The term hypersensitivity refers to those inappropriate immunological reactions, which rather than contributing to recovery, themselves produce tissue damage and forms an important and sometimes, a major part of the disease process. Hypersensitivity reactions can be provoked by many antigens; the cause of hypersensitivity reaction will vary from one individual to the next. Hypersensitivity is not manifested in first contact with the antigen, but usually appears on subsequent contact.
The hypersensitivity is classified into two types, i.e. immediate hypersensitivity and delayed hypersensitivity.
- Immediate hypersensitivity: This type of hypersensitivity includes the following:
- Type I: Anaphylactic or atopic reaction
- Type 2: Cytolytic or cytotoxic reaction or antibody cell surface reaction
- Type 3: Immune complex reaction
- Delayed hypersensitivity: This type of hypersensitivity include the following:
- Type 4: Hypersensitivity
Type I, II and III reactions depend on interaction of antigen with humoral antibody and tend to be called immediate type hypersensitive reactions although, some are more immediate than others. Type 4 reaction involves T cell recognition and because of longer time course, this is referred to delayed type of hypersensitivity reaction.
Hypersensitivity Type I: Anaphylactic or atopic reaction
IgE-MEDIATED – ALLERGY
This most common type of hypersensitivity is mediated by IgE and causes mild e.g. hayfever, to life threatening e.g. bee sting, clinical situations. Some individuals (atopic) have a genetic predisposition to make high levels of IgE. Skin tests can be used to test for sensitivity to allergens.
Allergy affects about 17% of the population through mild e.g. hayfever, to life threatening conditions e.g. bee sting allergy. It is mediated by IgE which is normally found in very small amounts in the circulation and has probably evolved to protect us against worm infestations.
Allergic reactions can occur to normally harmless antigens (such as pollen or foodstuffs) and microbial antigens (fungi, worms). Some individuals in the population are genetically predisposed to respond to certain antigens by producing IgE to these antigens and are said to be atopic. Testing for allergy (Prausnitz-Kustner test) involves introduction of the allergen intradermally. A positive skin test occurs in the form of a wheal (fluid accumulation) and flare (redness) reaction at the site of injection.
Sensitization phase :- Sensitization to a particular antigen is dependent on stimulation of IgE antibody production. Thus, B cell antigen receptors specific for the allergen bind, internalize, process and present the antigen in MHC class II molecules. CD4+ Th2 cells recognize the antigen presented by these B cells and induce class switching of antigen-specific B cells.
These T cells also secrete IL-4 which is important for B cell growth and differentiation Why certain individuals become sensitized to particular antigens by producing IgE is unclear, but the possibilities include: (i) the genetics of the individual; (ii) environmental factors (pollution) that condition mucosal tissues of the immune system to produce IL-4 which then predisposes a Th2 response; and (iii) that regulation of the response through Th1 cells is defective.
Effector phase – IgE-mediated mast cell degranulation :- Specific IgE antibodies produced as a result of previous contact with antigen (allergen) diffuse throughout the body, eventually coming in contact with mast cells and basophils.
These cells have high affinity receptors for the Fc region of IgE and therefore bind to these antibodies. This does not have any effect on the mast cells directly until the specific antigen (allergen) is reintroduced into the body and comes into contact with the mast cell bearing the IgE antibodies in sufficient numbers to crosslink the antibodies on the cell surface.
The mast cells now immediately release granules (degranulate) which contain large amounts of pharmacological mediators. These substances have a direct effect on nearby blood vessels causing vasodilation and an influx of eosinophils, which in turn release mediators that cause a prolonged ‘late phase’ reaction.
Locally, e.g. in the nose, mediator release results in the symptoms of redness, itching and increased secretions by mucosal epithelial cells leading to a runny nose. Systemic release of histamine and other substances released by mast cells can lead to severe vasodilation and vascular collapse resulting in life-threatening systemic anaphylactic reactions which require treatment with epinephrine to restore blood pressure.
Leukotrienes, histamine, prostaglandins and platelet activating factor released from mast cells are key mediators of type I hypersensitivity. One way of classifying this growing body of inflammatory mediators is by their effects on target cells and tissues.
Common antigens causing type I hypersensitivity :- These include grass and tree pollens, insect venoms, nuts, drugs and animal dander. Fungal and worm antigens also induce this type of hypersensitivity.
Drugs and immunotherapy (desensitization) :- Drugs used to counteract Type I hypersensitivity inhibit production or release of inflammatory mediators (nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and indomethacin, glucocorticoids and cromolyn) or inhibit the action of inflammatory mediators which then relieve symptoms (benadryl, dramamine, glucocorticoids). Epinephrine is used to counteract mediator effects such as low blood pressure and bronchospasm. The aim of desensitization is to induce an IgG immune response and/or divert the immune response away from production of IgE. This approach has been used successfully for only a few allergens (e.g. bee venom).
Hypersensitivity Type 2: Cytolytic or cytotoxic reaction
IgG AND IgM-MEDIATED
Antibody (IgM or IgG) directed mainly to cellular antigens (e.g. on erythrocytes) or surface autoantigens can cause damage through opsonization, lysis or antibody dependent cellular cytotoxicity. Also called cytotoxic hypersensitivity.
Antibody alone or together with complement can cause hypersensitive reactions. These reactions can be against foreign (often erythrocytes) or autoantigens and usually result in the direct lysis or removal of cells. Type II hypersensitivity is therefore also termed cytotoxic hypersensitivity.
Diseases caused by this type of hypersensitivity often involve erythrocytes (anemias) and self cells (autoimmune diseases). Cell death (or lysis) is mediated through normal mechanisms by which antibodies and complement carry out their function including phagocytosis, lysis and antibody dependent cellular cytotoxicity.
Examples of Type 2 Reactions :-
- Mismatched Transfusion Reactions :- blood group antigen. If a sensitized patient
received RBCs with a different blood cell antigen, IgM antibodies cause a hypersensitivity reaction against foreign antigen. The foreign red cells are agglutinated; complement
is activated leading to hemolysis.
- Hemolytic Disease of the Newborn :- When a sensitized Rh-negative mother carries a second or subsequent Rh-positive fetus, the mother’s anti-Rh antibodies cross the placenta and cause a type 2 hypersensitivity reaction in the fetus.
Goodpasture’s Syndrome :- Autoantibodies specific for some basement membranes, such as antigens bind to basement membranes of the kidney glomeruli and the alveoli of the lungs. Subsequent complement activation leads to direct cellular damage, because of ensuing inflammatory response. Damage to glomerular and alveolar basement membrane leads to progressive kidney damage and pulmonary hemorrhage. The tissue damage is due to the type 2 hypersensitivity reaction.
Graves’ Disease :- Graves’ disease is production of autoantibodies against thyroid-stimulating hormone (TSH) receptor. The antibodies induce or stimulate unregulated activation of thyroid hormones. The autoantibodies, so produced against TSH receptors are called long-acting thyroid stimulator (LATS), which is IgG in nature and can pass through the placental barrier and cause Graves’ disease in neonates.
These antigen-antibody complexes are deposited in and around blood vessels of joints, kidney, heart and skin leading to arthritis, nephritis, carditis, vasculitis respectively. These diseases caused by these complexes are collectively called immune complex diseases.
Drugs used :- Penicillin, as well as inducing an immediate type hypersensitivity through IgE
can also stimulate an IgG response. IgG can then bind to penicillin attached to erythrocytes which induces hemolysis in the presence of complement. This disappears when the drug is removed.
Hypersensitivity Type 3: Immune complex reaction
Normally, immune complexes are removed by phagocytic cells and there is no tissue damage. However when there are large amounts of immune complexes and they persist in tissues, they can cause damage which may be localized within tissues (Arthus reaction) or systemic. This type of hypersensitivity can be induced by microbial antigens, autoantigens and foreign serum components.
Mechanisms of type III hypersensitivity :- Much of the tissue damage is the result of complement activation leading to neutrophil chemoattraction and release of lytic enzymes by the degranulating neutrophils. Local deposition of immune complexes results in an Arthus reaction. Immune complexes (usually small) can also cause systemic effects such as fever, weakness, vasculitis, arthritis and edema and glomerulonephritis.
An example of this is when passive antibodies are given to patients to protect them against microbial toxins such as tetanus toxin. An antibody response can develop (serum sickness) against the horse antitetanus toxin and forms immune complexes with them. Serum immune complexes can deposit in blood vessels (vasculitis) or can become trapped in the blood vessels of the kidneys leading to glomerulonephritis.
Diseases associated with type III hypersensitivity :- Pulmonary diseases result from inhalation of bacterial spores (Farmer’s lung) or avian serum/fecal proteins (bird fancier’s disease). Systemic disease can occur from streptococcal infections (streptococcal nephritis), autoimmune complexes (e.g. systemic lupus erythematosus (SLE).
Drugs used :- penicillin or antisera made in animals.
Hypersensitivity Type 4
Unlike type 1 (immediate) hypersensitivity, this hypersensitivity reaction, the only type transferable by cells rather than antibodies, was shown to begin at least 24 h after contact with the eliciting antigen. It was first associated with T cell mediated immune responses to Mycobacterium tuberculosis (MTb) and was therefore initially termed ‘bacterial hypersensitivity’. Such responses often lead to the production of granulomas some weeks later.
This delayed type of hypersensitivity (DTH) now covers a range of T cell mediated responses including those induced by small molecules coming into contact with the skin – contact hypersensitivity. In addition to T cells, the key players in this type of sensitivity are dendritic cells, macrophages and cytokines. This type of hypersensitivity also plays a role in several clinical situations where there is persistence of antigen which the immune system is unable to remove, leading to chronic inflammation.
Mechanism of Delayed Hypersensitivity :- Activation of Th 1 cells by antigen on appropriate antigen-presenting cells, results in the secretion of various cytokines including IL-2, IFN-γ, macrophage inhibiting factor (MIF) and TNF-β. The overall effects of these cytokines is to draw macrophages to the area and to activate them promoting increased phagocytic activities and increased concentration of lytic enzymes for effective killing. The release of lytic enzymes into the surroundings lead to tissue destruction. These reactions typically take 98 to 72 hours to develop. As opposed to neutrophils found in type 3 reaction, macrophages are the major components of the infiltrate.
Examples of Delayed hypersensitivity Disorders
There are three common examples. They are contact dermatitis, tuberculin hypersensitivity and granulomatous hypersensitivity.
- Contact Dermatitis :- Delayed hypersensitivity, sometimes, result from skin contact with a variety of chemicals such as metals (nickel, chromium, etc.), dyes (picryl chloride, dinitrochlorobenzene, etc.), drugs (penicillin, etc.), formaldehyde, turpentine, cosmetics, poison oak and poison ivy. Sensitization is particularly liable, when contact is with an inflamed area of the skin and the chemicals applied in a oilybase. The substances themselves are not antigenic, but may acquire antigenicity in combination with skin protein.Molecules too small to cause immune reactions pass through the skin, where they become antigens by binding to normal proteins on Langerhans cells of the epidermis. These cells, which carry MHC II molecules migrate to lymph nodes, where they act as antigen-presenting cells to Th 1 cells. Within 4 to 8 hours after the next exposure, a hypersensitive reaction begins and eczema occurs within 48 hours.
- Tuberculin Hypersensitivity :- When a small dose of tuberculin or purified protein derivative (PPD) is injected intradernally in an individual sensitized to tuberculin protein by prior infection or immunization, an indurated inflammatory reaction occurs at the site within 48 to 72 hours. Similar antigens from the bacterium that causes leprosy (Mycobacterium leprae) and protozoa that causes leishmaniasis (Leishmania tropica) produce similar reactions in sensitized individuals. The antigen activates Th 1 cells, which in turn produce cytokines that attract large number of lymphocytes, monocytes and macrophages to infiltrate dermis. The normally soft tissue of the dermis becomes raised, hard red region called induration.
- Granulomatous Hypersensitivity :- Granulomatous type of hypersensitivity occurs when macrophages have engulfed pathogens, but have failed to kill them. Inside the macrophage, the protected pathogens survive and sometimes continue to multiply. Th 1 cells sensitized to the antigen of the pathogen elicit the hypersensitivity reaction attracting several cell types to the skin (leproma) or lung (tubercle).This kind of hypersensitivity is the most delayed of all, appearing 4 weeks or more after the exposure of the antigen. Such persistent and continuous antigenic stimuli are also typical of the bacterial disease, listeriosis and many fungal and helminthic infections.
There is no cure for these diseases, the treatment aims at symptom control only. Although type IV hypersensitivity diseases can cause significant inconvenience in terms of their signs and symptoms, with good treatment plan the most of the diseases can be well-controlled.
Depending on the severity of the allergic reaction, different treatment approaches are applied. Treatment options, either given alone or in combination, include the following:
- Allergen avoidance: prevention and avoidance of possible triggers are the mainstay of the treatment. However this is impractical in some diseases such as allergic contact dermatitis because some of the substance cannot be identified and remained unknown for a long period of time. However if known this is a useful and effective method for diseases with known external allergen. This is not applicable for T-cell mediated autoimmune diseases such as type 1 diabetes mellitus.
- Steroids: these drugs are used for late phase of allergic reaction, and they include prednisolone, dexamethasone, etc. Depending on the diseases, steroid could become a long-term medication. In such cases, long term use will need medical supervision for monitoring of potential side effects.
- Other drugs that alter the body’s immune system include interferon, cyclophosphamide, cyclosporine, etc. These drugs are used under specialist supervision.
- Immunology by saras publications.