A Report on Hypersensitivity diseases

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A Report on Hypersensitivity diseases

Type I Hypersensitivity

Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause a range of symptoms from minor inconvenience to death. The reaction usually takes 15 – 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 – 12 hours) 11.

Clinical features:

1. Anaphylaxis refers to an immediate hypersensitivity response that is inducible in a normal host of any given species upon appropriate antigenic exposure (called sensitization). The response may be either systemic (anaphylactic shock) or local but in all species is primarily characterized by smooth muscle contraction and increased capillary permeability.

2. Atopy refers to an immediate hypersensitivity response that occurs only in genetically predisposed hosts upon sensitization to specific allergens12. This condition differs from anaphylaxis in that it cannot be induced in normal hosts.

Immediate hypersensitivity is mediated byIgE. The primary cellular component in this hypersensitivity is the mast cell or basophil. The reaction is amplified and/or modified by platelets, neutrophils and eosinophils. A biopsy of the reaction site demonstrates mainlymast cells and eosinophils. The mechanism of reaction involves preferential production of IgE, in response to certain antigens (often called allergens). A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances

Figure 5: Immediate Hypersensitivity

Sequence of events of Immediate Hypersensitivity-

Figure 6: Sequence of events of Immediate Hypersensitivity

Cross-linking of IgE Fc-receptor is important in mast cell triggering. Mast cell degranulation is preceded by increased Ca++ influx, which is a crucial process; ionophores which increase cytoplasmic Ca++ also promote degranulation, whereas agents which deplete cytoplasmic Ca++ suppress degranulation.The agents released from mast cells and their effects are listed in Table 1. Mast cells may be triggered by other stimuli such as exercise, emotional stress, chemicals (e.g., photographic developing medium, calcium ionophores, codeine etc.), anaphylotoxins (e.g. C4a, C3a, C5a, etc.). These reactions mediated by agents without IgE-allergen interaction are not hypersensitivity reactions, although they produce the same symptoms.

Table 1: Pharmacologic Mediators of Immediate Hypersensitivity
Preformed mediators in granules
histamine bronchoconstriction, mucus secretion, vasodilatation, vascular permeability
tryptase proteolysis
kininogenase kinins and vasodilatation, vascular permeability, edema


attract eosinophil and neutrophils
Newly formed mediators
leukotriene B4 basophil attractant
leukotriene C4, D4 same as histamine but 1000x more potent
prostaglandins D2 edema and pain
PAF platelet aggregation and heparin release: microthrombi

The reaction is amplified by PAF (platelet activation factor) which causes platelet aggregation and release of histamine, heparin and vasoactive amines. Eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factors attract eosinophils and neutrophils, respectively which release various hydrolytic enzymes that cause necrosis. Eosinophils may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E, although this role of eosinophils is now in question12.

Cyclic nucleotides appear to play a significant role in the modulation of immediate hypersensitivity reaction, although their exact function is ill understood. Substances which alter cAMP and cGMP levels significantly alter the allergic symptoms. Thus, substances that increase intracellular cAMP seems to relieve allergic symptoms, particularly broncho-pulmonary ones and are used therapeutically Table 2. Conversely, agents which decrease cAMP or stimulate cGMP aggravate these allergic conditions.

Table 2 : Relationship between allergic symptoms and cyclic-nucleotides
Lowering of cyclic-AMP elevation of cyclic-AMP
stimulation of ?-adrenergic receptor

(nor-epinephrin, phenyl-epinephrin)

stimulation of ?-adrenergic receptor

(epinephrine, isoproterenol)


blocking of ?-adrenergic receptor


blocking of ?-adrenergic receptor


elevation of cyclic-GMP inhibition of phosphodiesterase


stimulation of ?-cholinergic receptor

(acetyl choline, carbacol)

binding of histamine-2 or PGE to their receptors

Diagnostic tests for immediate hypersensitivity include skin (prick and intradermal) tests, measurement of total IgE and specific IgE antibodies against the suspected allergens. Total IgE and specific IgE antibodies are measured by a modification of enzyme immune assay (ELISA). Increased IgE levels are indicative of an atopic condition, although IgE may be elevated in some non-atopic diseases (e.g. myelomas, helminthic infection etc.).

Symptomatic treatment is achieved with anti-histamines which block histamine receptors. Chromolyn sodium inhibits mast cell degranulation, probably by inhibiting Ca++ influx. Late onset allergic symptoms, particularly bronchoconstriction which is mediated by leukotrienes are treated with leukotriene receptor blockers (Singulair, Accolate) or inhibitors of the cyclooxygenase pathway (Zileutoin). Symptomatic, although short term, relief from bronchoconstriction is provided by bronchodilators (inhalants) such as isoproterenol derivatives (Terbutaline, Albuterol). Thophylline elevates cAMP by inhibiting cAMP-phosphodiesterase and inhibits intracellular Ca++ release is also used to relieve bronchopulmonary symptoms.

Hyposensitization (immunotherapy or desensitization) is another treatment modality which is successful in a number of allergies, particularly to insect venoms and to some extent, pollens. The mechanism is not clear but there is a correlation between appearance of IgG (blocking) antibodies and relief from symptoms. Suppressor T cells that specifically inhibit IgE antibodies may play a role.

Type II Hypersensitivity

Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement. Phagocytes and K cells may also play a role.

The lesion contains antibody, complement and neutrophils. Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence. The staining pattern is normally smooth and linear, such as that seen in Goodpasture’s nephritis (renal and lung basement membrane) and pemphigus (skin intercellular protein, desmosome).Treatment involves anti-inflammatory and immunosuppressive agents.

Figure 7: Mechanism of Type II Hypersensitivity

Type III Hypersensitivity

Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g. serum sickness) or may involve individual organs including skin (e.g. systemic lupus erythematosus, Arthus reaction), kidneys (e.g. lupus nephritis), lungs (e.g. aspergillosis), blood vessels (e.g. polyarteritis), joints (e.g. rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganisms.

The reaction may take 3 – 10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic infections) or endogenous (non-organ specific autoimmunity: e.g. systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is caused by platelets and neutrophils. The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process12.

Figure 8: Mechanism of type III Hypersensitivity

The affinity of antibody and size of immune complexes are important in production of disease and determining the tissue involved. Diagnosis involves examination of tissue biopsies for deposits of immunoglobulin and complement by immunofluorescence microscopy. The immuno fluorescent staining in type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture’s syndrome). The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (nephelometry) binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes anti-inflammatory agents.

Type IV Hypersensitivity

Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The classical example of this hypersensitivity is tuberculin (Montoux) reaction which peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by induration and erythema.

Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis etc.) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy), chemicals, heavy metals, etc.) in which the lesions are more papular. Type IV hypersensitivity can be classified into three categories depending on the time of onset and clinical and histological presentation Table 3.

Table 3 – Delayed Hypersensitivity Reactions
Type Reaction time Clinical appearance Histology Antigen and site
contact 48-72 hr eczema lymphocytes, followed by macrophages; edema of epidermis epidermal ( organic chemicals, poison ivy, heavy metals, etc.)
tuberculin 48-72 hr local induration lymphocytes, monocytes, macrophages intradermal (tuberculin, lepromin, etc.)
granuloma 21-28 days hardening macrophages, epitheloid and giant cells, fibrosis persistent antigen or foreign body presence (tuberculosis, leprosy, etc.)

Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T cells (Tc) cause direct damage whereas helper T (TH1) cells secrete cytokines which activate cytotoxic T cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage. The delayed hypersensitivity lesions mainly contain monocytes and a few T cells.Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, interleukin-2, interferon-gamma, TNF alpha/beta etc12.

Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test) and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lympho-cytotoxicity and IL-2 production. Corticosteroids and other immunosuppressive agents are used in treatment.

Figure 9: Type IV (delayed) Hypersensitivity

Comparison of Different Types of Hypersensitivity

Table 4 – Comparison of Different Types of Hypersensitivity
characteristics type-I





(immune complex)


(delayed type)

antibody IgE IgG, IgM IgG, IgM None
antigen exogenous cell surface soluble tissues & organs
response time 15-30 minutes minutes-hours 3-8 hours 48-72 hours
appearance weal & flare lysis and necrosis erythema and edema, necrosis erythema and induration
histology basophils and eosinophil antibody and complement complement and neutrophils monocytes and lymphocytes
transferred with antibody antibody antibody T-cells
examples allergic asthma, hay fever erythroblastosis

fetalis, Goodpasture’s nephritis

SLE, farmer’s lung disease tuberculin test, poison ivy, granuloma

Figure 10: Mechanisms of different types of Hypersensitivities14

Antigen-Antibody Reactions

A process of the immune system in which immunoglobulin-coated B cells recognize a specific antigen and stimulate antibody production. T cells also play an essential role in the reaction. An antigen-antibody reaction begins with the binding of antigens to antibodies to form antigen-antibody complexes. These complexes may render toxic antigens harmless (neutralization), agglutinize antigens on the surface of microorganisms or activate the complement system by exposing the complement binding sites on antibodies. Certain complement protein molecules immediately bind to these sites and trigger the activity of the other complement protein molecules, which cause antigen-bearing cells to lyse14. Antigen-antibody reactions may start immediately with antigen contact or as much as 48 hours later. They normally produce immunity but may also be responsible for allergy, autoimmunity and fetomaternal hematologic incompatibility. In the immediate allergic response, the antigen-antibody reaction activates certain enzymes and causes an imbalance between those enzymes and their inhibitors. Simultaneously released into the circulation are several pharmacologically active substances, including acetylcholine, bradykinin, histamine, immunoglobulin G and leukotaxine.

Although there are many different types of antigen–antibody reactions, blood bankers are often concerned with reactions between antigens on red blood cells and antibodies in serum/plasma. These antigen–antibody reactions can occur observably in varying proportions, with regard to volumes and strength of reactants used. They are also reversible and are influenced by many factors. Antigen–antibody reactions are enhanced in the laboratory to make them observable, in an effort to draw practical conclusions and report on clinical conditions with accuracy. Provided that the correct methods are followed, it is usually not difficult to determine blood groups and the nature and specificity of antibodies. Occasionally, however this is more challenging and it sometimes takes considerable knowledge, skill and experience to accurately assess anomalous test results, determine what should be performed next, carry out further tests appropriately and then correctly interpret the results.

First and Second stages of Antigen–Antibody Reactions

When a blood sample is drawn, it is taken either into a dry test tube or into a test tube containing an anticoagulant. Serum is the fluid part of a blood specimen taken into a dry test tube and allowed to clot. It has similar properties to plasma but the coagulation factors are missing because they have been utilized in the clotting process. The blood sample in the plain tube coagulates and in a short time the clot will retract (shrinks) sufficiently for the serum to be clearly visible. To prevent coagulation, the blood sample may be taken into an anticoagulant such as acid citrate dextrose (ACD) or ethylenediaminetetraacetic acid (EDTA). Laboratory tests involving reactions between serum/plasma containing blood group antibodies and red cells expressing the corresponding antigens, take place in two stages. Although the stages are distinct, they need not necessarily be entirely separate entities; the two stages may overlap to some extent.

First stage

This involves antigens and antibodies randomly bumping into each other in the test environment and when this occurs at the antigen site, the actual attachment of antibody to antigen takes place. It usually happens very quickly and is affected by many variables. The reaction is not visible.

Second stage

This involves the demonstrable effect of attachment of antibody to antigen. This stage takes a longer time to develop and may need to be enhanced in the laboratory in order for it to become observable. The most widely used strategy in the laboratory to enhance the visibility of antigen–antibody reactions is centrifugation. After allowing sufficient time for antibody to recognize and react with antigen, which may be within seconds or may take much longer up to 1 hour, tests can be centrifuged to force the cells closer together. In this way agglutination may be enhanced, whereas cells that have not reacted with antibody remain unagglutinated.

Common types of Antigen–Antibody reactions

Antigen–antibody reactions that are of particular relevance to blood bankers are introduced below. This is followed by the factors that influence reactions and the various agents that may be used to improve or enhance them.


Because they have similar negative electrical charges, red cells are kept apart. This is the natural repelling force that exists between molecules with similar electrical charges and is called zeta potential. The negatively charged red cells in saline or suspending medium attract a cloud of positively charged ions around them. IgM antibodies, being 300 Å long are able to span the distance between adjacent red cells and as a result, bring about haemagglutination of cells with the corresponding antigen. This is what typically happens in ABO blood grouping tests.The agglutination of red cells in this way is correctly called haemagglutination, although it is often simply referred to as agglutination. It takes place when serum/plasma antibody (e.g. anti-A) is mixed with red cells carrying the corresponding antigen (i.e. A antigen). This reaction may occur in a test tube or on a microscope slide, or in a microwell. The result is the development of a three-dimensional latticework of red cells held together by antibodies and visible as clumping.


Sensitizing antibodies are IgG antibodies that are about 120 Å in length. Although they are able to sensitize red cells with the corresponding antigens, zeta potential must be reduced or altered for the smaller IgG antibodies to achieve haemagglutination. Additives such as bovine serum albumin or proteolytic enzymes like papain or bromelin are able to reduce zeta potential and thereby change the environment surrounding the red cells so as to allow sensitized cells to become agglutinated.

Laboratory tests have therefore to be modified in a prescribed way to enable sensitization to become observable in-vitro. There is a notable exception to this rule and that is agglutinating IgG anti-A and anti-B .

There are two commonly used ways to cause sensitized cells to become agglutinated and these are described in detail later in this section. In brief, the principles of these methods are:

Ø Reduction of zeta potential – substances such as proteolytic enzymes or bovine serum albumin may be used to reduce the repelling force between red cells, bringing them closer together so that if sensitized, they are able to become agglutinated.

Ø Bridging the gap between sensitized cells – antihuman globulin (AHG) is an antibody to human globulin and is used in the laboratory to react with sensitizing globulins (antibodies), bridging the gap and bringing about the agglutination of the cells they had sensitized.

Antibody affinity and avidity

Ø The strength of the actual bond between a single antibody combining site and a single epitope is known as the affinity of the antibody and relates to its goodness of fit with the corresponding antigen.

Ø The combined strength of multivalent antibody binding to many epitopes on the same carrier (such as a red blood cell) is known as the avidity of the antibody. In blood banking terms, this condition could apply to IgM or IgG antibodies, as both have more than one binding site per molecule.


On rare occasions, an undiluted antibody with high avidity, when mixed with a suspension of red cells containing the corresponding antigen, will fail to show any demonstrable reaction in vitro, but will do so when diluted and mixed with these same cells. This is the result of antibody excess in the neat serum/plasma that prevents the development of a regular latticework of visible agglutination. When suitably diluted, the number of antibody molecules is reduced sufficiently to allow normal agglutination of the cells to take place.

Qualitative and quantitative agglutination tests

Ø Qualitative tests determine the presence or absence of an antigen or antibody. Blood grouping tests that are performed to determine the presence or absence of an antigen using an antibody of known specificity are qualitative tests. For example, ABO blood grouping may be carried out by cell (or forward) grouping using reagent anti-A and anti-B with red cells of unknown group and reverse grouping of unknown serum/plasma with reagent A and B cells.

Ø Quantitative tests determine the highest dilution at which an antibody is able to react with its corresponding antigen. This endpoint is the titre of the antibody, expressed as a reciprocal (or inverse) of the highest dilution at which agglutination was observed. For example, if the highest dilution at which a reaction is observable is 1 in 32, then the titre is expressed as 32. Quantitative tests may also be used to determine the international units of antibody in a serum/plasma sample.


Sometimes antigen–antibody reactions result in lysis, which is the breakdown or rupture of the cell membrane on which the epitopes or antigenic determinants are situated. When this involves red blood cells, it is called haemolysis and causes the release of haemoglobin. This is an observable reaction in laboratory tests and must be noticed and recorded. For this to occur, the antibody involved in the reaction must be able to utilize complement, present in fresh serum or in the bloodstream. Complement is a group of proteins that when triggered by antibody adherence (attachment or sensitization) to the cell, act in a chain reaction to attack and break or rupture the cell membrane. Haemolysis of this nature is therefore a demonstrable endpoint of certain antigen–antibody reactions.

Neutralization (agglutination inhibition)

The majority of individuals secrete water soluble ABO blood group antigens in their body fluids such as saliva. Should saliva containing A antigens be mixed with anti-A in the laboratory, then this anti-A will become neutralized. It will therefore be unable to react as expected with group A red cells subsequently added to the mixture. When an antibody has been neutralized, it means that its reactive sites have been blocked by antigen, which is free (not attached to a carrier molecule like a red blood cell). Such a neutralization reaction is usually not observable and can only be deduced by the subsequent lack of agglutination when in contact with the corresponding antigen.


Precipitation is commonly seen as a precipitin line, such as in immunodiffusion, when antibody and antigen are added to different wells cut into gel set onto a microscope slide. For example, anti-Z may be added to a central well cut into the gel and several unknown samples that may carry the corresponding soluble Z antigen added to different wells surrounding it. After allowing time under the correct conditions, for diffusion of all the solutions into the gel, it is examined for precipitin lines. If the antibody diffusing out from the central well comes into contact with the corresponding antigen that has diffused out from one of the peripheral wells, then a white line of reaction may be seen in the gel between them – where they have come into contact with each other. This is formed by the precipitation of insoluble antigen–antibody complexes.

Nature of Antigen-Antibody Reactions

Lock and Key Concept

The combining site of an antibody is located in the Fab portion of the molecule and is constructed from the hypervariable regions of the heavy and light chains. X-Ray crystallography studies of antigen-antibody interactions show that the antigenic determinant nestles in a cleft formed by the combining site of the antibody.

Non- Bonds covalent

The bonds that hold the antigen to the antibody combining site are all non-covalent in nature. These include hydrogen bonds, electrostatic bonds, Van der Waals forces and hydrophobic bonds. Multiple bonding between the antigen and the antibody ensures that the antigen will be bound tightly to the antibody.


Since antigen-antibody reactions occur via non-covalent bonds, they are by their nature reversible.

Affinity and Avidity


Antibody affinity is the strength of the reaction between a single antigenic determinant and a single combining site on the antibody. It is the sum of the attractive and repulsive forces operating between the antigenic determinant and the combining site of the antibody. Affinity is the equilibrium constant that describes the antigen-antibody reaction. Most antibodies have a high affinity for their antigens.


Avidity is a measure of the overall strength of binding of an antigen with many antigenic determinants and multivalent antibodies. Avidity is influenced by both the valence of the antibody and the valence of the antigen. Avidity is more than the sum of the individual affinities. To repeat, affinity refers to the strength of binding between a single antigenic determinant and an individual antibody combining site whereas avidity refers to the overall strength of binding between multivalent antigens and antibodies.

Specificity and Cross Reactivity


Specificity refers to the ability of an individual antibody combining site to react with only one antigenic determinant or the ability of a population of antibody molecules to react with only one antigen. In general, there is a high degree of specificity in antigen-antibody reactions. Antibodies can distinguish differences in:

Ø The primary structure of an antigen

Ø Isomeric forms of an antigen

Ø Secondary and tertiary structure of an antigen

Cross reactivity

Cross reactivity refers to the ability of an individual antibody combining site to react with more than one antigenic determinant or the ability of a population of antibody molecules to react with more than one antigen. Cross reactions arise because the cross reacting antigen shares an epitope in common with the immunizing antigen or because it has an epitope which is structurally similar to one on the immunizing antigen.

Tests for Antigen-Antibody Reactions

Factors affecting measurement of antigen-antibody reactions –

The only way that one knows that an antigen-antibody reaction has occurred is to have some means of directly or indirectly detecting the complexes formed between the antigen and antibody. The ease with which one can detect antigen-antibody reactions will depend on a number of factors15.


The higher the affinity of the antibody for the antigen, the more stable will be the interaction. Thus, the ease with which one can detect the interaction is enhanced.


Reactions between multivalent antigens and multivalent antibodies are more stable and thus easier to detect.

Antigen to antibody ratio

The ratio between the antigen and antibody influences the detection of antigen-antibody complexes because the size of the complexes formed is related to the concentration of the antigen and antibody.

Physical form of the antigen

The physical form of the antigen influences how one detects its reaction with an antibody. If the antigen is a particulate, one generally looks for agglutination of the antigen by the antibody. If the antigen is soluble one generally looks for the precipitation of the antigen after the production of large insoluble antigen-antibody complexes.

Factors That Influence Antigen–Antibody Reactions

Distance between reactive sites on antibodies

IgM antibody molecules are 300 Å long and able to react observably by haemagglutination of red cells in saline. IgG antibodies are 120 Å long and usually sensitize cells in saline.

Electric repulsion between red cells – zeta potential

The repelling force between red cells that carry the same negative electrical charge is called zeta potential, which prevents the agglutination of sensitized red cells in saline. Zeta potential must therefore be reduced or altered in some way for the smaller IgG antibodies to be able to achieve agglutination.

Site of the antigenic determinants

It is thought that some antigens (such as the A and B antigens) protrude from the red cell surface farther than others (such as the Rh antigens). Because of this, the actual distance between antigens on adjacent cells may vary to a certain extent, so affecting the nature of the reaction or the ability of corresponding antibodies to react with them.

Number of antigenic determinants

It is easier for antibodies to react with antigens, which are in abundance on each red cell, than to react with antigens that are located only sparsely on the cells. Cells that are homozygous for a particular antigen may carry more antigen sites (antigenic determinants or epitopes) than cells which are heterozygous. This is termed the dosage effect. For example, S positive red cells that are genetically S/S (with a double dose ofS) may react more strongly with anti-S than cells which are heterozygous S/s (with a single dose of S), depending on the anti-S used in the tests.

Number of antigenic determinants

It is easier for antibodies to react with antigens, which are in abundance on each red cell, than to react with antigens that are located only sparsely on the cells. Cells that are homozygous for a particular antigen may carry more antigen sites (antigenic determinants or epitopes) than cells which are heterozygous. This is termed the dosage effect. For example, S positive red cells that are genetically S/S (with a double dose of S) may react more strongly with anti-S than cells which are heterozygous S/s (with a single dose of S), depending on the anti-S used in the tests.

Number of antigenic determinants

It is easier for antibodies to react with antigens, which are in abundance on each red cell than to react with antigens that are located only sparsely on the cells. Cells that are homozygous for a particular antigen may carry more antigen sites (antigenic determinants or epitopes) than cells which are heterozygous. This is termed the dosage effect. For example, S positive red cells that are genetically S/S (with a double dose of S) may react more strongly with anti-S than cells which are heterozygous S/s (with a single dose of S), depending on the anti-S used in the tests.

Number of antigenic determinants

It is easier for antibodies to react with antigens, which are in abundance on each red cell than to react with antigens that are located only sparsely on the cells. Cells that are homozygous for a particular antigen may carry more antigen sites (antigenic determinants or epitopes) than cells which are heterozygous. This is termed the dosage effect. For example, S positive red cells that are genetically S/S (with a double dose of S) may react more strongly with anti-S than cells which are heterozygous S/s (with a single dose of S), depending on the anti-S used in the tests.

Goodness of fit

Antigens and antibodies react in a ‘lock-and-key’ way. When the combination between lock and key is precise, then the goodness of fit is high, and the reaction will be stronger; a weak fit results in a weaker reaction. The degree of goodness of fit is also known as antibody affinity16.

Effects of time

Reactants should be incubated for the optimum time for a good antigen–antibody reaction to develop. Too short an incubation period means that the antigen and the antibody may not have had sufficient time to form a good reaction. On the other hand, prolonged incubation may cause antigen–antibody complexes to dissociate. The best balance should be determined, documented and followed each time tests are performed.

Effects of temperature

Cold antibodies react well at +2°C to +10°C, agglutinating or sensitizing red cells in the cold. These antibodies will usually dissociate from the cells when the temperature of the tests is raised. Thus, cold antibodies may be eluted from red cells by raising the temperature from +2°C to +37°C. Most IgG antibodies react best with the corresponding antigens at +37°C. At this temperature, the speed of their reaction is also increased. In order to dissociate antigen–antibody complexes formed by antibodies with an optimum reaction temperature of +37°C, one would have to raise the temperature to about +56°C. At this temperature, antibody would be eluted (removed or forced to be released) from the cells and could then be isolated and further tested. Red cells however, become denatured at temperatures in excess of +50°C and would have to be discarded.

Effects of pH

pH is the measure of alkalinity or acidity of a solution. The optimal pH range for red cell antigen–antibody reactions to occur is between of 6·5 and 7·0, with an acceptable range of pH of 6·0–8·0. Outside this range, results become unreliable.

Effects of ionic strength

Negatively charged red blood cells attract a ‘cloud’ of positive ions from the surrounding medium, which is usually saline – sodium chloride dissolved in water. What is commonly known as normal ionic strength saline solution is isotonic with blood; it has the same tonicity as blood. It is a solution of about 0·85% to 0·9% weight to volume of sodium chloride in water. Low ionic strength saline solutions are commonly used to increase the sensitivity of antigen–antibody reactions, and details on this are to be found later in this section.

Concentration of antigen and antibody

Although most antigen–antibody reactions provide observable results at various concentrations of either antigen or antibody, the best results are obtained when a large number of antibody molecules are bound to each cell.

Number of fragment antigen binding sites

IgM antibodies have between 5 and 10 fragment antigen binding (Fab) sites, whereas IgG antibodies are monomers with a maximum of 2 Fab sites. To bring about the agglutination of two adjacent red cells, an IgM antibody could bind with several antigens on one cell and several on the second cell and form a fairly strong bond. An IgG molecule though, could bind to only one antigen on one cell and one antigen on another cell, and unless it is an avid antibody, may form a weaker bond. In both cases, many molecules of antibody are required to result in a demonstrable reaction, but the principle remains the same.

Hypersensitive Reaction Causes

Almost anything can trigger a hypersensitive reaction.

Ø The body’s immune system involves the white blood cells, which produce antibodies.

Ø When the body is exposed to an antigen, a complex set of reactions begins.

Ø The white blood cells produce an antibody specific to that antigen. This is called “sensitization.”

Ø The job of the antibodies is to detect and help destroy substances that cause disease and sickness. In hypersensitive reactions, the antibody is called immunoglobulin E or IgE.

Ø This antibody promotes production and release of chemicals and hormones called “mediators.”

Ø Mediators have effects on local tissue and organs in addition to activating more white blood cell defenders. It is these effects that cause the symptoms of the reaction

Ø Histamine is one of the better-known mediators produced by the body.

v Hypersensitive reactions are unique for each person. Reaction time to allergens can vary widely. Some people will have a hypersensitive reaction immediately, for others it will take time to develop.

v Most people are aware of their particular hypersensitive triggers and reactions.

v Vaccines and medications (antibiotics like penicillin, amoxicillin, aspirin, ibuprofen, iodine), general anesthesia and local anesthetics, latex rubber (such as in gloves or condoms), dust, pollen, mold, animal dander and poison ivy are well-known allergens17. Other known allergens can include detergents, hair dyes and the ink in tattoos.

v Bee stings, fire ant stings, penicillin and peanuts are known for causing dramatic reactions that can be serious and involve the whole body.

v Minor injuries, hot or cold temperatures, exercise, stress or emotions may trigger hypersensitive reactions.

v Often, the specific allergen cannot be identified unless you have had a similar reaction in the past.

v Allergies and the tendency to have allergic reactions run in some families.

v Many people who have one trigger tend to have other triggers as well.

v People with certain medical conditions are more likely to have hypersensitive reactions.

Hypersensitivity Reaction Symptoms and Signs

The look and feel of a hypersensitive reaction depends on the body part involved and the severity of the reaction. Some reactions may be localized and limited, while others could involve multiple body systems. Reactions to the same allergen vary among individuals.

v Anaphylaxis is the term for any combination of hypersensitive symptoms that is rapid or sudden and potentially life-threatening18. One sign of anaphylaxis is shock. Shock has a very specific meaning in medicine. The organs of the body are not getting enough blood because of dangerously low blood pressure. Shock may lead rapidly to death. The person in shock may be pale or red, sweaty or dry, confused, anxious or unconscious. Breathing may be difficult or noisy, or the person may be unable to breathe.

v Shock is caused by sudden dilation of many or large blood vessels. This is brought on by the action of the mediators. If the drop in blood pressure is sudden and drastic, it can lead to unconsciousness, even cardiac arrest and death.

v Symptoms and signs of an a hypersensitive reaction include any, some or many of the following:

§ Skin: irritation, redness, itching, swelling, blistering, weeping, crusting, rash, eruptions or hives (itchy bumps or welts)

§ Lungs: wheezing, tightness, cough or shortness of breath

§ Head: swelling or bumps on the face and neck, eyelids, lips, tongue or throat, hoarseness of voice, headache

§ Nose: stuffy nose, runny nose (clear, thin discharge), sneezing

§ Eyes: red (bloodshot), itchy, swollen or watery or swelling of the area around the face and eyes

§ Stomach: pain, nausea, vomiting, diarrhea, or bloody diarrhea

§ Other: fatigue, sore throat

When to Seek Medical Care

Because hypersensitive reactions can progress and worsen in minutes causing complications, medical attention is always recommended for all but the most minor and localized symptoms. If the symptoms of your reaction worsen over a few days or if they do not improve with recommended treatment and removal of the allergen, victim should seek health-care provider.

Hypersensitive reactions can be dangerous. Sudden, severe widespread reactions require emergency evaluation by a medical professional.

Sudden, severe or rapidly worsening symptoms, exposure to an allergen that previously caused severe or bad reactions, swelling of the lips, tongue or throat, wheezing, chest tightness, loud breathing, trouble breathing or hoarseness of voice, confusion, sweating, nausea or vomiting, widespread rash or severe hives, lightheadedness, collapse or unconsciousness19.

Hypersensitivity Reaction Diagnosis

For typical hypersensitive reactions, health-care provider will examine patient and ask questions about his symptoms and their timing. Blood tests and X-rays are not needed except under unusual circumstances.

In case of severe reactions, patient will be evaluated quickly in the emergency department in order to make a diagnosis20. The first step for the health-care provider is to judge the severity of the hypersensitive reaction.

  • Blood pressure and pulse are checked.
  • An examination determines whether patient need help breathing.
  • Often, an IV line is placed in case patient will need anti-allergy (antihistamine) medications quickly.
  • If patient can speak, he will be asked about allergy triggers and previous reactions.

Hypersensitivity Reaction Treatment

Self-Care at Home

Self-care at home is not enough in severe reactions. A severe reaction is a medical emergency.

  • Do not attempt to treat or “wait out” severe reactions at home. Go immediately to a hospital emergency department.
  • If no one is available to drive you right away, call an ambulance for emergency medical transport.
  • Use your epinephrine auto-injector if you have been prescribed one by your doctor due to previous allergic reactions.

Slight reactions with mild symptoms usually respond to nonprescription allergy medications.

  • Oral antihistamines21
  • Loratadine (Claritin or Alavert), cetirizine (Zyrtec), and fexofenadine (Allegra) are nonsedating antihistamines that can be taken over the long term.
  • Diphenhydramine (Benadryl) can also be taken but may make you too drowsy to drive or operate machinery safely. It can affect concentration and interfere with children’s learning in school. These medications should be taken for only a few days.
  • For rashes or skin irritations, an anti-inflammatory steroid cream such as hydrocortisone can be used.

For small, localized skin reactions, use a cold, wet cloth or ice for relief. Apply a bag of frozen vegetables wrapped in a towel as an ice pack.

Medical Treatment

Generally, antihistamine medications are the treatment of choice after the allergen is removed. Very severe reactions may require other therapy, such as oxygen for breathing difficulties or intravenous fluids to boost blood pressure in anaphylactic shock. Patients with very severe reactions usually require hospitalization22.

Hypersensitivity Reaction Medications

There are many types of anti-allergy medications. The choice of medication and how it is given depends on the severity of the reaction.

For relief of long-term allergies such as hay fever or reactions to dust or animal dander, the following medications may be recommended or prescribed:

  • Long-acting antihistamines, such as cetirizine (Zyrtec), fexofenadine (Allegra), and loratadine (Claritin), can relieve symptoms without causing sleepiness. Formerly available by prescription only, you can now find these medications over the counter. They are meant to be taken for months at a time, even indefinitely. Most can be taken once a day and last for 24 hours.
  • Nasal corticosteroid sprays are widely prescribed for nasal symptoms not relieved by antihistamines. These prescription medications work very well and are safe, without the side effects of taking steroids by mouth or injection. These sprays take a few days to take effect and must be used every day. Examples are fluticasone (Flonase), mometasone (Nasonex), and triamcinolone (Nasacort).

For severe reactions, the following medications are usually given right away to rapidly reverse symptoms:

  • Epinephrine

This drug is given only in very severe reactions (anaphylaxis). It is injected and acts as a bronchodilator (dilates the breathing tubes).It also constricts the blood vessels, increasing blood pressurure. Medication similar to epinephrine may be used, as in asthma. Antihistamines, such as diphenhydramine (Benadryl). This drug is given in an IV or in a muscle to rapidly reverse the actions of histamine.Oral diphenhydramine is usually enough for a less severe reaction.

  • Corticosteroids

Corticosteroids are usually given via IV at first for rapid reversal of the effects of the mediators. These drugs should not be confused with the steroids taken illegally by athletes to build muscle and strength. These drugs reduce swelling and many other symptoms of allergic reactions. Patient will probably need to take an oral corticosteroid for several days after this. Oral corticosteroids are often given for less severe reactions. A corticosteroid cream or ointment may be used for skin reactions. Corticosteroid nasal sprays reduce the discomfort of a “stuffy” nose.

Other medications may be given as needed23.

  • In some people, cromolyn sodium nasal spray prevents allergic rhinitis or inflammation of the nose that occurs as an allergic reaction.
  • Decongestants can restore sinus drainage, relieving symptoms such as nasal congestion, swelling, runny nose and sinus pain (pain or pressure in the face, especially around the eyes). They are available in oral forms and as nasal sprays. They should be used for only a few days, as they may have side effects such as high blood pressure, rapid heartbeat, and nervousness.
Treatments Effects Effective for Type of Reaction
CORTICOSTEROID MEDICATIONS suppress COMPLEMENT CASCADE, ANTIBODY activation, and eosinophil production

suppress mast cell release of histamine, LEUKOTRIENES, and PROSTAGLANDINS

type II, type III, type IV

type I when severe or nonresponsive to other treatment

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) suppress various immune response pathways type III
EPINEPHRINE injection stop the immune response type I when severe or anaphylactic
immunosuppressive agents other than corticosteroids suppress various immune response pathways type III and type IV
leukotriene receptor antagonist medications block leukotriene binding type I when ASTHMA present
MAST CELL stabilizers prevent degranulation within mast cells to block the release of histamine, leukotrienes, and prostaglandins type I when asthma present


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