More than 30% of the Indian population are said to be suffering from type 1 hypersensitivity reactions (what everyone calls ALLERGY). It includes conditions like asthma, hay fever, atopic dermatitis, hives, food allergies and even the life threatening systemic anaphylaxis. Everyone at some point of life must have experienced having an episode of allergy. In this article we will be learning the mechanism behind allergy in great detail.
The basics – ALLERGEN:
Before we even understand what happens in our body during an episode of allergy, it is essential to know what causes it.
Allergens are relatively harmless substances found in the environment that triggers our immune system to produce a type 1 hypersensitivity reaction. These include dust, pollen, nuts, seafood, milk, drugs like penicillin, venom of insects like bee etc.
Many years of research on allergens has opened up a new perspective on how allergens cause type 1 hypersensitivity reactions:
• Most allergens are proteins or glycoproteins which are multivalent in nature I.e they have many epitopes (site on antigen than binds to paratope of antibody).
• Majority of allergens have some intrinsic enzymatic activity. Allergens from dust mites, cockroaches and some fungi have intrinsic protease activity that are capable of disrupting the epithelial junctions and gain access to the underlying cells, which are part of the innate immune system. Research also shows that dust mite allergens have protease that cleave and activate compliment proteins.
• Some allergens are said to possess pathogen associated molecular pattern (PAMPs) which activate the immune system.
All these factors make it possible for a relatively harmless substance to wreck havoc in our bodies. Now that we have an idea about allergens, lets dig deeper and learn about the antibodies responsible for allergy.
Role of IgE in type 1 hypersensitivity reactions:
K. Ishizaka and T. Ishizaka through a series of experiments in the 20th century discovered the role of IgE in type 1 hypersensitivity reactions. This involved injecting serum of a person who was allergic to a substance into the skin of a normal individual, later when the normal individual was exposed to the allergen wheal and flare reactions were observed on the skin. Through various experiments the serum of an allergic individual was studied and a conclusion that IgE antibodies were responsible for type 1 hypersensitivity reaction was drawn.
IgE antibodies have a very short half life in the serum, but when cross linked with Fc receptors their half life extends to weeks.
IgE antibodies on their own are harmless and incapable of causing much trouble, but when cross linked with Fc receptor their potential to cause hypersensitivity reaction is realised. Studying Fc receptor is important in understanding how type 1 hypersensitivity reactions happen and the processes involved in regulation. Fc receptors for IgE are of two types:
FcER1:
They have high affinity towards IgE antibodies. They are located on mast cells and basophils mainly, they are also present in small numbers on eosinophils, langerhan cells, monocytes and platelets. This type of receptor is responsible for producing the symptoms of allergy by:
• Degranulation of the mast cell and basophils, which releases substances like histamine, heparin, protease etc.
• Release of inflammatory cytokines.
• Conversion of arachidonic into prostaglandin, leukotriene
FcER2:
They have low affinity towards IgE antibodies and are present on activated B cells which synthesise IgE antibodies. FcER2 is induced by the inflammatory cytokine IL-4. It is also known as CD23 and has binding sites for both IgE and a ligand called CD21. The outcome of the binding of ligand depends on the ligand itself:
• Binding of CD21 co stimulatory ligand to FcER2 increases the synthesis of IgE antibodies.
• If IgE antibody binds to the same receptor, it acts as a negative feedback and decreases the synthesis of IgE antibodies.
Role of FcGRIIB in suppressing allergies:
Inflammatory cells harbour receptors for IgG antibodies too, they are of FcGRIIB type. These receptors have a strong inhibitory action on the inflammatory cells and are involved in suppressing the allergic reactions. Allergens that induce both IgG and IgE antibodies are less likely to cause a severe allergic response when compared to IgE alone. The inhibitory effect of FcGRIIB predominates the effect of FcER1. This is a mechanism of how desensitisation of allergens work, they promote production of IgG antibodies against the allergen.
Now that we have a clear picture of the components involved in type 1 hypersensitivity reaction, let’s see how an allergen turns a peaceful environment into complete chaos.
Mechanism behind type 1 hypersensitivity reaction:
• Allergen gains entry into the body by various means as described above and are taken up by antigen presenting cells (APC). Allergens being polyvalent in nature, stimulate TH2 cells.
• TH2 cells become activated and release IL-4, IL-5 and other co stimulatory molecules which are responsible for activating the B cells.
• Activated B cells transform in plasma cells and start producing IgE antibodies against the allergen.
• IgE antibodies bind to the FcER1 present on inflammatory cells like mast cells and basophils (Majority).
• Next exposure to the same allergen results in cross linking of the allergen’s epitope with the IgE antibody on the mast cells and basophils. This causes degranulation of the cells resulting in the release of mediators (described below), release of inflammatory cytokines and conversion of arachidonic acid into leukotrienes and prostaglandins.
• All these above said produces effects like vasodilation, edema, bronchoconstriction, pruritis (if on skin), allergic rhinitis etc.
Let’s now have a look at the different chemical mediators that are released by the mast cells and basophils.
Chemical mediators involved in allergic reactions:
Mediators released by the mast cells and basophils are classified as primary and secondary mediators, lets see what are they:
Primary mediators:
• Histamine – increases vascular permeability and smooth muscle contraction.
• Serotonin – increase in vascular permeability and smooth muscle contraction.
• Eosinophil chemotactic factor- responsible for chemotaxis of eosinophils.
• Neutrophil chemotactic factor – responsible for chemotaxis of neutrophils.
• Proteases- degrade basement membrane, split complement molecules etc.
• Proteoglycans like heparin and chondritin sulphate.
Secondary mediators:
• Prostaglandins- vasodilation, bronchoconstriction and platelet aggregation.
• Leukotrienes- vasodilation and smooth muscle constriction.
• Platelet activating factor- activation of platelets and degranulation of their contents.
• Bradykinin- increase vascular permeability and smooth muscle contraction.
• Cytokines – mixed effects like inducing B cells to produce IgE, participating in systemic anaphylaxis etc.
Release of chemical mediators by the immune cells happen in phases, the early phase and the late phase.
Early phase
Begins usually within minutes after exposure to the allergen and is mediated mainly by the primary mediators which are released by the mast cells in that region. Later on basophils are also recruited and they also participate in the ongoing type 1 hypersensitivity reaction.
Late phase:
Due to release of chemotactic factors by the mast cells and basophils, there is increased expression of adhesion molecules in the nearby blood vessels and this causes influx of large number of neutrophils and eosinophils. From here the late phase begins. This happens hours after the primary contact with the allergen.
Eosinophils play a crucial role in this phase. Their recruitment leads to degranulation at the site of allergy and induces inflammatory responses causing extensive tissue damage.
Third phase:
This is a new phase which is being researched upon. This starts at the 3rd day and peaks on the 4th day. Third phase is characterised by a huge eosinophilic infiltration in the presence of basophils.
With this brief knowledge of the pathogenesis of type 1 hypersensitivity reaction, let’s now see it’s clinical presentation.
Systemic anaphylaxis:
This is a life threatening condition that happens after exposure to an allergen. Also called as anaphylactic shock, presents with severe respiratory smooth muscle contraction leading to asphyxiation, hypotension due to vasodilation mimicking a shock like state. Needs emergency medical intervention, without which it is fatal.
These are commonly triggered by venoms and sting of insects like honeybee, scorpion, wasp etc.
Epinephrine is the drug of choice given as an I/M injection.
Atopy:
Atopy is basically an individual being predisposed to create exaggerated immune response (allergic reaction) towards diverse antigens. This clinically presents as type 1 hypersensitivity reactions towards many common antigens that are harmless to others.
The exact cause behind atopy isn’t understood well, rather many studies point towards genetic abnormalities in the genes for cytokines ( chromosome 5q), beta 2 receptor, MHC II molecules ( chromosome 6p ), chromosome 11q that codes for high affinity IgE receptor (FcER1) and other genes involved in regulation of T cell functions.
Almost 10 to 30% of population in a developed country face this problem with 80% of these people having family history of atopy.
Atopic reactions:
They are localised hypersensitivity reaction towards an allergen. Commonly caused by pollens, dust etc. Allergen exposure leads to IgE cross linking in the local tissue causing degranulation of mast cells and basophils. The mediators are responsible for the symptoms that the patient experiences like running nose, teary eyes, difficulty in breathing, sneezing and coughing.
Examples for atopic reactions include allergic rhinitis, asthma, atopic dermatitis etc.
Atopic reactions are treated by oral antihistamine, leukotriene antagonist and steroids.
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