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Type I hypersensitivity

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TYPE I HYPERSENSITIVITY-PATHOGENESIS AND CLINICAL MANIFESTATIONS

Author: Sanketh DS, MDS

INTRODUCTION

The immune system protects the human body against disease by dispatching a bunch of immune cells whenever the body encounters foreign material or antigens. These immune cells or effector cells elicit an inflammatory response in order to remove or eliminate the foreign antigen without causing much damage to the host. However, under certain conditions, the host may elicit an exaggerated or an inappropriate immune response to a foreign antigen causing much damage to host tissues. This exaggerated or inappropriate immune response is termed hypersensitivity.  There are four types of hypersensitivity them being Type 1, Type 2, Type 3 and Type 4 hypersensitivity.

Type 1 hypersensitivity is also termed allergy or atopy and immediate hypersensitivity since symptoms manifest rapidly within minutes to hours. Antigens eliciting these allergic reactions are termed allergens. Allergens could be anything ranging from dust, food, pollen, drugs, insect products like bee venom, microbes and many different chemicals.

PATHOGENESIS

Certain individuals are genetically prone to develop type 1 hypersensitivity reactions because they may inherit certain genes making them susceptible to this exaggerated immune response. For example, they may inherit certain MHC genes making their T cells capable of recognizing an allergen or they may have abnormally high levels of circulating IgE making them more prone to develop these reactions.

When an exogenous antigen/allergen is inhaled or ingested by a susceptible individual, circulating dendritic cells or antigen presenting cells may pick these allergens, swim to a nearby lymph node and present it to a CD4+ helper T cell. These T cells are naïve or inactive T cells. An inactive T cell could differentiate into an effector Th1 cell or a Th2 cell depending on the stimuli and environment. The naïve T cell, after recognition of the antigen presented by the dendritic cell, differentiates into an active/effector Th2 cell. This may happen due to certain cytokines like interleukin (IL) 4 present locally. IL-4 drives naïve T cells to differentiate into the Th2 subset. On subsequent encounter with the antigen, Th2 cells produce a number of cytokines like IL-4, IL-5 and IL-13. Now, IL-4 besides stimulating differentiation of more Th2 cells also causes B cells to class switch. So, the B cells instead of producing IgM, produce allergen/antigen specific IgE antibodies. IL-5 activates and recruits eosinophils which may release a bunch of enzymes that could damage host tissue. IL-13 enhances IgE production and stimulates epithelial cells to secrete mucus.

Mast cells in the connective tissue, express certain high affinity receptors called FcεRI receptors, specific to the Fc portion of these IgE antibodies. The antigen specific IgE antibodies then, bind to these high affinity surface receptors on the mast cells. The individual, at this point is said to be sensitized.

On subsequent re-exposure, the antigen binds to these antibodies sitting on mast cells, cross linking them and causing degranulation of mast cell contents. The contents in mast cells are preformed chemical mediators already present within the cell, newly formed mediators and cytokines. These are powerful mediators responsible for the clinical manifestations of this reaction.  

Preformed mediators

Some of the preformed mediators contained in the mast cell granules are histamine, enzymes like chymase & tryptase and eosinohilic chemotactic factors.

a) Histamine causes smooth muscle contraction of the airways making it difficult to breath. It also causes vasodilation of blood vessels and increases their permeability. This causes increased blood supply to the site of action and leakage of fluid through the vessels causing edema and swelling.
b) Enzymes like chymase and tryptase cause damage to adjacent tissues and lead to generation of kinins and complement.
c) Eosinophilic chemotactic factors recruit eosinophils to the site of allergy and are implicated in late phase reactions.

Manifestations of these mediators are called early phase reactions, since these manifestations occur within 5- 30 minutes of the allergen exposure and may subside within 60 minutes.

Newly synthesized mediators

Newly synthesized mediators are arachadonic acid derivatives – leukotrienes and prostaglandins.

Leukotrienes C4 and D4 are several thousand times more powerful than histamines in causing smooth muscle contraction and increased vascular permeability and leukotriene B4 is chemotactic for neutrophils, monocytes and eosinophils.

Prostaglandin D2 is the most abundant prostaglandin produced and causes vasodilation, increased permeability and also bronchospasm.

Cytokines

Cytokines like IL-1 and TNF-α are pro-inflammatory cytokines cause further inflammation by recruiting leukocytes. IL-4 causes further differentiation of Th2 cells and amplify their response. IL-5 activates and recruits eosinophils.

These mediators are responsible for a late phase reaction which sets in 2-24 hours later and does not require additional antigen exposure. They may last for several days and are due to recruitment of more eosinophils, neutrophils, monocytes and CD 4+ T cells as well as the sustained inflammation.

Some of the clinical manifestations of type 1 hypersensitivity could be:

1. Itching, urticaria and edema, where there could be pruritic wheals surrounded by erythema.
2. Allergic rhinitis
3. Allergic asthma
4. Anaphylaxis, which is a widespread systemic manifestation of type 1 hypersensitivity characterised by bronchospasm resulting in difficulty in breathing, laryngeal edema further compromising breathing, abdominal cramps and diarrhoea. The patient may also develop ischemia in multiple organs due to widespread vascular permeability leading to anaphylactic shock and death.

REFERENCES

Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran: Pathologic Basis of Disease. 8 th ed. Elsevier; 2010.

Abbas AK, Litchman AH, Pillai S. Cellular and Molecular Immunology. 8th ed. Elsevier; 2015.

Buelow B, Routes JM. Immediate Hypersensitivity Reactions.2015. Available at http://emedicine.medscape.com/article/136217-overview

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