Allergy and Hypersennsitivity

1.            Hypersensitive immune reactions

a.         Allergic reactions:

i.          they occur when an individual who has produced IgE antibody in response to an innocuous antigen, or allergen.

ii.          this triggers the activation of IgE-binding mast cells in the exposed tissue, leading to a series of responses that are characteristic of allergy.

b.         Allergy is a member of a class of immune responses termed collectively as hypersensitive reactions.

c.         When an immune response results in exaggerated or inappropriate reactions harmful to the host, the term hypersensitivity or allergy is used.

d.         The clinical manifestations of these reactions are typical in a given individual and occur on contact with the specific antigen to which the individual is hypersensitive.

e.         The first contact of the individual with the antigen sensitizes, i.e. induces the antibody, and then the subsequent contacts elicit the allergic response.

f.            Hypersensitivity reactions can be subdivided into 4 main types: Type I, II, and III are antibody-mediated, whereas type IV is cell-mediated.

g.         Type I reactions are mediated by IgE, whereas types II and III are mediated by IgG.

2.         Types of Hypersensitivity reactions

3.            Mechanism of Type I Hypersensitivity

a.         An immediate hypersensitivity reaction occurs when antigen binds to IgE on the surface of mast cells with the consequent release of several mediators.

b.         The process begins when an antigen induces the formation of IgE antibody, which binds firmly by its Fc portion to basophils and mast cells.

c.            Reexposure to the same antigen results in cross-linking of the cell-bound IgE and release of pharmacologically active mediators within minutes.

d.            Allergens:

i.          there are certain antigens and routes of antigen presentation to the immune system that favor the production of IgE.

ii.            transmucosal presentation of very low doses of allergen is particularly efficient in inducing TH2-driven IgE responses (IgE production requires IL-4 from TH2 cells and can be inhibited by gamma interferon from TH1 cells.)

iii.         many parasites invade their hosts by secretion of proteolytic enzymes that break down the connective tissue and allows it access to the host tissue; these enzymes are active in promoting TH2 responses.

iv.         most allergens are small, highly soluble proteins that are inhaled in desiccated particles such as pollen grains or mite feces.

e.         Atopy:

i.          atopic disorders are immediate-hypersensitivity reactions that exhibit a strong familial predisposition and are associated with elevated IgE levels.

ii.          the predisposition to atopy is genetic, and symptoms are induced by exposure to the specific allergens.

iii.         these antigens are typically found in the environment but they do not elicit an allergic response in nonatopic individuals.

iv.            common clinical manifestations: hay fever, asthma, eczema and utricaria.

v.         many sufferers give immediate-type reactions to skin tests (injection, patch, or scratch) containing the offending antigen.

f.          Drug hypersensitivity:

i.          it is not the intact drug that induces antibody formation.

ii.          rather, a metabolic product of the drug, which acts as an hapten and binds to a body protein, does so.

iii.         the resulting antibody can react with the hapten or the intact drug to give rise to type I hypersensitivity.

iv.         when reexposed to the drug, the person may exhibit rashes, fevers, or local or systemic anaphylaxis of varying severity.

v.            reactions to very small amounts of drug can occur in a skin test with the hapten: skin test using penicillyol-polylysine to reveal an allergy to penicillin.

4.            Chemical mediators in Type I hypersensitivity

a.            Histamine:

i.          occurs in granules of tissue mast cells and basophils in a preformed state.

ii.          its release causes vasodilation, increased capillary permeability, and smooth-muscle contraction.

iii.            clinically, disorders such as allergic rhinitis (hay fever), urticaria, and angioedema can occur.

iv.         the bronchospasm so prominent in acute anaphylaxis is due, in part, to histamine release.

v.            antihistamine drugs block histamine receptor sites and can be relatively effective in allergic rhinitis but not in asthma.

b.         Slow-reacting substance of anaphylaxis (SRS-A):

i.          this consists of several leukotrienes, which not exist in a preformed state but are produced during anaphylactic reactions.

ii.          this accounts for the slow onset of SRS-A.

iii.            leukotrienes are formed from arachidonic acid by the lipoxygenase pathway and cause increase vascular permeability and smooth-muscle contraction.

iv.         they are the principal mediators in the bronchoconstriction of asthma and are not influenced by antihistamines.

c.            Serotonin:

i.            serotonin is preformed in mast cells and blood platelets.

ii.          when released during anaphylaxis, it causes capillary dilation, increased vascular permeability, and smooth-muscle contraction.

iii.         plays a minor role in human anaphylaxis.

d.            Prostaglandins and thromboxanes:

i.          they are derived from arachidonic acid via the cyclooxygenase pathway.

ii.            prostaglandins cause dilation and increased permeability of capillaries and bronchoconstriction.

iii.            thromboxanes aggregate platelets.

e.            Eosinophil chemotactic factor of anaphylaxis (ECF-A):

i.          this is a tetrapeptide that exists preformed in mast cell granules.

ii.          when released during anaphylaxis, it attracts eosinophils that are prominent in allergic reactions.

f.          Role of Eosinophils in allergic reactions:

i.          in a local allergic reaction, mast-cell degranulation and TH2 activation cause activated eosinophils to accumulate in large numbers.

ii.          their continued presence is characteristic of chronic allergic inflammation and they are the chief contributors to the tissue damage that occurs.

iii.            eosinophil degranulation causes the release of major basic protein, which in turn causes mast cell and basophil degranulation.

g.         Clinical manifestations of hypereosinophilia:

i.          these are sometimes seen in association with T-cell lymphomas in which unregulated IL-5 secretion drives dramatic blood eosinophilia.

ii.          the clinical manifestations of hypereosinophilia are damage to the endocardium and nerves, leading to heart failure and neuropathy caused by toxic effects of eosinophilic granule proteins.

h.            Eosinophil secretions:

5.            Temporal nature of Allergic responses

a.         The inflammatory response following IgE-mediated mast-cell activation occurs as an immediate reaction, starting within seconds, and a late reaction, which takes up to 8-12 hours to develop.

b.         The immediate reaction follows from the activity of histamine, prostaglandins, and other preformed or rapidly synthesized toxic molecules, which cause a rapid increase in vascular permeability and smooth muscle contraction.

c.         The second, late-phase reaction is caused by the induced synthesis and release of mediators including leukotrienes, chemokines, and cytokines from the activated mast cells.

d.         This late reaction is associated with a second phase of smooth muscle contraction and sustained edema.

e.         The late-phase reaction is an important cause of much more serious long-term morbidity as in chronic asthma because:

i.          the late reaction induces the recruitment of inflammatory leukocytes, including eosinophils and TH2 lymphocytes to the site of the mast-cell response.

ii.          this can easily convert into a chronic inflammatory response if antigen persists, allowing allergen-specific TH2 cells to promote eosinophilia and IgE production.

6.            Systemic anaphylaxis

a.         If an allergen is given systemically or is rapidly absorbed from the gut, the connective tissue mast cells associated with all blood vessels may be activated.

b.         This causes a very dangerous syndrome called systemic anaphylaxis.

c.            Disseminated mast-cell activation causes a widespread increase in vascular permeability, leading to a catastrophic loss of blood pressure, constriction of airways, and epiglottal swelling that may cause suffocation, a syndrome called anaphylactic shock.

d.         This can occur if drugs are administered to allergic people, or after an insect bite in individuals allergic to insect venom.

e.         Allergic reactions to Penicillin:

i.          the most frequent allergic reactions to drugs occur with penicillin and its relatives.

ii.          in people with IgE antibodies to penicillin, intravenous administration can cause anaphylaxis and even death.

iii.         great care should be taken to avoid giving drugs to patients with a past history of allergy to the same drug.

7.            Allergic rhinitis and Asthma

a.            Inhalation is the most common route for allergen entry.

b.         Allergic rhinitis:

i.          many people have mild allergies to inhaled antigens, manifesting as sneezing and a runny nose.

ii.          this is called allergic rhinitis or hay fever, and results from activation of mucosal mast cells beneath the nasal epithelium by allergens that diffuse across the mucosal membrane of the nasal passages.

iii.         allergic rhinitis is characterized by local edema leading to nasal obstruction, a nasal discharge, which is rich in eosinophils, and irritation of the nose from histamine release.

c.         A more serious syndrome is allergic asthma, which is triggered by allergen-induced activation of submucosal mast cells in the lower airways.

d.         This leads, within seconds, to bronchial constriction and increased fluid and mucus secretion, making breathing more difficult by trapping inhaled air in the lungs.

e.         Patients with allergic asthma often need treatment and asthmatic attacks can be life-threatening.

f.          An important feature of asthma is chronic inflammation of the airways, characterized by the continued presence of increased TH2 lymphocytes, eosinophils, neutrophils, and other leukocytes.

8.         Skin Allergy

a.         The skin forms an effective barrier to the entry of most allergens.

b.            However, this barrier can be breached by local injection of small amounts of allergen into the skin, for example, by a stinging insect.

c.         This causes a localized allergic reaction.

d.         Local mast-cell activation in the skin leads immediately to a local increase in vascular permeability, which causes extravasation of fluid.

e.         The mast-cell activation also stimulates a nerve axon reflex, causing vasodilation of surrounding cutaneous blood vessels.

f.          The resulting skin lesion is called a wheal-and-flare reaction.

g.         About 8 hours later, a more widespread and sustained edematous response appears in some individuals as a consequence of the late-phase response.

h.         A more prolonged allergic response is seen mainly in atopic children; they develop a chronic skin rash called eczema, due to a chronic inflammatory response.

I.          Skin test for allergy:

i.            allergists take advantage of the immediate response to test for allergy by injecting minute amounts of potential allergens intracutaneously.

ii.          another standard test for allergy is to measure the specific IgE-antibody levels to a particular allergen in a sandwich ELISA.

9.            Allergy to Food

a.         When an allergen is eaten, activation of mucosal mast cells associated with the gastrointestinal tract can lead to transepithelial fluid loss and smooth muscle contraction, generating vomiting and diarrhea.

b.            Histamine released by activated submucosal mast cells produces urticaria or hives – large, itchy red swelling beneath the skin.

c.         This is a common reaction when penicillin is ingested by an allergic patient.

10.            Treatment and Desensitization

a.         The principles of treatment of allergy is to shift the antibody response away from an IgE-dominated response towards one dominated by IgG.

b.         Acute desensitization:

i.          involves the administration of very small amounts of antigen at 15-minute intervals.

ii.          antigen-IgE complexes form on a small scale, and not enough mediator is released to produce a major reaction.

iii.         this permits the administration of a drug or foreign protein to a hypersensitive person, but hypersensitivity is restored days or weeks later.

c.         Chronic desensitization:

i.          involves the long-administration at weekly intervals of the antigen to which the patient is hypersensitive.

ii.          this stimulates the production of IgG-blocking antibodies in the serum, which can prevent subsequent antigen from reaching IgE on mast cells, thus preventing a reaction.

d.            Treatment:

i.            treatment includes drugs to counteract the action of mediators, maintenance of airway, and support of respiratory and cardiac function.

ii.            epinephrine is an effective inhibitor of anaphylactic reactions by stimulating the reformation of endothelial tight junctions, promoting the relaxation of constricted bronchial smooth muscle, and stimulating the heart.

iii.            antihistamines that block the H1 receptor reduce utricaria following histamine release from cutaneous mast cells and eosinophils.

iv.            systemic or local corticosteroids may be needed to suppress the chronic inflammatory changes seen in asthma, rhinitis, eczema.

e.            Approaches to treatment of allergy:

f.            Prevention relies on:

i.            identification of the allergen.

ii.          skin test

iii.            avoidance of that allergen.

11.       Type II Cytotoxic Hypersensitivity

a.            Mechanism of tissue damage:

i.            cytotoxic hypersensitivity occurs when antibody directed at antigens of the cell membrane activates complement.

ii.          this generates a membrane attack complex which damages the cell membrane.

iii.         the antibody attaches to the antigen via the Fab region and acts as a bride to complement via the Fc region.

iv.         the combination of cell-bound antibody and complement trigger clearance of the cell from the circulation, predominantly by tissue macrophages in the spleen which bears Fc and complement receptors.

v.         as a result, there is complement-mediated lysis as in hemolytic anemias, ABO transfusion reactions, or Rh hemolytic disease.

vi.            complement activation also attracts phagocytes to the site, with consequent release of enzymes that damage cell membranes.

b.            Hemolysis:

i.          drugs (e.g. penicillins, pehacetin, quinidine) can attach to surface proteins on blood cells and initiate antibody formation.

ii.          such autoimmune antibodies (IgG) then interacts with the cell surface and result in hemolysis.

iii.         the direct antiglobulin (Coombs) test is typically positive.

c.            Thrombocytopenia: other drugs (e.g. quinine) can attach to platelets can induce autoantibodies that lyse them to produce thrombocytopenia with bleeding tendency.

d.            Hydralazine may modify host tissue and favor the production of autoantibodies directed at cell DNA, with results resembling those of systemic lupus erythematosus.

e.         Certain infections, e.g. Mycoplasma pneumoniae infection, can induce antibodies that cross-react with red cell antigens, resulting in hemolytic anemia.

f.            Rheumatic fever: antibodies against the group A streptococci cross-react with cardiac tissue.

g.            Goodpasture’s syndrome: antibody to basement membranes of the kidneys and lungs form, resulting in severe damage to the membranes through activity of complement-attracted leukocytes.

12.       Type III Immune-complex Hypersensitivity

a.            Immune-complex hypersensitivity occurs when antigen-antibody complexes induce an inflammatory response in tissues.

b.            Normally, immune complexes are promptly removed by the reticuloendothelial system, but occasionally they persist and are deposited in tissues, resulting in several disorders.

c.            Mechanism of tissue damage:

i.          in persistent microbial or viral infections, immune complexes may be deposited in organs, e.g. the kidneys, resulting in damage.

ii.          in autoimmune disorders, ‘self’ antigens may elicit antibodies that bind to organ antigens or deposit in organs as complexes, especially in joints (arthritis), kidneys (nephritis), or blood vessels (vasculitis).

iii.            wherever immune complexes are deposited, they activate the complement system, releasing C3a and C5a.

iv.            neutrophils are attracted to the site by C5a; they release enzymes that destroy the endothelium, causing tissue injury and inflammation.

d.         Arthus reaction:

i.          if animals are given an antigen repeatedly until they have high levels of IgG antibody and that antigen is then injected subcutaneously or intradermally, intense edema and hemorrhage develop, reaching a peak in 3-6 hours.

ii.          antigen, antibody, and complement are deposited in vessel walls; neutrophil inflitration and intravascular clumping of platelets then occur.

iii.         these reactions can lead to vascular occlusion and necrosis.

iv.         a clinical manifestation of the Arthus reaction is hypersensitivity pneumonitis (allergic alveolitis) associated with the inhalation of thermophilic actinomycetes (‘farmer’s lung’).

e.         Serum sickness:

i.            following the injection of foreign serum or drug, the antigen is excreted slowly during which antibody production starts.

ii.          the simultaneous presence of antibody and antigen leads to the formation of immune complexes, which may circulate or be deposited at various sites.

iii.         typical serum sickness results in fever, urticaria, arthralgia, lymphadenopathy, splenomegly, and eosinophila a few days to 2 weeks after injection.

13.            Immune-complex diseases

a.            Subacute bacterial endocarditis / chronic viral hepatitis:

i.          an adaptive antibody response fails to clear an infectious agent.

ii.          the multiplying bacteria or viruses are continually generating new antigen in the presence of a persistent antibody response, which fails to eliminate the organism.

iii.         immune complex diseases ensues, with injury to small blood vessels in many organs including the skin, kidneys and nerves.

b.            Glomerulonephritis:

i.          its onset follows several weeks after a group A beta-hemolytic streptococcal infection, particularly of the skin, and often with nephritogenic serotypes of Streptococcus pyogenes.

ii.          lumpy deposits of immunoglobulin and C3 are seen along glomerular basement membrane by immunofluorescence.

iii.         it is assumed that streptococcal antigen-antibody complexes, after being deposited on glomeruli, fix complement and attract neutrophils, which start the inflammatory process.

c.            Rheumatoid Arthritis:

i.            rheumatoid arthritis is a chronic inflammatory autoimmune disease of the joints seen commonly in young women.

ii.          serum and synovial fluid of patients contain ‘rheumatoid factor’, i.e. IgM and IgG antibodies that bind to the Fc fragment of normal human IgG.

iii.            deposits of immune complexes on synovial membrane and in blood vessels activate complement and attract neutrophils, causing inflammation.

d.            Antigen-antibody complexes are involved in the pathogenesis of many other autoimmune diseases, e.g. systemic lupus erythematosus.

14.       Type IV Delayed Hypersensitivity

a.            Mechanism:

i.          delayed hypersensitivity is a function of helper (CD4) T lymphocytes, not antibody.

ii.          the response is ‘delayed’, i.e. it starts hours (or days) after contact with the antigen and often last for days.

iii.         it consists mainly of mononuclear cell infiltration (macrophages and helper T cells) and tissue induration, as typified by the tuberculin skin test.

iv.         these hypersensitive reactions also involves CD8 cells, which damages tissue mainly by cell-mediated cytotoxicity.

b.         Time course of reaction:

i.          the first phase involves uptake, processing, and presentation of the antigen by local antigen-presenting cells.

ii.          in the second phase, TH1 cells that were primed by previous exposure to the antigen migrate to the site of injection and become activated.

iii.         since these specific cells are rare, and there is no inflammation to attract cells to the site, it may take several hours for a T cell of the correct specificity to arrive.

iv.         these cells release mediators that activate local endothelial cells, recruiting an inflammatory cell infiltrate dominated by macrophages and causing accumulation of fluid and protein.

v.         at this point, the lesion becomes apparent.

c.         Contact hypersensitivity:

i.          this manifestation of cell-mediated hypersensitivity occurs after sensitization with simple chemicals (e.g. nickel, formaldehyde), plant materials (e.g. poison ivy, poison oak), topically applied drugs (e.g. neomycin), some cosmetics and soaps.

ii.          in all cases, the small molecules acting as haptens, enter the skin, attach to body proteins, and become complete antigens.

iii.         cell-mediated hypersensitivity is induced, particularly in the skin.

iv.         upon a later skin contact with the offending agent, the sensitized person develops erythema, itching, vesicles, eczema, or necrosis of skin within 12-48 hours.

v.         patch testing on a small area of skin can sometimes identify the offending antigen.

vi.            subsequent avoidance of the material will prevent recurrence.

d.            Tuberculin-type hypersensitivity:

i.          delayed hypersensitivity to antigens of microorganisms occurs in many infectious disease and has been useful as an aid in diagnosis, typified by the tuberculin reaction.

ii.          when a patient previously exposed to Mycobacterium tuberculosis is injected with a small amount of tuberculin (PPD) intradermally, there is little reaction in the first few hours.

iii.            gradually, however, induration and redness develop and reach a peak in 48-72 hours.

iv.         a positive skin test indicates that the person has been infected with the agent, but it does not confirm the presence of the current disease.

v.            however, if the skin test converts from negative to positive, it suggests that the patient has been recently infected.

e.         Type IV responses in allergy: