HYPERSENSITIVTY

There

are three basic ways in which the immune system may fail: HYPERSENSITIVITY, IMMUNODEFICIENCY, AUTOIMMUNITY.

 Hypersensitivity

refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity is a process of reactions of antigen with antibodies or sensitized lymphocytes that are harmful to the host. Hypersensitivity refers to processes in which the immune response itself is primarily responsible for the induction and/or exacerbation of disease.

 As

in all immune responses, hypersensitivity requires prior sensitization, is antigenspecific, and depends on the participation of antibodies or lymphocytes. Frequently, a particular clinical condition (disease) may involve more than one type of reaction.

 First

contact with potential antigen produces no detectable reaction but it may sensitize. If sensitized, exposure to same antigen elicits a reaction. The reaction is highly specific, elicited only by sensitizing antigen or a structurally related substance (cross reacting) Additional exposures to the same antigen may increase or sometimes decrease the severity of the reaction

There are four major types of hypersensitivity. Three are mediated by antibody, and the fourth is mediated by cellular mechanisms.

 All

individuals make an IgE response against parasitic infections. About 20% of the population, however, are also genetically predisposed to make an IgE response against relatively harmless environmental antigens e.g. grasses, weeds, and cat or dog proteins. These individuals are called atopic. a. Common allergens in type I reactions causing respiratory symptoms include: . Tree, grass, and weed pollens . Cat antigen and other animal dander antigens . Dust mite faecal pellet antigens . Mold spores

 It

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 from minor inconvenience to death. The reaction takes 15-30 minutes from the time of exposure to the antigen. Sometimes the reaction may have a delayed onset (10-12 hours)

 Type

1 hypersensitivity is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen Exposure may be by ingestion, inhalation, injection, or direct contact. The difference between a normal immune response and a type I hypersensitive response is that plasma cells secrete IgE This class of antibodies binds to Fc receptors on the surface of tissue mast cells and blood basophils.

The mechanism of reaction involves preferential production of IgE, in response to certain antigens (allergens). IgE has very high affinity for its receptor 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 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.

 First

host Macrophages and B cells present epitopes to T h2 cells, which produce interleukin (IL)-4 IL-4 causes class switch to IgE. Mast cells and basophils Bind IgE to high-affinity receptors. IgE cross-linking initiates granule release.

exposure sensitizes

Within 12 h of an acute allergic reaction a latephase reaction occurs, which is characterized by a cellular infiltrate of CD4+ cells, monocytes and eosinophils. The cells also synthesize Prostaglandins and Leukotrienes LTC 4 and LTD 4 which mediate the late-phase ( 4-6 hours later) Inflammatory response.

 The

preformed or primary mediators that are released from the granules are: Histamine. Heparin Eosinophil chemotactic factor A for anaphylaxis (ECF-A) Neutrophil chemotactic factor (NCF-A) Platelet activating factor

 Histamine

- bronchoconstriction, mucus secretion, vasodilatation, vascular permeability Tryptase proteolysis Kininogenase - kinins and vasodilatation, vascular permeability, edema ECF-A (tetrapeptides)attract eosinophil and neutrophils

 Leukotriene-

B4 basophil attractant Leukotriene C4, D4 - same as histamine but 1000x more potent Prostaglandins D2 - oedema and pain PAF - platelet aggregation and heparin release: microthrombi Under normal circumstances, these mediators help orchestrate the development of a defensive acute inflammatory reaction. In a run away reaction their bronchoconstrictive and vasodilatory reactions can be life threatening.

 Histamine

itself is responsible for many of the immediate symptoms of allergic reactions including bronchoconstriction, vasodilatation, mucus secretion and oedema caused by leakage of plasma proteins from small vessels. Tryptase released by mast cells activates receptors on endothelial cells that selectively attract eosinophils and basophils.

 In

humans, generalized anaphylaxis presents with itching erythema, vomiting, abdominal cramps, diarrhoea and respiratory distress. In severe cases, laryngeal oedema, vascular collapse and death can occur. Only a timely intravenous injection of adrenaline to counter smooth muscle contraction and capillary dilatation can prevent death.

 Skin

(prick and intradermal) tests Measurement of total IgE and specific IgE antibodies against the suspected allergens 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.)

Avoidance of the allergen Antihistamine (Benadryl) to block histamine receptors Chromolyn sodium to stabilize mast cell membranes Epinephrine to increase intracellular cyclic AMP Epinephrine to increase bronchial dilation and increase heart rate to raise blood pressure Theophylline (xanthines) to block phosphodiesterase enzyme that breaks down cyclic AMP

Immunotherapy by injecting small amounts of allergen to switch the response from Th2 to The lymphocyte type, resulting in decreased IgE production and increased IgG type Corticosteroids to reduce both inflammation and production of antibody f3-Adrenergic agonists-bronchial dilators that relax smooth muscle in airways, e.g., albuterol or terbutaline

 The

reaction time is minutes to hours. It is primarily mediated by antibodies of IgM or IgG class and complement, Phagocytes and K cells may also play a role (ADCC). Either IgG or IgM is made against normal self antigens as a result of a failure in immune tolerance or a foreign antigen resembling some molecule on the surface of host cells enters the body and IgG or IgM made against that antigen then cross reacts with the host cell surface.

Type II: Antibodymediated hypersensitivity against our own cells or receptors or membranes. There are several other mechanisms which account for type II hypersensitivity. These include opsonisation via C3b receptors which also exist on surfaces of macrophages and resultant phagocytosis.

 Excessive

cell lysis may occur when cell surface antigen couples to antibody, fixes complement and activates the entire complement cascade. Finally a distinct mechanism in type II hypersensitivity is that mediated by K cells, in what is known as antibody dependant cellular cytotoxicityADCC

 Haemolytic

disease of the newborn is an important clinical example of type II cytotoxic hypersensitivity. In its severest form it is known as erythroblastosis foetalis. In the foetus this disease is due to the transport across the placenta of IgG specific for one of the Rhesus (Rh) protein antigens (RhD).

 If

a pregnant woman is Rh-ve and the father is Rh+ve, there is a chance that the foetus will also be Rh+. This situation will pose no problem in the first pregnancy, as the mother's immune system will not usually encounter foetal red blood cell antigens until placental separation at the time of birth.

 At

birth, Rh+ve foetal red blood cells will enter the maternal circulation and stimulate a T-dependent immune response, eventually resulting in the generation of memory B cells capable of producing IgG antibody against RhD. In a subsequent pregnancy with another Rh+ve foetus, this maternal IgG can be transported across the placenta, react with foetal Rh+ve red cells, and activate complement producing haemolytic disease.

 Haemolytic

disease of the newborn can be prevented by treating the Rh-mother with RhoGAM TM, a preparation of human antiRhD IgG antibody, at 28 weeks of gestation and again within 24 hours after birth. This antibody effectively eliminates the foetal Rh+ red cells before they can generate RhD-specific memory B cells in the mother. Anti-RhD antibody should always be given to any Rh-ve individual following termination of any pregnancy.

 Noncytotoxic

type II hypersensitivity is also due to the production of tissue-specific IgG autoantibody. Instead of causing cytotoxic tissue destruction, however, the antibody in these cases alters cellular structure or function. In Graves disease, an IgG autoantibody against the thyroid-stimulating hormone receptor mimics the hormone but stays bound for an excessive length of time, resulting in hyperthyroidism.

 On

transfusion of mismatched red cells, the donor red cells are rapidly coated with the hosts isohaemagglutinins and severe reactions ensue, which utilize complement. Since IgM is involved, cross linking of just a few determinants is sufficient to set off the entire complement cascade.

 Drugs

coupled to the bodys own cells become antigenic and the humoral immune system recognizes the drug-cell complex as foreign, resulting in an antibody attack which destroys the cells as well. When the drug is withdrawn, the sensitivity is no longer evident. With drugs such as chlorpromazine and phenacetin, red cells become coupling agents and a type II haemolytic anaemia is seen.

 Goodpasture

syndrome: An autoantibody produced against the patient's own type IV collagen present in basement membranes of kidney and lung. Autoimmune haemolytic anaemia: An autoantibody produced against the patient's own red blood cell antigens (e.g., I antigen).

 Autoimmune

thrombocytopenic purpura: An autoantibody produced against the patient's own platelet integrin. Hyperacute graft rejection: The recipient of a graft already has pre-formed antibody against the graft; after receiving the graft it is rejected within hours.

 With

hold allergen drug . Remove antibodies: by - Exchange transfusion - Plasmapheresis Use immunosuppressive agents: - Corticosteroids - Cytoxan - Cyclosporin A

 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.

 Type

III (immune complex) hypersensitivity is caused by high levels of circulating, soluble immune complexes containing IgG or IgM antibody. The term immune complex disease refers to a group of diseases whose pathogenesis involves tissue damage from excessive antigen-antibody reactions. The reaction may take 3-10 hours after exposure to the antigen (as in Arthus reaction).

This results in systemic, rather than organspecific, damage, as the circulating immune complexes overwhelm the ability of the mononuclear phagocyte system to remove them. The excess complexes then deposit in various tissues (e.g., skin, glomeruli, blood vessels, synovium, lungs) and activate complement. The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus eythematosus, SLE).

The subsequent attempt by neutrophils to remove them results in degranulation and tissue damage. Example of type III hypersensitivity immune complex diseases are: Serum sickness Hypersensitivity pneumonitis Post-streptococcal glomerulonephritis Lupus Rheumatoid arthritis Certain infectious diseases, e.g., hepatitis B, HIV, and mycobacterium

 The

body may be exposed to excessive amounts of antigen in a number of circumstances, such as persistent infection with microbial agents, autoimmune reactions and repeated contact with environmental agents. The subsequent attempt by neutrophils to remove them results in degranulation and tissue damage.

When antigen and antibody couple to form insoluble complexes at fixed sites, tissue reaction and tissue damage occur. If complement is involved, C3a and C5a, two potent vasoactive amines, are released; this causes increased vascular permeability. Increased vascular permeability leads to deposition of immune complexes in tissues. Antigen in complex reacts with IgE on circulating basophils, causing platelet clumping, this forms microthrombi, causes degranulation and the subsequent release of histamine, serotonin and other chemotactic factors.

 Chemotactic

factors lead to influx of polymorphonuclear leukocytes. This leads to extracellular release of polymorph granular contents which include proteolytic enzymes, kinin forming enzymes and other proteins which will damage tissues and intensify the inflammatory process. When large insoluble complexes form, or when the clearing system is deficient, immune complexes are deposited in tissues with resultant damage. Deposition can occur anywhere in the body, but some organs such as the kidney are affected more often than others.

 Diagnosis

involves examination of tissue biopsies for deposits of Ig and complement by immunofluorescence. Presence of immune complexes in serum and depletion in complement level are also diagnostic. Treatment includes anti-inflammatory agents.

 It

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

 Delayed

hypersensitivity is a cell mediated immune reaction in an individual previously sensitized to an antigen. DTH gets its name from the long time (24 to 96 hours) that it takes for a skin reaction against the antigen to develop. Antibody and complement play no role in DTH. Th1 cells recognize the antigenic peptide presented by an antigen presenting cell and secrete cytokines (interferon-y) that activate macrophages.

Macrophage mediators then produce the damage in tissues. Th2-type cells producing IL-4 and IL-5 can also produce tissue damage through their ability to recruit eosinophils. Antigens may be intracellular bacterial pathogens (Mycobacterium tuberculosis, Mycobacterium leprae), viruses, fungi, or intracellular parasites. Contact dermatitis is caused by environmental substances (e.g., poison ivy, nickel), which, acting as haptens, enter the skin, attach to body proteins, and become complete antigens.

 The

best known example of this reaction is the positive Mantoux reaction (i.e. the delayed appearance of an indurated and erythematous reaction that reaches a maximum at 2448 h and is characterized histologically by infiltration with mononuclear phagocytes and lymphocytes.) where tuberculin is injected into the skin of an individual, in whom previous exposure to Mycobacterium tuberculosis has induced a state of cell mediated immunity (CMI).

 Poison
Nickel

ivy

Formaldehyde Latex Chromium Dyes

in clothing and cosmetics

 The

skin rashes of small pox and measles and the lesions of herpes simplex have been attributed to delayed type hypersensitivity reactions with associated cytotoxic T cell damage to virally infected cells. Cell mediated hypersensitivity is also evident in fungal diseases such as candidiasis, dermatomycosis, coccidioidomycosis and histoplasmosis and in parasitoses such as leishmaniasis and schistosomiasis.

 Unlike

other forms of hypersensitivity, delayed hypersensitivity does not involve antibody and cannot be transferred from a sensitized individual to a non sensitized individual with serum antibody. Continuing provocation of delayed hypersensitivity by persisting antigen leads to formation of chronic granulomas.

 Distinctions

between different types of hypersensitivity. Mechanisms of immune-mediated damages. Examples of different types of hypersensitivity and overlap among them. Diagnostic test for hypersensitivity diseases and treatments.