28 Hypersensitivity Reactions-I

Dr. M. N. Gupta

1. Objectives

•  To know what is hypersensitivity and why it happens.

•  To know about classification of hypersensitivities.

•  To understand allergy which is type I or IgE mediated hypersensitivity.

2. Concept Map

3. Description

Under certain conditions, immune system over reacts and while making efforts to protect the animal, ends up in damaging tissues. In certain cases, this may even be fatal.

In earlier years, hypersensitivity was used as synonym of allergy. So, investigating allergic reactions led us to the realization that hypersensitivity is not just about allergy.

We now call allergy a type I hypersensitivity. The earlier books/literature lists anaphylactic reactions only under type I hypersensitivity. It now covers all allergic reactions.

Features of hypersensitivity

Hypersensitivity reactions are antigen specific.

Apart from “inappropriate” responses to microbial antigens, hypersensitive reactions also occur against self antigens. So, autoimmunity in a way is a subset of hypersensitive reactions.

Hypersensitivity is not the first response to an antigen. It occurs if a previous exposure taken place. Hence, in many cases, these adverse reactions originates/involves memory lymphocytes.

Hypersensitivity is a part of normal immune response. It is in a way clinical manifestation when immune response is localized and/or the large amount of antigen (and hence antibody/ immune cells) is involved.

Classification

The time period in which clinical manifestations occur and which components are involved has formed the basis of classification of hypersensitivities. Gell and Coombs divided hypersensitivity into 4 classes, later on, 5th one has been created.

It is necessary to realise that such a classification helps in efforts to understand these reactions. In reality, more than one type of hypersensitivity can be involved.

As we know from our common understanding of allergy, not all individuals react the same way to an antigen. Environments, genetics and age play important roles.

Types of sensitivity

Some cases involve external antigenic substances which are harmless to others.

Types I, II, III and V all involve interaction of antigen and antibody and response is “fast” (speaking relatively to type IV hypersensitivity response). Type IV depends upon T-cell mediation and takes much longer time to manifest. Hence, this is often referred to as delayed type hypersensitivity.

Gell and Coomb did recognize some distinct features of type V and had referred to as „stimulatory‟. This is now treated as a separate class-Type V.

Type I (immediate hypersensitivity) response is seen within minutes and hence is also called “immediate” type. IgE isotype antibodies are involved. Mast cells release vasoactive amines and chemokines which mediate acute inflammation.

Type II is also sometimes called antibody-mediated as antibody dependent cytotoxicity by NK cells/ macrophages or complement mediated lysis is involved.

Type III is also called immune complex mediated type.

Type V involved antibody binding to a cell receptor such as hormone receptor to „switch on‟ the cell.

Type I hypersensitivity or allergy

This is mediated by IgE. It is believed that IgE evolved to protect us from worms.

The immune mechanisms which operate against bacteria, viruses, fungi, protozoa, and worms differ.

Bacteria and fungi which do not invade cells are opsonised by the specific antbody, phagocytosis or complement mediated lysis takes place.

Microbe with intracellular habitat (viruses, some bacteria and protozoa) are taken care of by Tc/Nk cells.

Fungi require initially Th1 response. If the fungal infection is severe or persists, Th2 cells respond.

Both B-cells and T-cells are involved in fighting against protozoa. That is why vaccine development against protozoa caused diseases is difficult.

Worms (helminths) vary in their sizes and complexity. Infection by worms in responded by class switch to IgE and cells eosinophils, mast cells, macrophage and CD4+ T cells are involved. It is the Th2 response which results in class switch to IgE.

While the size of worms makes it difficult to deal with them via phagocytosis, the IgA, IgE and IgG can opsonise. This allows macrophages, easoinophils and mast cells to bind via Fc receptors. Eosinophils and mast cells degranulate and release their contents.

Incidence of allergic diseases

The incidence level in the ndustrial world is as high as 30% of the population. The % is less in developing countries like India but we are catching up fast.

This trend is not easy to explain. In UK % of some diseases like asthma, allergic rhinitis and atropic dermatitis seem to be reaching a plateau, others like urticaria, food allergy and angioderma seen to be on the rise.

Poor hygiene may correlate with lower incidences of allergy (hygiene hypothesis). This may be done to increase Th1 response in these individuals. We will take about the „sensitization‟ phase little later to understand this.

We have used the word atopic dermatitis while discussing the trend of allergic incidences. Atopy actually is used for conditions which display type I hypersensitivity such as asthma, hay fever and eczema. Increased risk of atopy is associated with gene loci such as HLA, the cytokines (IL-4, IL-5, IL-10 and IL-13) and leukotrienes (LTRI, LTRII) receptors and chemokines CCR3. We will discuss it in more detail later on.

In western countries, 40% of the population are prone to show IgE response to common environmental allergens. Atopy can also be called this situation and is marked by higher levels of IgE in the circulation and higher levels of eosinophils than non-atopic (normal) individuals.

IgE production

IgE is produced by plasma cells in lymph nodes which drain the site of antigen entry or at the local sites where allergic reactions occur. In the later case, the germinal centres within the inflammed tissue has plasma cells which release IgE.

Unlike other isotypes, IgE is mostly found in tissues in bound form to mast cells which have high affinity receptors for IgE. These are called FcεRI

Basophils and activated eosinophils also have FcεRI and hence take part in type I reactions.

Nature of Allergens

Allergic rhinitis (commonly known as hay fever) is the most common allergen in USA and affects 20% of the population. The causes are grass and tree pollens. Systemic release of worm (Echinococcus) antigen from hydatid cysts can cause anaphylaxis which we will discuss shortly.

About 300 million people are affected by asthma globally. About 2.5× more incidences occur for children as compared to adults. Allergic asthma can be caused by variety of allergens. At early stages, it is mediated by IgE.

Many allergens enter through inhalation. Many of these are proteins. Inhalation of all proteins, however, does not cause allergy.

Allergen proteins tend to be highly soluble proteins which do not have very high molecular weight. Pollen grains and mite faeces act as their carriers. In the mucosa of the airway, these dissociate from carrier and diffuse into mucosa.

The main APCs in the respiratory mucosa are myeloid dendritic cells. After processing antigen, these migrate to local lymph nodes, become professional APCs with co-stimulatory activity that favors Th2 cells.

Only very low dose of allergen is involved. For example, in whole of an year total exposure per person to ragweed (artmisia artemisiifolia) is less than 1 µg. These small doses are enough to cause Th2 causing class switching to IgE isotype.

In fact, allergens can be defined as antigen which provoke Th2 cells to cause class switching to IgE.

IgE production requires Th2 and is inhibited by IFN-γ producing Th1 cells. We have learnt earlier that low doses of antigen favour Th2 activation rather than Th1 activation.

Enzymes and allergy

IgE is important in host defence against parasites. IgE mediates activation of accessory cells which play an important role in resistance to parasites.

The role of mast cells has already been mentioned. Mast cells are located near the body surface and are able to recruit both specific and nonspecific components of the immune system near the immediate site of entry of infectious agents. They can cause muscular contraction which can lead to expulsion of pathogens from lungs or gut.

In helminth infection, mast cells accumulate in intestine. This is known as mastocytosis.

Infection by parasites especially helminths leads to increase in eosinophile count in blood and tissues (eosinophilia). Eosinophils obviously have a critical role in defence against helminths. If polyclonal anti-eosinophil antibody is infected to deplete eosinophils, it  increases the severity of the infection by worm Schistosoma mansoni. Microscopic examination of infected tissues show degranulated eosinophil bound to the worm. The binding, as explained before is mediated by opsonisation by specific IgE, IgG or IgA antibodies.

Similarly blood sucking xodid ticks provokes participation of IgE, mast cells, basophils and eosinophils. The skin near the tick bite shows degranulated mast cells and accumulation of basophils and eosinophils that are degranulated.

Many parasites during invasion of the host secret proteolytic enzymes for breaking down connective tissues for gaining access.

These enzymes promote Th2 responses.

Many enzymes are allergens.

Dust mite (Dermatophagoides pterongssimus) is responsible for allergy in 20 % of north American populations. The allergin is present in its faeces and it is a cysteine protease called Der p 1.

Der p1is homologous to papain. Papain is a protease isolated from papaya latex. It is a nonspecific protease and commonly used as a meat tenderizer. The people isolating it routinely at a large scale develop allergy.

Such allergies are called occupational allergy. One major application of industrial enzymes is in detergents. Subtilisin, a bacterial enzyme is routinely incorporated in detergents. Its inhalation is known to cause asthma. The first generation of enzyme based detergents (decades back) were withdrawn from the market as large incidence of allergy in housewives were reported.

Coming back to Der p1, it cleaves occludin which is part of intracellular tight junctions. Thus der p1 breaks the integrity of epithelial tissue and reaches subepithelial APCs, mast cells and eosinophils.

Papaya latex also contain another protease called chymopapain. It is used to treat patients with sciatica by hydrolysing protein component of intervertebral discs. A major complication, although fortunately rare, is the acute systemic response called anaphylaxis (we will discuss anaphylaxis in detail later on).

Enzymes are being increasingly employed in place of chemical catalysts. In general, these are considered greener options. However, this must not be confused with safety. All enzymes are proteins and proteins are good antigens. Hence, safe handling of enzymes is required in all occupations where in they are routinely handled and often in large amounts. One should especially avoid their inhalation as enzyme powders are one of the commonest form of enzyme preparations.

Enzymes are not the only allergens. Many plant proteins are known to be good allergens.

Two allergens from filarial worms are enzyme inhibitors.

While it is true that inactivated papain when injected does not provoke IgE response, no systematic association between enzyme activity/biological activity of the allergen and its allergenicity has been found.

Typical allergens are about 3-30 µm in diameter. Pollens, house dust mite faeces, fungal spores, animal skin flakes are common allergens. Inhaled in small quantities, these adhere to mucous membranes of nasal passages and airways.

The route of entry of other allergens and its consequences are shown in this table.

The symptoms thus depends upon whether the allergen is inhaled, swallowed or injected.

We will later discuss how various physiological symptoms occur.

The allergic reactions can be discussed in terms of three stages.

•  Sensitization
•  Immediate response
•  Late phase response

Sensitization

Sensitization is the development of an allergen-specific IgE response in a susceptible individual.

The allergen carries out clonal selection of the B-lymphocyte. Upon binding through the receptor, B-cells internalize the allergen.

The B-lymphocytes act as APC and present the antigen to CD4+ Th2 cells. The Th2 cells secrete IL-4 for growth and differentiation of the B-lymphocyte. Class switching to IgE isotype also takes place.

The dendritic cells uptake allergens and direct naïve T-cells to become Th 2 cells.

The net result is allergen specific memory B-cells and IgE.

IgE produced diffuses throughout the body and come into contact with mast cells and basophils.

Effector phase

The sensitization phase results in allergen specific memory B-cells. It also produces mast cells and basophiles bound to the allergen specific IgE through their FcεR receptors.

The second exposure of the allergen results in the allergen crosslinking of IgE molecules on the mast cells. There is an instant degranulation. The biologically active mediator molecules released are given on table.

The degranulation releases substances which cause vasodilation of blood vessels and attracting eosinophiles. Eosinophiles also release some substances.

Leukotries, histamines, prostaglandins, and platelet activating factor from mast cells is responsible for “immediate reaction” of type I hypersensitivity.

Apart from blood vessels mast cells degranulation also affects other tissues depending upon route of entry.

For example, “immediate reactions” in the nose causes redness, itching and increased secretion (runny nose) by mucosal epithelial cells.

The “late phase reactions” are often seen after 2-12 hrs of “immediate reaction”. These are caused by mediators of T-cell cytokines acting together. Primarily, leukotries and chemokines act and macrophages, basophils and other polymorphonuclear cells are recruited to the local site.

A more detailed description of late phase reactions is given in the figure. Eosinophiles and basophiles play an important role here.

It is the release of eosinophil chemotactic factors (ECF-A) by mast cells which recruits eosinophils to the site. Histamine and other mediates facilitate their movement by enhancing vascular permeability.

Cytokines including granulocyte macrophage colony-stimulating factors (GM-CSF), IL-3, IL-5 cause eosinophil growth and differentiation.

Eosinophil after binding to Fc portion of IgE and IgG bound to the allergen degranulate in turn and release leukotries which cause muscle contraction.

Eosinophiles also release platelate activating factor (PAF) and major basic protein (MBP). MBP destroy parasites but also cause tissue damage in mammalian epithelium of the respiratory tract.

After the eosinophilic cationic protein (ECP) is released which, apart from destroying allergens, also causes tissue damage.

Similarly mast cell attracts neutrophils by releasing neutophil chemotactic factor (NLF). Neutrophils degranulate after binding to antibody bound to allergen and release lysosomal enzymes, leukotries and PAF. Again, apart from destroying allergens, issue damage accompanies these activities.

IgE is vital to the immune defense against parasites especially worms. The hypersensitivity reactions occur against allergens which perhaps is an unintended consequence of IgE mediated responses. The tissue damage is the collateral damage which accompanies this immune response. We will continue discussing type I hypersensitivity reactions in the next module little more before moving over to description of Type II hypersensitivity.

Summary

•  Hypersensitivity is of five types.

•  Type I hypersensitivity is also called allergy

•  Allergy has three stages: sensitization, immediate reaction and late phase reactions.

•  Immediate reaction are IgE mediated; basophils, neutrophils and eosinophils are recruited in the late phase reactions.

•  Degranulation of mast cells, eosinophils and neutrophils releases soluble factors which participate in the overall set of reactions.