Hypersensitivity refers to excessive, undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by

the normal immune system. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. Hypersensitivity
reactions can be divided into four types: type I, type II, type III and type IV, based on the mechanisms involved and time taken
for the reaction. Frequently, a particular clinical condition (disease) may involve more than one type of reaction.

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).

Immediate hypersensitivity is mediated by IgE. 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 mainly mast cells and eosinophils.

The mechanism of reaction involves preferential production of IgE, in response to certain antigens (often called allergens).
The precise mechanism as to why some individuals are more prone to type-I hypersensitivity is not clear.
However, it has been shown that such individuals preferentially produce more of TH2 cells that secrete IL-4, IL-5
and IL-13 which in turn favor IgE class switch. IgE has very high affinity for its receptor (Fcε; CD23) on mast
cells and basophils.

A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various
pharmacologically active substances (figure 1). 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 

MEDIATOR

Preformed mediators in granules

histamine bronchoconstriction, mucus secretion, vasodilatation, vascular permeability

tryptase proteolysis

kininogenase kinins and vasodilatation, vascular permeability, edema

attract eosinophil and neutrophils

ECF-A
(tetrapeptides)
 

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 question.
 
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 seem 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 α-adrenergic receptor stimulation of β-adrenergic receptor

(nor-epinephrin, phenyl-epinephrin) (epinephrine, isoproterenol)

or blocking of α-adrenergic receptor

(phenoxybenzamine)
blocking of β-adrenergic receptor
(propanolol) inhibition of phosphodiesterase
(theophylline)
elevation of cyclic-GMP
 stimulation of γ-cholinergic receptor
(acetyl choline, carbacol)

WORSENING OF SYMPTOMS binding of histamine-2

IMPROVEMENT or PGE to their receptors
OF SYMPTOMS
 

Diagnostic tests for immediate hypersensitivity include skin (prick and intradermal) tests (fig. 1A), 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 immunoassay (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.).

There appears to be a genetic predisposition for atopic diseases and there is evidence for HLA (A2) association.

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.

The use of IgG antibodies against the Fc portions of IgE that binds to mast cells has been approved for treatment of
certain allergies, as it can block mast cell sensitization.

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
Figure 1A normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II
close-up view of intradermal hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is
skin test with multiple positive minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement (Figure 2).
allergen responses  Phagocytes and K cells may also play a role.
© Bristol Biomedical Image Archive. Used with
permission
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) (figure 3A) and
pemphigus (skin intercellular protein, desmosome) (figure 3B).
  Figure 2. Treatment involves anti-inflammatory and immunosuppressive agents.
Type II cytotoxicity
mechanism  

TYPE III HYPERSENSITIVITY

Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general ( e.g., serum sickness) or
  Figure 3A   may involve individual organs including skin ( e.g., systemic lupus erythematosus, Arthus reaction), kidneys ( e.g., lupus nephritis),
Immunofluorescent stain of lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be
immunoglobulin G (IgG) the pathogenic mechanism of diseases caused by many microorganisms.
showing linear pattern in
Goodpasture's syndrome © The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune
Bristol Biomedical Image Archive. Used with
permission 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 (Figure 4). The lesion contains primarily
neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the
Figure 3B healing process.
Pemphigus vulgaris -

immunofluorescence  © Bristol
Biomedical Image Archive. Used with
permission
Figure 4. Mechanism of
damage in immune complex
hypersensitivity
Figure 5 
Mantoux intradermal
tuberculin skin test for
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 immunofluorescent 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 (figure 5) which peaks 48 hours after the injection of antigen (PPD or old
tuberculin). The lesion is characterized by induration and erythema.
Table 3  -   Delayed hypersensitivity reactions
 Reaction Clinical
tuberculosis Type Histology Antigen and site
time appearance

lymphocytes, followed by epidermal ( organic

contact 48-72 hr eczema macrophages; edema of chemicals, poison ivy, heavy
epidermis metals, etc.)

local lymphocytes, monocytes, intradermal (tuberculin,

tuberculin 48-72 hr
induration macrophages lepromin, etc.)

persistent antigen or foreign

21-28 macrophages, epitheloid
granuloma hardening body presence (tuberculosis,
days and giant cells, fibrosis
leprosy, etc.)
 

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 (figure 6), 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).
 
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 (figure 4). The delayed hypersensitivity lesions mainly contain
Figure 6 monocytes and a few T cells.
Poison Ivy CDC
Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, interleukin-2, interferon-
gamma, TNF alpha/beta, etc.

Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test (figure 5)) 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.

Table 5  -  Comparison of Different Types of hypersensitivity

type-III
type-I type-II type-IV
characteristics (immune
(anaphylactic) (cytotoxic) (delayed type)
complex)

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

erythema and erythema and

appearance weal & flare lysis and necrosis
edema, necrosis induration

basophils and antibody and complement and monocytes and

histology
eosinophil complement neutrophils lymphocytes

transferred with antibody antibody antibody T-cells

examples allergic asthma, erythroblastosis SLE, farmer's tuberculin test,

hay fever lung disease poison ivy,
fetalis, granuloma
Goodpasture's  
 nephritis

Pathophysiology
Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies. T helper (TH) cells, which are
CD4+, have been divided into 2 broad classes based on the cytokines they produce: TH1 and TH2. 5,6 Regulatory T cells (Tregs) are CD4+CD25+ and may also play a
role.7

TH1 cells produce interferon gamma, interleukin (IL)–2, and tumor necrosis factor-beta and promote a cell-mediated immune response (eg, delayed hypersensitivity
reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. Therefore, TH2 cells play
an important role in the development of immediate hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio.
Interestingly, the cytokines produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells. 8,5,6 Current evidence suggests that
Tregs may also actively inhibit TH2 responses to allergens. 7

The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is
then processed by the dendritic cell, an antigen-presenting cell. 9 The antigen-presenting cells then migrate to lymph nodes, where they prime naive TH cells (TH0
cells) that bear receptors for the specific antigen.

TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of allergen sensitization, the TH0
cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center B cells) and possibly to histamine-primed dendritic cells, both
of which cause them to develop into TH2 cells. These primed TH2 cells then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of
antigen-specific IgE antibodies.

For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present peptides from it,
bound to the major histocompatibility class II molecules found on B-cell surfaces, to the antigen receptors on TH2 cells. The B cell must also bind to the TH2 cell and
does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the
B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production (see image below).

Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure to the antigen can then
result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical
mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are
described as follows:5,6

Preformed mediators

 Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract,
increased vasopermeability and vasodilation, enhanced mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.
 Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a as well as C5. 10 Tryptase is found in all
human mast cells but in few other cells and thus is a good marker of mast cell activation.
 Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the
preformed proteases and may play a role in the production of alpha-tryptase.
 Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in
neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later
phases of allergic reactions.

Newly formed mediators

 Arachidonic acid metabolites

o Leukotrienes - Produced via the lipoxygenase pathway
 Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability
 Leukotrienes C4 and D4 - Potent bronchoconstrictors, increase vascular permeability, and cause arteriolar constriction
 Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability
 Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis
o Cyclooxygenase products
 Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator, coronary and pulmonary artery
vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer of histamine release from basophils
 Prostaglandin F2-alpha - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor
  Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction
 Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is
also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of
eosinophils and neutrophils.
 Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release.
 Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or alternative) route of kinin
generation, involving activation of the contact system via factor XII by mast cell – released heparin, has been described. 11,12 Bradykinin increases
vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-
mediated allergic reactions has not been clearly demonstrated. 3

Cytokines

 IL-4: IL-4 stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis.
 IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release.
 IL-6: IL-6 promotes mucus production.
 IL-13: This cytokine has many of the same effects as IL-4.
 Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other cytokines by T cells. 13

The actions of the above mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

 Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper
layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather
than pruritic.
 Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery
eyes.
 Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the
airways, resulting in chest tightness, shortness of breath, and wheezing.
 Anaphylaxis: Systemic release of the above mediators affects more than one system and is known as anaphylaxis. In addition to the foregoing symptoms, the
GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea. Systemic vasodilation and vasopermeability can result in significant
 hypotension and is referred to as anaphylactic shock. Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat
swelling and asphyxiation.3,6

Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds
to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils
and resident lymphocytes are activated by mast cell mediators.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or
symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal
discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-48 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) can result in chronic allergic inflammation. Tissue from sites
of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (eg, major basic protein), which can
cause tissue damage and thus increase inflammation. This can result in structural and functional changes to the affected tissue. Furthermore, a repeated allergen
challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2
cell/IgE–mediated responses.6