Allergic Reactions: Types and Mechanism (With Diagram)

In this article we will discuss about the types and mechanism of allergic reactions.

Types of Allergic (hypersen­sitivity) Reactions:

Allergic or hypersensitivity reactions are classified in different ways. It may be humoral or cellular types. The antibody responsible for allergic reactions mainly belongs to IgE isotypes, but IgG isotype also involve in non-IgE mediated allergy like, classical “serum sickness”. It has been observed that in Allergic Broncho-Pulmonary Aspergillosis (ABPA) both IgE and IgG are involved.

If symptoms occur within minutes following antigen exposure, it can be called an immediate reaction, if symptoms start after hours, it is a late reaction, and if starts after days it is a delayed reaction.

Based on the different immunological mechanisms P.G.H.Gell and R.R.A.Coomb (1963) categorized the hypersensitivity reactions into four principal groups (Fig.10.5) viz. Type I – IV, of which Type I, II and III are caused by antibodies and Type IV is caused by lymphocytes.

Type I (IgE-mediated hypersensitivity):

This reaction is initiated by the antigen reacting with tissue mast cells passively sensitized by antibodies (IgE) elsewhere, leading to pharmacologically active mediator release.

The reaction is manifested within seconds or minutes after exposure and referred to as immediate hypersensitivity. It includes general anaphylaxis and local manifestation of symptoms in various organs or systems. The examples include bronchial asthma, rhinitis, urticaria, vomiting, diarrhoea, etc.

Type II (Antibody-mediated cytotoxic/cytolytic hypersensitivity):

In this case the antibody (IgG/IgM) is directed against the antigen on an individuals’ own cells (target cells) or foreign antigen, e.g., transfused red blood cells. This may lead to cytotoxic action by killer cells or by complement mediated lysis. The examples are mismatched blood transfusion, transplant rejection, etc.

Type III (Immune Complex-mediated hypersensitivity):

In a type III reaction, antibodies (IgG and IgM) form complexes with antigen and complement, generating neutrophil generating factors. The immune complexes are deposited in the tissue. The complement cascade is activated and polymorphs are attracted to the site of deposition causing local damage. The examples include the Arthus reaction, serum sickness, etc.

Type IV (Cell-mediated hypersensitivity):

This type of reaction is initiated by the action of antigen sensitized T-lymphocytes, releasing lymphokines following a secondary contact with the same antigen. Lymphokines induce inflammatory reaction and activate macrophages which release mediators. The reaction takes more than 12 hours to develop. The examples are tuberculin hypersensitivity, graft rejection, contact dermatitis, etc.

The type I reaction is characterized by an allergic reaction occurs due to contact with allergen. In 1973 Pepys referred allergy as type I and type III reactions. Such restricted meaning was not originally introduced by von Pirquet.

It is only in recent years that ‘allergy’ has become synonymous with type I hypersensitivity. Allergic reactions are dependent on the specific triggering of the unique antibody IgE sensitized mast cells, which release mediators to produce inflammatory reactions.

Mechanism of allergic (Type I) reactions:

Allergy is an area where the immune system behaves in a manner which is detrimental to the individual. It is not the pollen grain or spore itself, but factors (i.e., allergen) located on or within it, that may induce allergic disease. Allergens are principally proteins or glycoproteins (sometimes nucleic acids or polysaccharides may act as allergen) that are capable of eliciting the formation of IgE antibodies through the bodies immune system.

Hypersensitivity is induced by pollen grains, because pollen make contact with the upper respiratory tract, the nostrils, oral cavity (mouth) and eyes. Following a direct contact of pollen with moist eye surface pollen release proteins to induce hay fever or rhinitis. Pollen grains deposited in the uppermost ciliated portion of the respiratory tract, cannot reach to lungs.

The nasal cavity filtering them out by inducing a high degree of turbulence in the airflow that are deposited in the trachea and upper bronchi. Most pollen grains are swallowed and become accumulated in stomach. Pollen discharge their proteins while passing through the stomach and a moderate proportion of proteins are introduced into the bloodstream to start hypersensitivity reaction.

Antibodies are produced from different antibody forming cells of lymphoid tissues of allergic individuals in response to first exposure to allergens (proteins) obtained from pollen grains (Fig.10.6).

These IgE antibodies circulate in the serum in the blood­stream and it becomes attached to the surface of mast cells or basophilic granulocytes by its foot piece (by Fc region of IgE). About 100,000 IgE molecules may remain bound to the surface of a single mast cell for a period of several weeks.

Each IgE molecule has two arms with terminal recognition site for its specific allergen and is in communication with the mast cell membrane through the membrane glycoprotein to which it is attached.

In human, mast cells are found in the lungs, in the membranes of upper respiratory tract, in the skin and in the intestinal tract. Mast cells are rich in granules which contain histamine and several other biologically active substances like bradykinin, prostaglandins, etc.

Later, when the specific allergens (from similar type of pollen) are again encountered (second exposure), they bind to pairs of adjacent IgE molecules on the mast cell surface (Fig.10.6). This binding interaction triggers the rapid release of tissue mediators mainly histamine from granules secreted by the mast cells.

This type I reactions appear very quickly after exposure to an allergen, as a rule within 10-20 minutes, but occasionally within a couple of minutes. Histamines and other chemicals show up the symptoms of allergic diseases (Type I).

Histamine effects blood vessel dilation and increase capillary permeability, ensuing oedema (Fig.10.6). Histamine also contracts the smooth muscles and stimulates the exocrine glands. In the bronchi histamine contracts the smooth muscles, swells the membranes, and produces thick mucous leading to congestion, making breathing more strenuous (Fig.10.7).

In the skin, histamine produces wheal and elevated patches with itching and adjoining redness. Symptoms also appear in nose and eyes like sneezing, blocked nose, cold plus reddened, swollen and itching eyes.

The detailed mechanism:

The detailed mechanism of Type I allergy may be grouped into two phases namely:

(a) The sensitization phase(Fig. 10.8), and

(b) the effector phase(Fig10.9).

(a) The sensitization phase:

Antigen presentation:

After inhalation the allergens are diffused into the mucous layer of the respiratory tract and these are engulfed by the Antigen Presenting Cells (APCs) like Macrophages, B-Cells and Dendritic Cells. The antigens are cleaved into smaller peptides and presented on the surface of APC in combination with Major Histocompatibility Complex (MHC) Class II molecules (HLA-II or human Leucocyte Antigen class-II).

This is followed by recognition of the antigen derived peptides presented on APCs by specific T_H cells (Helper T-cell), through the T-cell receptor (TCR). Subsequently, TCR recognizes only small peptides of the allergens in complex with the HLA-II molecules. These small peptide stretches are called T-Cell epitopes.

T-Cell and B-Cell co-operation:

The T-Cells involved in the recognition of antigen peptides bound to HLA-II on APCs, all express the TCR co-receptor CD4 (thus denoted CD4⁺). The allergen response turns the naive CD4⁺ cells to become T_H2 cells, in contrast to a non-allergic reaction, which develops T_H1 cells.

Several factors indicate the type of T-cells that are formed, namely antigen type (intra-cellular or extra-cellular), route of entry, type of APC, cytokine microenvironment, co-stimulatory signals and genetic factors.

The T_H1 and T_H2 cells differ in their cytokine secretion profile, which are responsible for the nature of subsequent reactions. T_H2 cells secrete interleukins (IL) 4,5,10 and 13, while the T_H cells secrete predominantly IL-2, interferon (IFN) y, tumor necrosis factors α and β.

The T_H1 cell cytokines inhibit the production of T_H cell cytokines and vice-versa. With respect to type-I allergy, the most important cytokines are IL-4, IL-5, IFN- α and IL-2. IL-4 activates B-Cells and induces isotype switch from IgM/IgD to IgE (Fig. 10.8).

Class-switching:

Synthesis of antibody light chain involves three segments of genes V, J and C. The V segment encodes the first 95 – 101 amino acids and contains all Complementary Determining regions (CDRs), and the J and C encode the constant region of the light chain. The heavy chain synthesis involves four gene segments V, D, J and C. Five different C segments exist for the heavy chain C_δ, C_µ, C_y, C_ε and C_α.

Each region determines the isotype of the antibody giving IgD, IgM, IgG, IgE and IgA respectively. Upon isotype switch, the B-Cell switches the antibody production from IgM/ IgD to IgE which involves the use of the same light chain and V, D, J regions and for the heavy chains C_ε instead of C_µ. Thus the same CDRs are passed on. Similar mechanisms are involved when IgM/IgD to non-IgE switch occurs.

Production of IgE:

Thus when a potentially allergic subject is exposed to an allergen, a T- Cell receptor of T_H2 type is initiated. This, in turn, activates B-Cells and induces isotype switching from IgM/IgD to IgE.

The activation of IgE production requires at least two signals between T-Cells and B-Cells: one is the action of IL-4 and the other is the interaction between CD40 (a receptor on the B-Cell surface) and its ligand gp³⁹ (on the T-Cell surface). As an intermediate response, IgE antibodies secreted by plasma cells can bind to the high affinity IgE receptor FC_ε RI on the surface of Mast cells and Basophils.

(b) The effector phase:

In this phase, the receptors of IgE, present on the surface of mast cells and basophils, get cross-linked by the polyvalent allergen molecules leading to the release of vasoactive amines, responsible for the production of clinical symptoms.

The steps are as follows (Fig. 10.9):

Receptor cross-linking:

IgE-mediated degranulation begins when an allergen cross­links IgE that is bound to the Fc receptor on the surface of the mast cells and basophils. Monovalent allergens, which cannot cross-link two Fc receptors via the IgE molecules, are unable to trigger degranulation.

Intracellular events:

The cytoplasmic domains of the β- and y- chains of the FC_εRI are associated with Protein Tyrosine Kinases (PTKs), resulting in the phosphorylation of Tyrosines within the ITAMs (Immunoreceptor Tyrosine- based Activation motif; conserved stretches of sequences in the cytosolic domains) of the y subunit as well as phosphorylation of the residues on the P subunit and on phosphorylase C.

These phosphorylation events persuade the production of a number of second messengers that mediate the process of degranulation. Within 15 seconds after cross-linking of FC RI, methylation of various membrane phospholipids is observed, resulting in an increase in membrane fluidity and the formation of Ca²⁺ channels. An increase in Ca²⁺ reaches a peak within two minutes of FC_εRI cross-linking.

This increase in intensity is due to the increase in uptake of extra-cellular Ca²⁺ and to a release of Ca²⁺ from the intra-cellular stores of endoplasmic reticulum. The Ca²⁺ increase eventually leads to the formation of Arachidonic acid, which is converted into two classes of potential mediators the Prostaglandins (products of cycloxygenase pathway) and Leucotrinenes ( products of lipoxygenase pathway).

Moreover, the amplified Ca²⁺ promotes the assembly of microtubules and the contraction of microfilaments, necessary for the movements of the granules towards the plasma membranes and resultant degranulation. Blocking of Ca²⁺ influx and thereby inhibiting the mast cell degranulation are the mode of actions of several anti-allergic drugs such as cromolyn sodium, antihistamine.

Release of the mediators: During the phospholipid methylation and calcium influx, there is a transient increase in membrane-bound adenylate-cyclase (AC) activity, with a rapid increase in cytosolic cyclic AMP (cAMP)- content, showing a peak within one minute of FC_εRI cross-linkage. cAMP, in turn, activates the cAMP – dependent protein kinases, which phosphorylates the granule-membrane proteins, thereby increasing the permeability of the granules to Ca²⁺ and water.

This eventually leads to the swelling of granules, their fusion with the plasma membrane and the release of their contents. The increased cAMP-content then falls down rapidly. This is important for the degranulation to keep on. There are certain drugs to increase the intra-cellular cAMP level and thereby inhibit the degranulation process.

The above study regarding the kinetics of biochemical events, that follow the cross-linkage of FC_eRI-bound IgE, was done by Ishizaka (1985).

In their study, IgE bound on the surface of cultured human basophils, were cross-linked by Fab fragment of anti-IgE and the kinetic measurements were done, which contributed significantly to our understanding of the biochemical events during the effector phase of the allergic reaction cascade.

The mediators:

The clinical manifestation of Type I hypersensitive reactions are related to the biological effects of the mediators release during mast cell or basophil degranulation. These mediators are pharmacologically active agents that act on local tissues as well as on populations of secondary effector cells, including eosinophils, neutrophils, T-lymphocytes, monocytes and platelets. The mediators maybe classified either as primary or secondary:

(a) Primary mediators:

Histamine, Serotonin, Eosinophil Chemotactic Factor (ECF-A), Neutrophil Chemotactic Factor (NCF-A), Proteases

(b) Secondary mediators:

Prostaglandins, Bradykinins, Platelet activating factor, Leukotrienes, Cytokinins( IL-1 & TNF- α), IL-2, IL-3, IL-4, IL-5, IL-6, TGF- β, GM-CSF

The primary mediators are produced before degranulation and are stored in the granules. On the other hand, the secondary mediators are synthesized after target cell activation or are released by the breakdown of membrane phospholipids during degranulation process.

Common pollen/spore allergies:

Allergic diseases may involve any part of the body the most frequently involved being the nose, eye and chest with resultant symptoms of hay fever, rhinitis or asthma. The skin and eyes also commonly show allergic symptoms. Some of the common pollen allergies are described below.

Hay fever:

This is a seasonal type of allergy. The pollen grains of certain grasses, weeds and trees are the main causes of this type of allergy, although mold spores can also cause the symptoms. Depending on where the patients live and the pollination period of a particular plant, attacks may occur seasonally either in spring, summer, winter or rainy season.

Various symptoms may occur. The lining of the nose becomes swollen and exudes a runny discharge. Spells of sneezing and itchiness of the throat and palate also occur and the eyes may be similarly affected.

The British Scientist, Dr. Blackley in 1873 was the first to prove that pollen grains are the causative agent for hay fever. Later, Wyman (1876), Dunbar (1903) and others directly proved that the pollen grains of ragweed or Ambrosia are responsible to cause the common hay fever of United States.

Rhinites:

It is perennial type of allergy. The symptoms are similar to hay fever, but appear all the year round. The condition is caused by non-seasonal allergens such as pollen grains of grasses and other plants which flower round the year. Sometimes house dust components and certain mold spores are also the causative agents for rhinitis.

Conjunctivitis:

The people are more likely to suffer from an allergic condition of the eyes as an adult. Allergic conjunctivitis is often associated with allergic rhinitis. A general complaint is of itchiness of the eyes which are rubbed frequently.

Asthma:

Asthma may be allergic or non- allergic in origin. In allergic asthma environmental allergens like pollen grains and spores trigger the disease when inhaled. The patients may suffer from attacks which obstruct the flow of air to the lungs due to the swollen mucous membrane and formation of phlegm inside the mucous membrane.

Breathing becomes difficult and forced breathing becomes necessary. A wheezing sound appears due to the rush of air through the narrowed airways. At the same time, a troublesome cough can develop. Asthma may begin at any age and if neglected trends to recur and become chronic.