Hypersensitivity

Hypersensitivity

 Hypersenitivity

state is the undesirable effects of the specific IR following re-exposure to an antigen in a genetically susceptible individual.

Classification  Gell

and Coombs described 4 types of hypersensitivity reactions(typeI,II,III and IV).  The first 3 types are antibodymediated and the fourth is mediated primarily by T cells and macrophages.

Anaphylactic Reaction  When

a hypersensitive person is exposed to an antigen(allergen) a cytophilic antibody IgE is formed in excess and can bind toFc receptors on mast cells and basophils (sensitized cells).

 The

sensitized cell appears to present a number of IgE Fab fragments,and to initiate a response, antigen must bind to two independent fragments forming IgEantigen-IgEbridge.

 Within

minutes, this binding causes the mast cells to degranulate, releasing certain preformed mediators stored in mast cell granules specially histamine, as well as bradykinin and slow reacting substances of anaphylaxis,subsequently the degranulated cell begins to synthesize and release additional

 The result is two phase response;  1-An initial phase which has an

immediate effect on blood vessels, smooth muscles and glandular secretion, this phase is characterized grossly by erythema, localized edema and pruritis.

 2-The

second phase is followed few hours later by cellular infiltration (eosinophils and neutrophils) of the involved site.

 In

man there are two types of anaphylactic reaction, systemic and local which are related to the mode of entry in the body of the shocking dose of antigen.

 If

the antigen is injected parentrally, as in case of foreign serum (e.g. horse anti-tetanic serum), a drug such as penicillin, or by insect bite, the systemic form of anaphylaxis is likely to develop.

 The

symptoms include dyspnea with bronchospasm and peribronchial and laryngeal oedema, sometimes skin rashes, a fall in blood pressure and occasionally death.

 If,

on the other hand, the antigen comes in contact with respiratory mucous membrane, in a sensitized individual (atopic patient), the local form of anaphylaxis will develop,i.e.hay fever or asthma.

 If

the appropriate antigen (e.g. nuts,egg,chocolate,fish or strawberries), comes in contact with the intestinal mucous membrane of a susceptible individual, a mixed form of reaction may develop; vomiting,diarrhoea and skin rashes(urticaria).

Prevention of Anaphylaxis (Desensitization)  Consideration

of the mechanism of systemic anaphylaxis makes it seems likely that if the parenterally injected antigen could be prevented from reaching the tissue-fixed IgE,then anaphylaxis would not develop.

 This

can be achieved by injecting frequent small doses of the antigen to which the patient is sensitized; this induces the formation of increased levels of IgG antibody which by circulating in the blood and tissue fluids,mops up the injected antigen so that it does not reach the tissue fixed IgE.

 The

IgG antibody has been termed blocking antibody and its induction is the basis of desensitization treatment of allergic individuals.

Treatment of Anaphylactic Reactions  This

is designed to counteract the effect of released chemical mediators or to block their action.  In systemic anaphylaxis, the main efforts are directed at maintaining ventilation and cardiac function, epinephrine is given subcutaneously.  Corticosteroids may be administered.

Hypersensitivity Test  The

following test should be done for persons that need treatment with a foreign protein as horse serum, or a drug such as penicillin to detect if the person is sensitive or not to this allergen.

Skin test  0.1

ml of the diluted antigen is injected intradermally in the flexor surface of the arm.  A reaction in the form of oedema surrounded by a zone of erythema about 2-10 cm appears in a few minutes and disappears in 20-60 minutes.

Cytolytic or Cytotoxic reaction  Reactions

of this type are initiated by an antigenic component that is either:  1-Part of a tissue cell(e.g.:antigens of the ABO group and Rh antigen) or  2-A foreign antigen closely associated with a cell(e.g.: drug attached to the cell wall).  The antibodies (IgM or IgG) directed against such a cell associated

Mechanisms of action  A-Complement

mediated lysis

Antibody directed at cell surface antigens activates complement to damage the cells. The antibody (IgG or IgM) attaches to the antigen via Fab region and so complement will attach to the Fc portion of the antibody causing cytolytic effect on the cells, as occurs in haemolytic aneamias, incompatible blood transfusion and Rhesus (Rh)

B-Phagocytosis  The

antibody (opsonin) bound to the cell antigen leading to opsonization which will enhance phagocytosis.

C-Antibody dependent cellular cytotoxicity (ADCC)

This is a process different from phagocytosis and independent of complement.  The antibody coated cells can be killed by several numbers of cells as natural killer cells which possess Fc receptor for IgG and therefore can interact and cause cytotoxic damage to target cells.  This cytotoxic activity occurs on 

Type 2 hypersensitivity

Toxic Complex Syndrome (Type III These

reactions are due to combination of antigen with circulating antibody (Ig G) leading to formation of microprecipitates in and around small blood vessels with consequent inflammation and sometimes mechanical blockage of the vessels, causing interference with blood supply to surrounding tissues.

 There

are two types of reaction that fall into this category;

A

systemic form or serum sickness.

A

local form or Arthus reaction.

 Serum

sickness, develops in individuals given injections of large amounts of foreign serum or drugs as penicillin which is eliminated from the circulation over a period of few weeks.

 The

symptoms are dependent on deposition of immune complexes ( antigen+ IgG antibody) in blood vessels which activate complement and cause inflammatory changes.

 Typical

serum sickness results in fever, urticaria, arthralgia, lymphadenopathy, splenomegaly and eosinophilia a few days to 2 weeks after injection of foreign serum or drug.  The symptoms disappear whenever all the foreign antigen is eliminated.

 Arthus

reaction, like serum sickness, is brought about by formation of complexes but in this case the phenomenon is a localone at the site of injection of antigen.

 Arthus

reaction occurs in walls of small blood vessels in the presence of large quantities of IgG antibody which form microprecipitates with antigen.

 Vasculitis

develops a few hours after

injection and persists for 12 to 24 hours. Liberation of vasoactive amines such as histamine causes an increase in vascular permeability and consequent oedema.

 These

reactions may occur in diabetics who have received many intradermal injections of insulin and have developed high levels of IgG antibody to antigenic constituents in insulin preparation.

Delayed Hypersensitivity(Type IV or cell mediated  These

reactions are characteristically induced by intracellularinfectious agents including salmonella, brucella, mycobacteria, pathogenic fungi, and a wide range of viruses.

 This

form of hypersensitivity reaction may be defined as a specifically provoked, slowly evolving (48 hours), mixed cellular reaction particularly lymphocytes and macrophages.

The classical example of this type of reaction is the tuberculin response which occurs when an individual previously infected with tubercle bacilli is given an intradermal injection of 0.1 ml of protein extract of tubercle bacilli ( purified protein derivative or PPD), 48 hours later an indurated inflammatory reaction of variable size can be seen in the skin.

 The

reaction is initiated by activation of antigen specific Th-cells, which then release lymphokines. These compounds together with bioactive substances released by antigen presenting cells serve to attract additional inflammatory cells from the circulation.

 Some

of the lymphokines promote differentiation and activation of macrophages and so enhance the phagocytic, and bactericidal function of these cells.

 Delayed

hypersensitivity reactions sometimes develop after sensitization to a variety of metals such as nickel and chromium.  Skin sensitization to penicillin is not uncommon after the topical application of antibiotic in ointments or creams.

 These

substances are not themselves antigenic and only become so on combination by covalent bonds with proteins in the skin.  The clinical signs induced in these contact hypersensitivity reactions ( contact dermatitis) include redness, swelling, vesicles, scaling and exudation of fluid.

Type IV hypersensitivity

Delayed hypersensitivity