It is an exaggerated or inappropriate reaction harmful to host. First response sensitizes the immune system and subsequent contacts cause allergic reaction. Hypersensitivity is of four types;

Type I hypersensitivity – Anaphylactic shock.

Type II hypersensitivity – Cytotoxic hypersensitivity

Type III hypersensitivity – Immune complex hypersensitivity.

TYPE IV hypersensitivity -Delayed hypersensitivity.

Type I or immediate hypersensitivity or anaphylactic hypersensitivity


These disorders are characterized by abnormally strong Th2 responses against environmental antigens such as pollen, foods, insect proteins, some drugs, and so on. Term anaphylaxis was coined by Portier & Richet. They were studying the effect of toxins from sea anemone on dog. Instead of developing immunity, in successive dosage the dog presented excessive salivation, defecation, difficulty in respiration, paralysis of hind limbs & death within a few minutes of dose. It is an IgE mediated reaction.  Antigen binds to IgE on surface of mast cells that leads to the release of mediators. Process begins when antigen induces the formation of IgE antibodies, which bind firmly with their Fc portion to the basophils and mast cells. Re-exposure to Antigen causes cross linkage of the antibodies on surface of mast cells. When the cross linkage occurs, the chemical mediators are released within minutes. An increase in amount of cyclic GMP within these cells increases mediator release whereas and increase in cyclic AMP decreases the release. So the drugs with increase intracellular concentration of AMP such as epinephrine are used for treatment of anaphylactic shock.

Clinical manifestations:

Urticaria, eczema, rhinitis, conjunctivitis & asthma are identifying clinical features. In most severe form bronchospasm and hypotension occurs, ultimately leading to death. Type I reaction occurs in three steps:

  1. Sensitization phase
  2. Activation phase
  3. Effector phase

Sensitization phase is the first exposure of antigen which triggers the production of antibodies. Activation phase is when re-exposure of antigen causes the release of contents of basophils & Mast cells. Effector phase is when the clinical manifestations are presented by patient.

1) Sensitization phase:

Antibodies responsible for Type I hypersenstivity is IgE which is called is reaginic antibody. About 50% of population generates an IgE response to airborne antigens, which are encountered on the mucosal surfaces (Lining of nose, Lung & Conjuctiva). About 10% of these develop clinical features i.e. hay fever etc. on repeated exposures.

Atopy (uncommon):

These are immediate hypersensitive response which exhibit strong familial predisposition and are associated with raised IgE level. Several factors play a role in Atopy. Increased production of interleukines, failure of regulation of T-cell level, increased IgE synthesis, enhanced uptake of antigen and hyperactivity of target cells. Atopy is genetically controlled.

Prausnitz- Kustner reaction (passive cutaneous anaphylaxis):

Atopic hypersensitivity is transferrable by serum. Serum from the patient is taken and is injected into the skin of normal person. Some hours later antigen is injected which causes wheal & flare reaction (Not done presently because of transmission of infection). IgE production is T-cell dependent. (In experimental animals neonatal thymectomy abolishes capacity to produce it). IL-4 produced by CD4 + Th2 cells is important in production of IgE(B cell).

2) Activation phase:

Re-entry of Antigen into body causes the cross-linkage of antigen on the surface of mast cells which causes release of substances. It is most rapid of all hypersensitive reaction and takes place within 10-15 minutes.

3) Effector phase:

It consists of release of pharmacological active substances. There are two categories for it:

i) Pre-formed mediators:

  1. Histamine: It is present in tissue mast cells & basophils. It‘s release causes vasodilation, increase in capillary permeability & smooth muscle contraction. Bronchospasm is acute in histamine release. Clinically manifests as allergic rhinitis (Hay Fever), urticaria and angioedema.
  2. Serotonin: It is present in mast cells of only certain species such as rhodents. Action is similar to histamine.
  3. Eosinophilic chemotactic factor of anaphylaxis: It is a set of low molecular weight polypeptides. It helps in attraction of eosinophils to the site of release of peptides. These exist in pre-formed mast cell granules. The role of eosinophils in type one hypersensitive reaction is uncertain. But eosinophils secrete histaminases and auryl sulphate which degrade the important factors of type one reaction i.e. histamine and leucotrins so these reduce the severity of type one response
  4. Neutophils chemotactic factor (NCF’s): Activated mast cells release several substances which act as chemotactic factor for neutrophils. These act in late phase of hypersensitive reaction.
  5. Heparin: It is an acidic proteoglycan that constitute matrix of the granules to which basic mediators, histamines and serotonin are bound. Release of heparin causes inhibition of coagulation.

ii) Newly formed mediators:

  1. Leucotrines (slow reacting substances [SRS-A] of anaphylaxsis): There presence was demonstrated by Schlutz-Dale raction. When uterine horn of pig is treated with histamine contraction occurs. As soon as histamine is washed the muscles relax. As well as when anti histamine and histamine is added no contraction occurs. However, slow prolonged contraction results that cannot be relieved by washing. These led to discovery of SRS-A. They are the products of arachadonic acid pathway. They are named as LTB4, LTC4, and LTD4. They cause prolonged contraction of smooth muscles.
  2. Prostaglandins and Thromboxanes (TXA’s): These are related to Leucotrines. They are derived from cyclo-oxygenase pathway from arachdonic acid. Prostaglandins cause dilation of vessels and increase vascular permeability and broncho-constriction. TXA’s cause platelet aggregation in contrast to anaphylactic reaction which is IgE mediated anaphylacoid reaction which are clinically similar to anaphylactic one are not IgE mediated. In this reaction the inciting antigenent is drugs or iodinated contrast media which directly induces the mast cells and basophills to release there contents without involvement of IgE

Drugs and type I hyper sensitivity: Drugs may induce type I, II or type III reaction, but in case of anaphylactic reaction (based on clinical presentation), it is usually the metabolic product of the drug that acts as haptan and joins with protein to induce this reaction. An important clinical reaction is skin test using penecilloyl  polylysine to reveal an allergy to penicillin.


To stop the release of high amount of mediators of anaphylaxis desensitization is done.

Acute desensitization: It Involves  administration of very small amount of antigen mediators in 15 min. Intervals IgE & antigen complexes form but these do not stimulate release of large amount of mediators to cause major reaction .This helps in giving to hypersensitive patient but hypersensivity is restored within few days

Chronic desensitization:  In this case of antigen is administered in a definite quantity in weekly intervals for a long time which leads to formation of blocking antibodies. The blocking IgG prevent antigen to bind with IgE on mast cell surface because it attaches to antigen prior to its any reaction with IgE. This prevents hypersenstivity.


Epinephrine, antihistaminics and chromolyn sodium

Type II or Cytotoxic Hypersenstivity


It occurs when antibodies directed against antigen of cell membrane activates complement which leads to generation of membrane attack complex. IgG or IgM attached to membrane by Fab portion and fix the complement by Fc portion resulting in complement mediated lysis.



  • Penicillins, phenacetin & quinidine attaches to proteins of surfaces of RBC and initiate antibodies formation then IgG react with these Antigen’s result in haemolysis. Direct  coomb’s test is positive.
  • Quinine attaches to platelets and result in thrombocytopenia.
  • Procainamide and hydralazene result in antibodies against DNA & result in SLE like condition.


  • In myoplasma pneumoniae antibodies cross react with RBC’s.
  • In rheumatic fever Group A streptococci react with cardiac tissue.
  • In Goodpasture syndrome antibodies are directed against basement membrane of glomerulus & Lung.
  • ABO Blood group & Rh incompatibility.

Type III Hypersenstivity or Immune Complex Hypersenstivity


It occurs when immune complexes induce inflammatory changes in tissues. Under normal conditions immune complexes are promptly removed from circulation but in chronic bacterial or viral infections these are deposited in tissues resulting in several disorders.

There are two types type of TypeIII hyersenstivity:

  • Arthus reaction
  • Serum sickness
  1. Arthus reaction: In this reaction when antigen is given repeatedly to an animal high level of IgG are attained after sometime in that animal. After development of large amount of IgG, if that animal is injected with antigen subcutaneously intense oedema and hemorrhage develops reaching peak in 3-6 hours. It is because of the deposition of immune complexes, complement, PMN’s and intravascular clumping of platelets. Differentiating feature from type I reaction is that much more IgG is required i.e.  antibodies are required to produce Type III reaction. Typical example of Type III hypersensitivity is “Farmer’s Lung” which is caused by inhalation of monophilic Actinomycetes.
  2. Serum sickness: Following the injection of a drug or foreign serum, these act as antigens which are secreted slowly from body. Antibodies form against these foreign antigens & until they are excreted antibodies & antigens form immune complexes which deposits in various parts of body. Atypical serum sickness results in fever, urticaria, arthralgia, LAP, splenomegaly, eosinophillia in few days to weeks after injection. Serum sickness is commonly caused by drugs like penicillins,etc.

Some immune complex diseases are:

  1. Glomerulonephiritis:  It is caused by antibodies against β hemolytic group A streptococci several weeks after infection. It is usually after skin infection and generally with nephrogenic serotype of S. pyogens. Serum complement is low lumpy deposits of immunoglobulins and C3 are seen on glomular basement membrane. After being deposited it fixes complement and causes attraction to neturophils which cause the damage.
  2. Rheumatoid Arthritis: Synovial fluid in the joints contain contains rheumatoid factor.  IgG & IgM which are directed against rheumatoid factor cause deposition of the immune complexes on the synovial membrane and blood vessels leading to fixation of complement which attracts neutrophils and causes damage to the tissue.
  3. SLE (Systemic Lupus Erytheromatosis): In this case antibodies are directed against the DNA of the cells which causes damage to various organs.

Type IV hypersensitivity or delayed hypersensitivity


This is cell mediated hypersensitivity. In this type of reaction antigen is first ingested by macrophages which is then broken down and present on surface of cell by MHC II  which in turn activates CD4+ve T-cells which secretes IL1, IL2 & Gamma Interferon. For more information please read  “Major Histocompatibility Complex”. This type of immunity starts in hours and last for days and weeks. In mononuclear infiltrates mainly macrophages and CD4+ve cells are found.

Clinically seen reactions:

  1. Contact hypersensitivity: It occurs when body comes in contact with chemicals (like Nickel, Formaldehyde), drugs (sulphonamides & neomycin), plant materials (poison ivy& poison oak), Some cosmetic soaps etc. These act as haptans & combine with proteins to form complete Antigen which initiate hypersensitive reaction. On later contact with this antigen person develops erythema, itching, eczema etc.<!> and necrosis of skin within 12-48 hours. In delayed type of hypersensitivity contact with antigen and production of cells mediated immune response takes time but on second contact reaction occur within 12-48 hours.
  2. Tuberculin hypersenstivity test: In case of mycobacterial infection, when person is injected intradermally with tuberculin or PPD a little reaction occurs in first few hours but it gradually flares up in next 48-72 hours. A positive test indicates that person is infected currently or previously but does not confirm disease. When we do lepromin test, if it is positive  that means that antibodies are present as in tuberculoid type but if the test is negative it indicates that antibodies are absent in it is of lepromatous type.


Tolerance is unresponsiveness for certain specific antigens. Antigens present during embryonic life are considered “self” and do not stimulate immune response. Clonal deletion is destruction of self reactive T-cells in thymus.  It is called as central tolerance. Tolerance acquired outside thymus is called peripheral tolerance. Because some self reactive T-cells are not killed in thymus peripheral tolerance is required. This is called as Clonal anergy.  This is the functional inactivation of surviving self reacting T-cells. Proper signals are not present for T-cells to produce interleukins, so it remains attached to the APC and does not react further. Same thing occurs with B-cells but in bone marrow.

Some facts:

  • T-cells become tolerant more readily and remain tolerant for longer time than B-cells.
  • Administration of cross reacting antigens tends to terminate tolerance.
  • Administration of immunosuppressive drugs enhance tolerance i.e. in cases of transplants.
  • Tolerance is maintained best if antigen is constantly present.
  • Most important step in autoimmune disease is activation of CD4 cells which lead to stimulation of cell mediated or antibody mediated immune response
  • Most of autoimmune disease are antibody mediated (with some CMI also). Allergic enchephalomelytis is T-cell and macrophage mediated.
Type of hypersensitivity

Immunopathological mechanism

Mechanism of tissue injury

Type 1 hypersensitivity (Anaphylactic shock)

IgE antibody

Mast cells and their mediators (Vasoactive amines, lipid mediators, cytokines etc.)

Type 2 hypersensitivity  (Cytotoxic hypersensitivity or Antibody mediated hypersensitivity)

IgG, IgM antibodies acting against extracellular matrix antigens.

  • Opsonization and phagocytosis of cells
  • Complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils and macrophages)
  • Abnormalities in cellular functions e.g. hormonal receptor signalling .

Type 3 hypersensitivity       (Immune complex hypersensitivity)

Immune complexes of circulating IgG, IgM antibodies and antigens.

Complement and Fc receptor mediated recruitment and activation of leukocytes.

TYPE 4 hypersensitivity

(Delayed hypersensitivity or T-cell mediated hypersensitivity )

  • CD4 +ve T-cells (delayed type hypersensitivity)
  • CD8 +ve T-cells mediated cytolysis.
  • Macrophage activation cytokine mediated inflammation.
  • Direct target cell killing cytokine mediated inflammation.




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