Hypersensitivity reactions, types II till V

A principal biological role of the immune system is an eradication of both external as well internal violators of integrity of the organism. External „enemies“ are represented mainly by germs; those of internal origin belong especially to potentially malignant cells that appear in our organisms as the results of a breakdown of their replication mechanisms.Under certain circumstances, however, the immune response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity. Although the word hypersensitivity implies an increased response, the response is not always heightened but may, instead, be an inappropriate immune response to an antigen.
Several forms of hypersensitive reaction can be distinguished, reflecting differences in the effector molecules generated in the course of the reaction. In immediate hypersensitive reactions different antibody isotypes induce different immune effector molecules. IgE antibodies, for example, induce mast cell degranulation with release of histamine and other biologically active molecules. IgG and IgM antibodies, on the other hand, induce hypersensitive reactions by activating complement. The effector molecules in these reactions are the membrane-attack complex and such complement split products as C3a, C4a and C5a. In delayed-type hypersensitivity reactions, the effector molecules are various cytokines secreted by T helper cells and macrophages. As it became clear that different immune mechanisms can give rise to hypersensitive reactions, P. G. H. Gell and R. R. A. Coombs proposed a classification scheme in which hypersensitive reactions are divided into four types, I, II, III, and IV, each involving distinct mechanisms; later type V was added. Antibodies mediate four types of hypersensitive reactions: IgE-mediated (type I), cytotoxic (type II), immune complex (type III), and stimulatory/inhibitory (type V) hypersensitivity, respectively. T cells initiate the last type of hypersensitivity (type IV) and clinical symptoms appear more days after exposure; it is therefore referred to as delayed-type hypersensitivity (DTH). However, a great deal of com¬plexity exists within each type of reactions that blurs the boundaries between them.

A principal biological role of an immune response is to set up various effector mechanisms with the aim to remove antigen. Under certain circumstances, however, this inflammatory response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity. Although the word hypersensitivity implies an increased response, the response is not always heightened but may, instead, be an inappropriate immune response to an antigen.
    Several forms of hypersensitive reactions can be distinguished. P. G. H. Gell and R. R. A. Coombs were the first who proposed a classification scheme in which hypersensitive reactions are divided into four types, I, II, III, and IV; later type V was added. The term allergy is rather use as type I hypersensitivity reaction in clinical medicine and because of its great importance and occurrence rate, it is described separately. In this article, we offer an overview of type II till V describe hypersensitive reactions

1. Type II hypersensitivity reactions: Antibody-mediated cytotoxicity

Type II hypersensitive reactions involve antibody-mediated destruction of cells. This type of reaction is best seen by blood-transfusion reactions, in which host antibodies react with foreign antigens on the incompatible transfused blood cells and mediate destruction of these cells. Antibody can mediate cell destruction by activating the complement system to create pores in the membrane of the foreign cell. Antibody can also mediate cell destruction by antibody-dependent cell-mediated cytotoxicity (ADCC). In this process, cytotoxic cells with Fc-receptors bind to the Fc-region of antibodies on target cells and promote killing of the cells.

ABO incompatibility
If a blood group A individual is accidentally transfused with blood from a blood group A donor, the anti-B isohaemagglutinins bind to the B blood cells and mediate complement-mediated lysis  a massive intravascular of the transfused red blood cells follows. Typical symptoms of a transfusion reaction include fever, chills, nausea, and pain in the lower back. Within hours, free haemoglobin can be detected in the plasma; it is filtered through the kidneys, re¬sulting in haemoglobinuria. Some of the haemoglobin converts to bilirubin, which at high levels is toxic to brain. There is a clotting within blood vessels, too. A treatment involves prompt termination of the transfusion and maintenance of urine flow with a diuretic because the accumulation of haemoglobin in the kidney can cause acute tubular necrosis. Transfusion reactions can be prevented by a proper cross¬-matching between the donor's and the recipient's blood. The cross-matching can reveal the presence of the antibodies in donor or recipient sera that can cause these reactions.

Haemolytic disease of the newborn
Haemolytic disease of the newborn develops when maternal IgG antibodies specific for foetal blood-group antigens cross the pla¬centa and destroy foetal red blood cells. It most commonly develops in the Rh-negative mother bearing her Rh-positive foetus (i.e. the Rh(D) anti¬gens are expressed on its red blood cells). During her first pregnancy the Rh-negative woman is usually not exposed to sufficient quantity of foetal red blood cells (RBC) to activate her Rh(D)-specific B cells. At the time of delivery, however, separation of the placenta from the uterine wall allows larger amounts of foetal umbilical-cord blood to enter the mother's circulation. These foetal red blood cells activate the Rh(D)-specific B cells, resulting in production of the Rh(D)-specific antibodies and appearance of memory B cells in the mother. The secreted IgM antibody clears the Rh(D)+ foetal red blood cells from the mother's circulation and disappear in the time course; however, the memory B cells remain. When the woman is pregnant the second time, the Rh(D)-positive erythrocytes of the foetus cross the placenta and activate the memory B cells what results in production of antibodies. However, this time, they are of the IgG class (the secondary immune response. The IgG anti-Rh(D) antibodies cross the placenta and bind to the Rh(D) antigens; the complement system activation follows resulting in destruction of foetal red blood cells. Depending on the extent of RBC lysis, less severe haemolytic anaemia or more severe, sometimes also fatal, erythroblastosis foetalis, develops.
   The development of haemolytic disease of the newborn by Rh(D) incompatibility can be detected by testing materna1 serum at intervals during pregnancy for antibodies to Rh(D) antigen. A rise in the titer of these antibodies as pregnancy progresses indicates that the mother has been exposed to Rh(D) antigens and is producing increasing amounts of antibodies. The presence of maternal IgG on the surface of foetal erythrocytes can be detected by a Coombs test.
The treatment haemolytic disease caused by the Rh(D) incompatibility is based on an exchange transfusion, primary to remove bilirubin; the infant is also exposed to low levels of UV light to break down the bilirubin and prevent any cerebral damage.
   To prevent the Rh-isoimmunisations, all Rh-negative women are given anti-Rhesus antibodies 72 h after delivery at the latest. The antibodies originate from immunisation of men by the Rhesus-positive erythrocytes. The antibodies destroy foetus RBC and so prevent of the immunisation of the Rh-negative women.

Drug-induced haemolytic anaemia
Some drugs (e.g. penicillins, cephalosporins, etc.) can adsorb non-specifically 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 anaemia. When the drug is withdrawn, the haemolytic anaemia disappears.

2. Type III hypersensitivity reactions: Immune complexes induced inflammation
Complexes between antigens and antibodies, so called immune complexes, are formed whenever an antigen binds to its specific antibody; mononuclear phagocytes engulf and degrade them immediately. However, in dependence from relative concentration ratios of antigens and antibodies, respectively, immune complexes can sometimes induce immunopathological reactions. Large immune complexes are insoluble and are rapidly cleared by mononuclear phagocytes; also small complexes fail cause any damage, as they do not activate the complement system. However, when intermediate size immune complexes are formed, they tend to be deposited into tissues and organs where they induce inflammation and their damage.
   The extent of immune complex deposition depends from a general capacity of the organism to degrade them, esp. from a physiological status of the monunuclear-phagocytic system and the complement system. Phagocytosis disorders are connected with persistence of immune complexes and their deposition to the tissues. Similarly, the deficiencies of C2 and C2 components of the complement system are associated with immune complex diseases, e.g. with SLE.
When immune complexes are deposited in tissues, they induce an inflammatory process. They activate the complement system what results in formation of C3a and C5a anaphylatoxins. These molecules activate mast cells to release permeability factors permitting localisation of immune complexes along the endothelial cell basement membranes. Neutrophils, macrophages, lymphocytes and other cells with membrane Fc-receptors are activated. The activated neutrophils are especially important. They release proteolytic enzymes and produce reactive oxygen intermediate products (ROI) that cause a damage of the tissue. Platelets can be subsequently activated resulting in blood clotting and microtrombi formation; local ischemy and tissue necrosis follows. As it contains fibrin, the term fibrinoid necrosis was coined.
   Historically, generalized type III reactions were often observed at the administration of antitoxins containing foreign proteins, such as horse anti-tetanus or anti-diphtheria serum; the condition is known as serum sickness. The clinical symptoms include fever, weakness, generalised vasculitis (rash) with oedema and erythema, lymphadenopathy, arthritis, and sometimes glomerulonephritis. As immune complexes are continuously degraded, the clinical manifestations spontaneously vanish.
   Formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum sickness. These include SLE (systemic lupus erythematosus), rheumatoid arthritis, Goodpasture's syndrome, poststreptococcal glomerulonephritis and others.
   Except of generalised type III hypersensitivity reaction, there is also a localised type. It was Nicholas Maurice Arthus who first described it in 1903. Arthus showed that injection of an antigen intradermally or subcutaneously into an animal that had had high levels of circulating antibody spe¬cific for the antigen produced local inflammation that progressed to a haemorrhagic necrotic ulcerating skin lesion.
   Arthus reactions are rare in humans. After an insect bite, a sensitive individual may have a rapid, localized type I reaction at the site. Often, some 48 hrs later, a typical Arthus reaction also develops at the site, pronounced by erythema and oedema.

3. Type IV hypersensitive reactions: Delayed type of hypersensitivity
Type IV hypersensitive reactions (delayed type of hypersensitivity - DTH) develop when antigen activates sensitised TDTH cells; these cells belong to TH1 subset, although sometimes cytotoxic T cells (CTLs) are involved. Activation of T cells by antigen on appropriate antigen-presenting cells results in the secretion of various cytokines, including IL-2, IFN-gama, MIF (macrophage migration inhibitory factor, and TNF (tumour necrosis factor). The overall effect of these cytokines is to draw macrophages into the area and activate them, promoting increased phagocytic activity and increased concentrations of lytic enzymes for more effective killing. As lytic enzymes leak out of the activated macrophages into the surrounding tissue, localised tissue destruction can ensue. These reactions typically take  48 to  72 h to develop, the time required for initial T cell activation and cytokine secretion to mediate accumulation of macrophages and the subsequent release of their lytic enzymes. The hallmarks of a type IV reaction are the delay in time required for the reaction to develop and the recruitment of macrophages as opposed to neutrophils, as found in a type III reaction. Macrophages are the major component of the infiltrate that surrounds the site of inflammation.
   The type IV reaction is important in host defence against parasites and bacteria that can live within cells, such as Mycobacterium tuberculosis, Mycobacterium leprae, Brucela species and others. Once these organisms are inside the host's cells, circulating antibodies cannot reach them. However, the heightened phagocytic activity and the build up of lytic enzymes from macrophages in the area of infection lead to non-specific destruction of cells, and thus of the intracellular pathogen. When this defence process is not entirely effective, the continued presence of the pathogen's antigens can provoke a chronic DTH reaction, which is characterised by excessive numbers of macrophages, continual release of lytic enzymes, granuloma formation and consequent tissue destruction.
   T cells mediate many contact dermatitis reactions, including the responses to formaldehyde, trinitrophenol, nickel,  various cosmetics and hair dyes, poison oak, poison ivy, and others. Most of these substances are small molecules that can complex with skin proteins. This complex is internalised by antigen-presenting cells in the skin (i.e. Langerhans cells), processed and presented together with class II MHC molecules, causing activation of sensitised T cells. In the reaction to poison oak, for example, a pentadecacatechol compound from leafs of the plant complexes with skin proteins. When TH cells react with this compound appropriately displayed by local antigen presenting cells, they differentiate into sensitised T cells; a subsequent exposure to pentadecacatechol will elicit activation of T cells and induce cytokine production. Approximately 48-72 h after this secondary exposure, the secreted cytokines cause macrophages to accumulate at the site. Activation of these macrophages and release of their lytic enzymes results in the redness and pustules that characterise a reaction to poison oak.

4. Type V hypersensitivity reactions
Type V hypersensitivity reactions were additionally added to the scheme originally described by Coombs and Gell. Contrary to type IV and in agreement with types I, II, and III, respectively, they are mediated by antibodies too. The type V reactions are sometimes considered as a subtype of the type II hypersensitivity. As its mechanisms do not destroy target cells, they are responsible for induction of organ/tissue dysfunctions only most of authors prefer it to be and independent, the 5th type of hypersensitivity reactions.
   Cells receive information from their microenvironment in which they live; they sense signals that process and transduce into the cell nucleus by means of second signals. The specificity of binding between the signal and its receptor is mediated by complementarities of structures. For instance, thyroid-stimulating hormone (TSH) released from the adenohypophysis, by binding to its receptors in membranes of the thyroid gland stimulates adenylate-cyclase system what results in production of hormones.
   Morbus Graves is characterised by production of antibodies directed against the TSH binding receptor that subsequently stimulate the thyroid gland, resulting in production of hormones (thyroxine and triiodothyronine). Contrary to physiological situation, there is no feedback mechanism – the increased levels of the thyroid gland hormones do not stop its hormones production as at the physiological condition when elevated amounts of thyroxines switch off the production of TSH and subsequent synthesis of hormones. The result is the hormone overproduction and appearance of clinical symptoms of hyperthyroidism. As antibodies increase the function of a target organ, this type of hypersensitivity is called stimulatory.
   Autoantibodies cannot only stimulate cells of a target organ/tissue, however, on the contrary, also to inhibit it (hence the designation - inhibitory hypersensitivity reactions). A prototype of such a situation is myastenia gravis. It is an autoimmune disease characterised by production of autoantibodies directed against the acetylcholine receptors (AchR) present in neuro-muscular plates. By occupying the receptors, they inhibit a physiological binding of acetylcholine to, resulting in precluding signal transmission and muscle activation. The result of the events is a paralysis of striated muscles. In some cases the anti-acetylcholine receptors antibodies activate the complement system; a destruction of cell present in neuro-muscular plates follows; the condition is more severe than in the previous situation and is incurable.
   Pernicious anemia (PA) is a disease is characterised by vitamin B12 deficiency caused by the absence of intrinsic factor. Vitamin B12 cannot be produced by the human body and must be obtained from the diet. When foods containing B12 are eaten, the vitamin is usually bound to protein and is released by stomach acid. Following its release, most B12 is absorbed by the body in the ileum after binding to a protein known as intrinsic factor. It is produced by parietal cells of the gastric mucosa and the intrinsic factor-B12 complex is absorbed by receptors on the ileum epithelial cells. In patients suffering from PA, antibodies to parietal cells cause the destruction of the gastric mucosa, in which the parietal cells are located, leading to the subsequent loss of intrinsic factor synthesis. In other subgroup of PA patients, antibodies to intrinsic factor are directly induced. Without intrinsic factor, the ileum can no longer absorb the B12 and the disease develops.


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