activates protein tyrosine kinase (PTK).
• PTK then phosphorylates phospholipase C which converts phosphatidylinositol 4,5 bisphosphate (PIP2) into diacetylglycerol (DAG) and inositol triphosphate (IP3).
• IP3 is a potent mobilize which causes pore formation and release Ca++ ions
• DAG activates protein kinase c (PKC).

Methylation:

• Cross linakage of FcERI also activates an enzyme that converts phosphatidyl serine (PS) into phosphatidylethanolamine (PE).
• Eventually PE is methylated to form phosphotidyl choline (PC) by the enzyme phopholipid methyl transferase I and II (PMT I and PMT II).
• The accumulation of PC on exterior surface of plasma membrane causes an increased membrane fluidity and facilitates the formation of Ca++ channel and Ca++ ions enter through the channel.
• Ca++ ion and PTK activates Mitoegn-activated protein kinase (MAPK).
• MAPK activates phopolipase A2 which promotes breakdown of phosphotidyl cholone (PC) into Lyso PC and Arachidonic acid.
• Arachidonic acid is converted into potent mediator Leckotrines and prostaglandin D2.
• Activated MAPK also induces secretion of cytokines by increasing transcription of cytokine genes.

Adenylation:

• FcERI cross linkage also activates the membrane adenylate cyclase enzyme leading to transient increase of cAMP within 15 seconds.
• A later drop in cAMP is mediated by protein kinase and is required for degranulation of mast cell.
• cAMP dependent protein kinase phosphorylates the granule membrane protein, thereby changing the permeability of the granules to water and Ca++ ions causing swelling of granules.
• Consequently swelling of granules and formation of Soluble N-ethylmaleimid attachment receptor (SNARE) protein complex, facilitates fusion of membrane and release of pharmacological chemical products, which is responsible for allergic symptoms.

Clinical manifestation of Type I hypersensitivity reaction:

Clinical symptoms ranges from life threatening conditions such as systemic anaphylaxis and severe asthma to localized reaction such as hey fever and eczema.

i. Systemic anaphylaxis:

• It is a shock like and often fatal state, which is usually initiated by allergen directly into blood stream or absorbed from gut or skin.

The symptoms are;

• Labored breathing
• Drop in blood pressure
• Smooth muscle contraction
• Bronchiole constriction
• Suffocation

ii. Localized hypersensitivity:

• It is limited to specific target tissue or organs, often involving epithelial surface at the site of allergen entry.
• The tendency to manifests hypersensitivity reaction is inherited and is called atopy.

Atopic allergy includes wide range of IgE mediated disorders such as:

• Hey fever (allergic rhinitis)
• Asthma (allergic or intrinsic)
• Food allergy
• Atopic dermatitis (eczema)

Type I hypersensitivity reaction: mechanism and clinical manifestation

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Hypersensitivity:

• When immune system works properly, it helps in elimination or removal of antigens from host body by means of effector molecules. The effectors molecules generally induce local inflammatory response and removes antigen without extensively damaging host tissues. However in certain conditions such as when immune system does not work properly or over activated, it causes deleterious effects resulting in significant tissue damage, serious disease and even death. Such unwanted, inappropriate and damaging immune response is termed as hypersensitivity.
• Although the word ‘hypersensitivity’ implies an increased response, the immune response in hypersensitivity reaction is not always heightened but may instead be an inappropriate response.
• Hypersensitivity reaction may develops in course of either cell mediated or humoral immune response

Gell and Coomb’s Classification of Hypersensitivity reaction

• Hypersensitivity reactions are classified as Immediate or delayed type on the basis of time required by sensitized host to response to shocking dose of antigen.
• Hypersensitivity reactions can be distinguished by immune response and difference in effectors molecules generated in course of reactions.
• G.H Gell and R.R.A Coomb classified hypersensitivity reactions into four types.

1. Type-I hypersensitivity reaction: IgE antibody mediated
2. Type-II hypersensitivity reaction: Antibodies mediated
3. Type-III hypersensitivity reaction: Antigen-antibody complex mediated
4. Type-IV hypersensitivity reaction: Activated T-cell and cytokines mediated

** Two additional types, Type-V and Type-VI hypersensitivity reaction are also proposed.

5. Type-V hypersensitivity reaction: Antibody mediated

6.  Type-VI hypersensitivity reaction: Both antibody and cell mediated

Immediate hypersensitivity reaction:

• Immediate hypersensitivity reaction is mediated by humoral antibody and manifests within minutes to few hours.
• The anaphylactic reaction initiated by antibody or Ag-Ab complex are referred as immediate hypersensitivity because it occurs within minutes or few hours after a sensitized host encounter with antigen
• Type-I, II and III hypersensitivity reaction are immediate

Delayed hypersensitivity reaction:

• Delayed hypersensitivity reaction is mediated by sensitized CD4 T cells and manifests slowly usually after 24 hours or more.
• It is called delayed because symptoms appears days after exposure to antigen.
• In delayed hypersensitivity reaction, the effector molecules are various cytokines secreted by activated CD4 T cells themselves.
• Type-V hypersensitivity depends upon activation of T cells and occurs within cell mediated branch of immune response and termed as delayed type hypersensitivity reaction (DTH).

Hypersensitivity and Types of Hypersensitivity reaction

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