Hypersensitivity

Hypersensitivity

 Hypersensitivity reactions are pathologic processes that result from exaggerated specific interactions between antigens (exogenous or endogenous) and either humoral antibodies or sensitized lymphocytes, resulting in tissue injury. It occurs only if the host has had a previous contact with the antigen (allergen).  The initial or sensitizing dose sensitizes the immune system and the subsequent contact (shocking dose) with the same antigen or allergen causes hypersensitivity.

Hypersensitive reactions are classified based on

·         Duration between exposure of antigen and reaction – immediate type and delayed type hypersensitivity. In immediate hypersensitivity, the symptoms manifest within minutes or hours after second encounter with antigen. In Delayed-type hypersensitivity (DTH) the symptoms occur even days after exposure.

·         Immune component involved in reaction – antibody mediated and cell mediated hypersensitivity

·         Gell – Coombs classification- typeI, type II, type III and type IV

Type I -  IgE-Mediated Hypersensitivity

Antigen induces crosslinking of IgE bound to mast cells and basophils with release of vasoactive mediators.

Typical manifestations include systemic anaphylaxis and localized anaphylaxis such as hay fever, asthma, hives, food allergies, and eczema.

Type II - IgG-Mediated Cytotoxic Hypersensitivity

Antibody directed against cell surface antigens mediates cell destruction via complement activation or ADCC (Antibody-dependent cell-mediated cytotoxicity)

Typical manifestations include blood transfusion reactions, erythroblastosis fetalis, and autoimmune hemolytic anemia

Type III - Immune Complex-Mediated Hypersensitivity

Antigen - Antibody complexes deposited in various tissues induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils

Typical manifestations include localized Arthus reaction and generalized reactions such as serum sickness, necrotizing vasculitis, glomerulnephritis, rheumatoid arthritis, and systemic lupus erythematosus.

Type IV - Cell-Mediated Hypersensitivity

Sensitized TH1 cells release cytokines that activate macrophages or TC cells which mediate direct cellular damage

Typical manifestations include contact dermatitis, tubercular lesions and graft rejection.

Type I -  IgE-Mediated Hypersensitivity

Type I hypersensitive reaction is induced by certain types of antigens known as allergens, and is similar to a normal humoral response. That is, an allergen induces a humoral antibody response resulting in the generation of antibody-secreting plasma cells and memory cells. But here, the plasma cells secrete IgE that binds to Fc receptors on the surface of tissue mast cells and blood basophils. Mast cells and basophils coated by IgE are said to be sensitized.

A later exposure to the same allergen cross-links the membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells. The IgE-antigen reaction occurring on the surface of basophils and mast cells leads to receptor cross-linking and degranulation, ie release of vasoactive amines (histamine and serotonin) and other agents (heparin, eosinophil and neutrophil chemotactic factors, platelet-activating factor, a variety of cytokines and prostaglandins and leukotrienes) from the cytoplasmic granules.  These molecules cause contraction of smooth muscle cells, vasodilation, increased vascular permeability and platelet aggregation and degranulation. These reactions can affect a single tissue or organ (as in asthma, hay fever or eczema) or multiple ones (as in generalised anaphylaxis) depending on local or general re-exposure to the allergen.

The clinical manifestations of type I reactions can range from life-threatening conditions, such as systemic anaphylaxis and asthma, to hay fever and eczema, which are merely irritating. So type I reactions are of two types – Anaphylaxis and Atopy

 

 The mediators can be classified as either primary or secondary.

The primary mediators are produced before degranulation and are stored in the granules and these are histamine, serotonin, proteases, eosinophil chemotactic factor, neutrophil chemotactic factor, and heparin.

The secondary mediators either are synthesized after target-cell activation or are released by the breakdown of membrane phospholipids during the degranulation process. They include platelet-activating factor, leukotrienes, prostaglandins, bradykinins, and various cytokines.

Histamine, which is formed by decarboxylation of the amino acid histidine, is a major component of mast-cell granules, and induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules, and increased mucus secretion by goblet cells.

Serotonin is derived by decarboxylation of tryptophan and cause smooth muscle contraction, increased vascular permeability and vasoconstriction.

Leukotrienes and prostaglandin are formed during the mast cell degranulation and the enzymatic breakdown of phospholipids in the plasma membrane. Their effects are more pronounced and long lasting. The leukotrienes are formed through lipooxygenase pathway and mediate bronchoconstriction, increased vascular permeability, and mucus production. Prostaglandin are formed through  cyclooxygenase pathway causes bronchoconstriction.

Slow reacting substance of anaphylaxis (SRS-A) are a family of leukotrienes (LTC4, D4, E4).

Platelet activating Factor (PAF) is release from basophils and causes aggregation of platelets.

Anaphylaxis  (Ana – without and Phylaxis - protection) is a shock-like and often fatal state whose onset occurs within minutes of a type I hypersensitive reaction. This is due to the systemic vasodilation and smooth-muscle contraction brought on by mediators released in the course of the reaction. The symptoms include edema, decreased coagulability of blood, decrease in blood pressure and temperature, leucopenia and thrombocytopenia.  Tissues or organs involved are known as shock organ or target organs.

A wide range of antigens have been shown to trigger this reaction in susceptible humans, including the venom from bee, wasp, hornet, and ant stings; drugs, such as penicillin, insulin, and antitoxins; and seafood and nuts. If not treated quickly, these reactions can be fatal.

Epinephrine is the drug of choice for systemic anaphylactic reactions. Epinephrine counteracts the effects of mediators such as histamine and the leukotrienes.

Cutaneous anaphylaxis – This is a skin test for type I hypersensitivity.  When small dose of antigen is administered intradermally to a sensitized host, localized wheal and flare effect occurs with a central puffi area surrounded by area having hyperemia and erythema. 

Passive Cutaneous anaphylaxis – when small volume of antibody or serum is intradermally injected to normal animal followed by intravenous injection of antigen along with Evans Blue 4-24 hour later, bluing at the intradermal site occurs due to vasodilation and increased vascular permeability. 

In vitro anaphylaxis – when intestinal or uterine muscle strip from a sensitized animal is place in Rogers solution in presence of antigen, the muscle strip contract vigorously.  This is known as Schultz-Dale phenomenan. 

Anaphylactoid reaction – intravenous injection of peptone or trypsin provoke a reaction resembling anaphylactic shock.

In Localized anaphylaxis (atopy), (atopy means out of place / strangeness) the reaction is limited to a specific target tissue or organ, often involving epithelial surfaces at the site of allergen entry. The localized anaphylactic reactions is inherited and is called atopy. Atopic Allergies include allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), and food allergies.

Allergic Rhinitis, commonly known as hay fever results from the reaction of airborne allergens with sensitized mast cells in the conjunctivae and nasal mucosa to induce the release of pharmacologically active mediators from mast cells; these mediators then cause localized vasodilation and increased capillary permeability.

The symptoms include watery exudation of the conjunctivae, nasal mucosa, and upper respiratory tract, as well as sneezing and coughing.

Asthma -In some cases, airborne or blood-borne allergens, such as pollens, dust, fumes, insect products, or viral antigens, trigger an asthmatic attack (allergic asthma);

In other cases, an asthmatic attack can be induced by exercise or cold, apparently independently of allergen stimulation (intrinsic asthma).

Like hay fever, asthma is triggered by degranulation of mast cells with release of mediators, but instead of occurring in the nasal mucosa, the reaction develops in the lower respiratory tract. The resulting contraction of the bronchial smooth muscles leads to bronchoconstriction. Airway edema, mucus secretion, and inflammation contribute to the bronchial constriction and to airway obstruction.

Food allergies – Food allergen crosslinking of IgE on mast cells along the upper or lower gastrointestinal tract can induce localized smooth-muscle contraction and vasodilation and thus such symptoms as vomiting or diarrhea.

Mast-cell degranulation along the gut can increase the permeability of mucous membranes, so that the allergen enters the bloodstream.

Some individuals develop asthmatic attacks after ingesting certain foods. Others develop atopic urticaria, commonly known as hives, when a food allergen is carried to sensitized mast cells in the skin, causing swollen (edematous) red (erythematous) eruptions; this is the wheal and flare response, or P-K reaction (Prausnitz – Kustner reaction).  It includes swelling, produced by the release of serum into the tissues (wheal), and redness of the skin, resulting from the dilation of blood vessels (flare).

Atopic dermatitis (allergic eczema) is an inflammatory disease of skin. The allergic individual develops skin eruptions that are erythematous and filled with pus.

 Type II Hypersensitivity Antibody-Mediated Cytotoxic Hypersensitivity

Type II hypersensitive reactions involve antibody-mediated destruction of cells. Antibody can activate the complement system, creating pores in the membrane of a foreign cell  or it can mediate cell destruction by antibody dependent cell-mediated cytotoxicity (ADCC).

Transfusion Reactions

An individual possessing one type of blood-group antigen recognize other type on transfused blood as foreign and mount an antibody response. In some cases, the antibodies have already been induced by natural exposure to similar antigenic determinants on a variety of microorganisms present in the normal flora of the gut.  Antibodies to the A, B, and O antigens, called isohemagglutinins, are usually of the IgM class.  Antibodies to other blood-group antigens may also result from repeated blood transfusions and these antibodies are usually of the IgG class.

If a type A individual is transfused with blood containing type B cells, a transfusion reaction occurs in which the anti-B isohemagglutinins bind to the B blood cells and mediate their destruction by means of complement-mediated lysis.

The clinical manifestations of transfusion reactions result from massive intravascular hemolysis of the transfused red blood cells by antibody plus complement. These manifestations may be either immediate or delayed.

In the immediate type, symptoms include fever, chills, nausea, clotting within blood vessels, pain in the lower back, and hemoglobin in the urine.

Delayed hemolytic transfusion reactions generally occur in individuals who have received repeated transfusions of ABO-compatible blood that is incompatible for other antigens. The reactions develop between 2 and 6 days after transfusion.   Symptoms include fever, low hemoglobin, increased bilirubin, mild jaundice, and anemia.

Hemolytic Disease of the Newborn

Hemolytic disease of the newborn develops when maternal IgG antibodies specific for fetal blood-group antigens cross the placenta and destroy fetal red blood cells. The consequences of such transfer can be minor, serious, or lethal.

Severe hemolytic disease of the newborn, called erythroblastosis fetalis, most commonly develops when an Rh+ fetus expresses an Rh antigen on its blood cells that the Rh– mother does not express. During pregnancy, fetal red blood cells are separated from the mother’s circulation by a layer of cells in the placenta called the trophoblast. During her first pregnancy with an Rh+ fetus, an Rh– woman is usually not exposed to enough fetal red blood cells to activate her Rh-specific B cells. At the time of delivery, larger amounts of fetal umbilical-cord blood enter the mother’s circulation. These fetal red blood cells activate Rh-specific B cells, resulting in production of Rh-specific plasma cells and memory B cells in the mother.

Activation of the memory cells in a subsequent pregnancy results in the formation of IgG anti-Rh antibodies, which cross the placenta and damage the fetal red blood cells. Mild to severe anemia can develop in the fetus and conversion of hemoglobin to bilirubin cause brain damage with fatal consequences.

Hemolytic disease of the newborn can be prevented by administering antibodies against the Rh antigen to the mother within 24–48 h after the first delivery. These antibodies, called Rhogam, bind to any fetal red blood cells that enter the mother’s circulation at the time of delivery and facilitate their clearance before B-cell activation and ensuing memory-cell production can take place.

Drug-Induced Hemolytic Anemia

Certain antibiotics (e.g., penicillin, cephalosporin, and streptomycin) can adsorb nonspecifically to proteins on RBC membranes, forming a complex similar to a hapten-carrier complex. In some patients, such drug-protein complexes induce formation of antibodies, which then bind to the adsorbed drug on red blood cells, inducing complement mediated lysis and thus progressive anemia. When the drug is withdrawn, the hemolytic anemia disappears.

Immune Complex–Mediated (Type III) Hypersensitivity

The reaction of antibody with antigen generates immune complexes and these complexes are cleared by phagocytic cells.

Type III hypersensitive reactions develop when immune complexes activate the complement system and the C3a, C4a, and C5a complement products cause localized mast-cell degranulation and consequent increase in local vascular permeability. C3a, C5a, and C5b67 are chemotactic factors for neutrophils and attract neutrophils to the complex deposition site and the tissue is then injured due to granular release from the neutrophil.

Generally, complex deposition is observed on blood-vessel walls, in the synovial membrane of joints, on the glomerular basement membrane of the kidney, and on the choroid plexus of the brain.  Larger immune complexes are deposited on the basement membrane of blood vessel walls or kidney glomeruli, whereas smaller complexes may pass through the basement membrane and be deposited in the subepithelium.

·         Much of the tissue damage is due to release of lytic enzymes by neutrophils as they attempt to phagocytose immune complexes. During the process, the C3b complement component acts as an opsonin and coat immune complexes.  A neutrophil binds to a C3b-coated immune complex and since the complex is deposited on the basement membrane surface, phagocytosis is impeded, and the lytic enzymes are released during the unsuccessful attempts.

·         The  membrane-attack mechanism of the complement system also contribute to the destruction of tissue.

·         The activation of complement induce aggregation of platelets, and the resulting release of clotting factors lead to microthrombi formation.

When the complexes are deposited in tissue very near the site of antigen entry, a localized reaction develops.  When the complexes are formed in the blood, a generalized reaction develop.

Localized Type III Hypersensitivity

This is known as Arthus reaction.  When the antigen enter for the second time, at the site of antigen entry, localized tissue and vascular damage results in accumulation of fluid (edema) and red blood cells (erythema) at the site.  The severity of the reaction can vary from mild swelling and redness to tissue necrosis.

After an insect bite, a sensitive individual may have a rapid, localized type I reaction at the site.  Some 4–8 h later, a typical Arthus reaction develops at the site, with pronounced erythema and edema.

Intrapulmonary Arthus-type reactions induced by bacterial spores, fungi, or dried fecal proteins can also cause pneumonitis or alveolitis. These reactions are known as, “farmer’s lung” after inhalation of thermophilic actinomycetes from moldy hay, and “pigeon fancier’s disease” resulting from inhalation of dried pigeon feces.

Generalized Type III Hypersensitivity

This is a systemic form and occurs 7-12 days after injection of foreign serum and is known as serum sickness.  Serum sickness differs from other hypersensitivities in that a single injection can serve both as sensitizing dose and shocking dose. 

When large amounts of antigen enter the bloodstream and bind to antibody, circulating immune complexes can form and they can cause tissue- damaging type III reactions at various sites.

Historically, generalized type III reactions were often observed after the administration of antitoxins containing foreign serum, such as horse antitetanus or antidiphtheria serum. In such cases, the recipient develops antibodies specific for the foreign serum protein antigens which then form circulating immune complexes with the antigens.  Within days or weeks after exposure, individual begins to manifest a combination of symptoms that are called serum sickness. These symptoms include fever, weakness, generalized vasculitis (rashes) with edema and erythema, lymphadenopathy, arthritis, and sometimes glomerulonephritis, endocarditis, vasculitis, abdominal pain, nausea, vomiting, etc.

The precise manifestations of serum sickness depend on the quantity of immune complexes formed as well as the size of the complexes and the site of their deposition.   

Formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum sickness. These include the following:

Autoimmune Diseases

Systemic lupus erythematosus, Rheumatoid arthritis, Goodpasture’s syndrome

Drug Reactions

Allergies to penicillin and sulfonamides

Infectious Diseases

Poststreptococcal glomerulonephritis, Meningitis, Hepatitis, Mononucleosis, Malaria, Trypanosomiasis

Type IV or Delayed-Type Hypersensitivity (DTH)

When some subpopulations of activated TH cells encounter certain types of antigens, they secrete cytokines that induce a localized inflammatory reaction called delayed-type hypersensitivity (DTH). The hallmarks of a type IV reaction are the delay in time required for the reaction to develop and the recruitment of macrophages. 

·         The development of the DTH response begins with an initial sensitization phase of 1–2 weeks after primary contact with an antigen. During this period, TH cells are activated by antigen presented together with the class II MHC molecule on an appropriate antigen presenting cell including Langerhans cells and macrophages.

·         A subsequent exposure to the antigen induces the effector phase of the DTH response. In the effector phase, TH1 cells secrete a variety of cytokines that recruit and activate macrophages and other nonspecific inflammatory cells.

·         A DTH response generally peaks 48–72 h after second contact. The delayed onset of this response is due to the time required for the cytokines to induce localized influxes of macrophages and their activation.

·         Macrophages are the principal effector cells of the DTH response. Cytokines released by TH1 cells induce blood monocytes to migrate from the blood into the surrounding tissues. During this process the monocytes differentiate into activated macrophages.

·         The heightened phagocytic activity and the buildup of lytic enzymes from macrophages  cause nonspecific destruction of cells. This intense inflammatory response develops into a visible granulomatous reaction.

·         A granuloma develops when macrophages adhere closely to one another and fuse to form epitheloid cells and then multinucleated giant cells. These giant cells displace the normal tissue cells, forming palpable nodules, and release high concentrations of lytic enzymes, which destroy surrounding tissue and blood vessels and lead to extensive tissue necrosis.

The response to Mycobacterium tuberculosis is an example for the double-edged nature of the DTH response. Immunity to this intracellular bacterium involves a DTH response in which activated macrophages wall off the organism in the lung and contain it within a granuloma-type lesion called a tubercle.  However, the concentrated release of lytic enzymes from the activated macrophages within tubercles damages lung tissue.  

 

Tuberculin type - The presence of a DTH reaction can be measured experimentally by injecting small dose of tuberculin antigen intradermally into an animal and observing whether a characteristic skin lesion develops at the injection site.  Development of a red, slightly swollen, firm lesion at the site between 48 and 72 h later indicates previous exposure. The skin lesion results from intense infiltration of cells to the site of injection during a DTH reaction; 80%–90% of these cells are macrophages.  Similar hypersensitivity is observed against fungi, viruses, parasites, allograft, etc. 

Cutaneous basophil hypersensitivity – this resembles tuberculin reaction, but it is a delayed type hypersensitivity.  Here the intradermal injection site will be infiltered with basophils.

Contact Dermatitis – contact with a allergen in a sensitized individual leads to contact dermatitis.  The allergens include formaldehyde, trinitrophenol, nickel, turpentine, and active agents in various cosmetics and hair dyes, poison oak, poison ivy, etc. Most of these substances are small molecules that can complex with skin proteins. This complex is internalized by antigen-presenting cells in the skin (e.g., Langerhans cells), then processed and presented together with class II MHC molecules, causing activation of sensitized TH1 cells. The immune reaction results in formation of macules and papules that develops to vesicles that break down resulting in raw weeping areas.

In the reaction to poison oak, a pentadecacatechol compound from the leaves of the plant forms a complex with skin proteins.  When TH cells react with this compound displayed by local antigen-presenting cells, they differentiate into sensitized TH1 cells. A subsequent exposure to pentadecacatechol will elicit activation of TH1 cells and induce cytokine production. Approximately 48–72 h after the second exposure, the secreted cytokines cause macrophages to accumulate at the site. Activation of these macrophages and release of lytic enzymes result in the redness and pustules that characterize a reaction to poison oak.

Shwartzman reaction – this is not an immune reaction.  But resembles hypersensitivity.

If Salmonella typhi culture filterate is injected intradermally followed 24 hours later by intravenous injection of same or any other endotoxin, lesion develops at the intradermal site.  There is no specificity in the reaction.  If both injections are intravenous, then the animal dies 12-24 hours after the second dose.

The initial or preparatory dose causes accumulation of leucocytes that damage capillary walls.  The second dose or provocative dose cause intravascular clotting due to necrosis of vessel walls and hemorrhage.