Introduction to hypersensitivity

Hypersensitivity is an exaggerated or inappropriate reaction harmful to the host. The first response sensitizes the immune system and subsequent contacts cause an 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 and Richet. They were studying the effect of toxins from sea anemone on dogs. Instead of developing immunity, in successive dosage, the dog presented excessive salivation, defecation, difficulty in respiration, paralysis of hind limbs and death within a few minutes of dose. It is an IgE mediated reaction.  An antigen binds to IgE on the surface of mast cells causing the release of chemical mediators. The process begins when an 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 the surface of mast cells. When the cross-linkage occurs, the chemical mediators are released within minutes. An increase in the amount of cyclic GMP within these cells increases mediator release whereas and the increase in cyclic AMP decreases the release. So, the drugs with increase intracellular concentration of AMP such as epinephrine are used for the treatment of anaphylactic shock.

Clinical manifestations

Urticaria, eczema, rhinitis and conjunctivitis & asthma. 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

     The sensitization phase is the first exposure of antigen which triggers the production of antibodies. The activation phase is when re-exposure of antigen causes the release of contents of basophils and mast cells. The effector phase is when the clinical manifestations are presented by the patient.

Sensitization phase:

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

  • Atopy (uncommon): This is an immediate hypersensitive response that exhibits strong familial predisposition and is associated with raised IgE levels. Several factors play a role in Atopy. Increased production of interleukins, 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 a normal person. Some hours later, the antigen is injected which causes wheal and 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 the production of IgE (B cell).

Activation phase:

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

Effector phase:

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

Pre-formed mediators:

  1. Histamine: It is present in tissue mast cells & basophils. Its release causes vasodilation, an increase in capillary permeability and 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 rodents. Action is similar to histamine.
  3. Eosinophilic chemotactic factor of anaphylaxis: It is a set of low molecular weight polypeptides. It helps in the attraction of eosinophils to the site of the release of peptides. These exist in preformed mast cell granules. The role of eosinophils in type one hypersensitive reaction is uncertain. But eosinophils secrete histaminases and auryl sulfate which degrade the important factors of type one reaction i.e. histamine and leukotrienes so these reduce the severity of type one response
  4. Neutrophils chemotactic factor (NCF’s) –activated mast cells release several substances that act as a chemotactic factor for neutrophils. These act in the late phase of the hypersensitive reaction.
  5. Heparin– It is an acidic proteoglycan that constitutes a matrix of the granules to which basic mediators, histamines and serotonin are bound. The release of heparin causes inhibition of coagulation.

Newly formed mediators:

  1. Leukotrienes (slow-reacting substances [SRS-A] of anaphylaxis): There presence was demonstrated by Schlutz-Dale reaction. In this reaction, when the uterine horn of pig is treated with histamine contraction occurs. As soon as histamine is washed the muscles relax. Similarly, when antihistamine and histamine is added no contraction occurs. However, slow prolonged contraction results that cannot be relieved by washing. These led to the discovery of SRS-A. They are the products of the arachidonic 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 the cyclo-oxygenase pathway from arachidonic acid. Prostaglandins cause dilation of vessels and increase vascular permeability and broncho-constriction. TXA’s cause platelet aggregation. In contrast to the anaphylactic reaction which is IgE mediated, anaphylacoid reaction which is clinically similar to anaphylactic one is not IgE mediated. In this reaction, the inciting antigen is drugs or iodinated contrast media which directly induces the mast cells and basophils to release their contents without the involvement of IgE



Drugs and type I hypersensitivity

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

Desensitization

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

Acute desensitization: It Involves the administration of a very small amount of antigen mediators in 15 min. Intervals. IgE and antigen complexes form but these do not stimulate the release of a large amount of mediators to cause a major reaction. This helps the hypersensitive patient but hypersensitivity is restored within a 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 the formation of blocking antibodies. The blocking IgG prevents antigen to bind with IgE on the mast cell surface because it attaches to antigen prior to its any reaction with IgE. This prevents hypersensitivity.

Treatment

Epinephrine, antihistaminics and chromolyn sodium

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Type II or Cytotoxic Hypersensitivity:

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

Examples:

Drug:

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

Infections:

  • In mycoplasma pneumoniae, antibodies cross-react with RBC’s.
  • In Rheumatic fever Group A streptococci react with cardiac tissue.
  • In Goodpasture syndrome antibodies are directed against the basement membrane of glomerulus and Lung.
  • ABO Blood group and Rh incompatibility.

Type III Hypersensitivity or Immune Complex Hypersensitivity:

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

There are two types type of TypeIII hypersensitivity:

  1. Arthus reaction
  2. Serum sickness

Arthus reaction:

In this reaction when the antigen is given repeatedly to an animal, a high level of IgG are attained after some time in that animal. After the development of a large amount of IgG, if that animal is injected with antigen subcutaneously intense edema and hemorrhage develop reaching a 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. A typical example of Type III hypersensitivity is “Farmer’s Lung” which is caused by inhalation of monophilic Actinomycetes.

Serum sickness:

Following the injection of a drug or foreign serum, these act as antigens that are secreted slowly from body. Antibodies form against these foreign antigens and until they are excreted antibodies and antigens form immune complexes that deposit in various parts of the body. A typical serum sickness results in fever, urticaria, arthralgia, LAP, splenomegaly, eosinophilia in a few days to weeks after injection. Serum sickness is commonly caused by drugs like penicillins, etc.

Some immune complex diseases are:

  1. Glomerulonephritis: It is caused by antibodies against β hemolytic group A streptococci several weeks after infection. It is normally after skin infection and generally with the nephrogenic serotype of S. pyrogens. Serum complement is low lumpy deposits of immunoglobulins and C3 are seen on the glomerular basement membrane. After being deposited it fixes the complement and causes attraction to neutrophils which cause the damage.
  2. Rheumatoid Arthritis: Synovial fluid in the joints contain contains the 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 Erythematosus): 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, the antigen is first ingested by macrophages which is then broken down and present on the surface of the cell by MHC II  which in turn activates CD4+ve T-cells which secretes IL1, IL2 and Gamma Interferon. This type of immunity starts in hours and lasts for days and weeks. In mononuclear infiltrates mainly macrophages and CD4+ve cells are found.



Clinically seen reactions

Contact hypersensitivity: It occurs when the body comes in contact with chemicals (like Nickel, Formaldehyde), drugs (sulphonamides & neomycin), plant materials (poison ivy and poison oak), Some cosmetic soaps, etc. These act as haptens and combine with proteins to form complete Antigen which initiates the hypersensitive reaction. On later contact with this antigen, the person develops erythema, itching, eczema, etc and necrosis of skin within 12-48 hours. In a delayed type of hypersensitivity contact with antigen and production of cells, mediated immune response takes time but on second contact reaction occurs within 12-48 hours.

Tuberculin hypersensitivity test: In the case of mycobacterial infection, when a person is injected intradermally with tuberculin or PPD a little reaction occurs in the first few hours but it gradually flares up in next 48-72 hours. A positive test indicates that the person is infected currently or previously but does not confirm the 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.

Type of hypersensitivityImmunopathological mechanismMechanism of tissue injury.
Type 1 hypersensitivity (Anaphylactic shock)IgE antibodyMast 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 signaling.
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.

Tolerance

Tolerance is unresponsiveness for certain specific antigens. Antigens present during embryonic life are considered “self” and do not stimulate the immune response. Clonal deletion is the 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. The same thing occurs with B-cells but in the bone marrow.

Some facts:

  • T-cells become tolerant more readily and remain tolerant for a longer time than B-cells.
  • The 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 the antigen is constantly present.
  • A most important step in autoimmune disease is the activation of CD4 cells which lead to stimulation of cell-mediated or antibody-mediated immune response
  • Most of the autoimmune diseases are antibody-mediated (with some CMI also). For example, allergic encephalomyelitis is T-cell and macrophage-mediated.

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