Lecture Notes: Immune Hypersensitivity (Kaushik, 2024) PDF

Type-II hypersensitivity During a type II HS response, clinical damage is sustained when the pathological Abs bind directly to Ags on the surfaces of cells and induce their lysis. Involves Ab-mediated destruction of cells by various Ig isotypes (mainly IgM or IgG) other than IgE. In so...

Type-II hypersensitivity During a type II HS response, clinical damage is sustained when the pathological Abs bind directly to Ags on the surfaces of cells and induce their lysis. Involves Ab-mediated destruction of cells by various Ig isotypes (mainly IgM or IgG) other than IgE. In some cases, these Abs attack leukocytes/RBCs (mobile cells) & in others, they attack fixed cells in solid tissues. The Ag recognized may be a foreign entity that has become “ stuck” in some way on the surface of a mobile or fixed cell or may be an autoantigen. In the latter case, the pathological Abs are autoantibodies. They are free in the periphery to bind to self antigen and can manifest as autoimmune disease.  Type-II hypersensitivity Examples of type-II hypersensitivity Includes Blood-transfusion reactions Hemolytic disease of the newborn or Rh disease Some forms of anemia Reaction to certain drugs (drug-induced hemolytic anemia) Some platelet disorders Some types of tissue transplant reaction Several autoimmune disorders (not discussed here)  Type-II hypersensitivity Ab bound to a cell-surface Ag can induce death of Ag-bound cell by one of the three distinct mechanisms 1. Complement activation which results into creating pores in the membrane of a cell. 2. Antibody-dependent cell-mediated cytotoxicity (ADCC). 3. Ab bound to foreign cell or C3b deposition can serve as an opsonin & mediates its ‘phagocytosis’ by phagocytic cells. Autoimmune hemolytic anemia. (Frustrated phagocytosis) Read details from the textbook. Fig 18.5. Examples of Type-II hypersensitivity  Hemolytic anemias Hemolytic anemia: lytic destruction of RBCs (hemolysis) caused by a pathological Ab in a type II HS (Fig 18.5A). Destruction may occur within blood vessels or spleen or liver & may be due to autoantibodies or alloantibodies.  Autoimmune hemolytic anemias Occurs when the individual makes Abs directed against epitopes on his/her own RBCs. Autoantibodies are either warm (37oC) or cold (below 37oC) depending on temp at which they show optimal activity. Most auto immune hemolytic anemias are due to warm Abs, acute in onset & treatment usually involves glucocorticoids. For the patient with cold autoantibodies, onset of winter may be enough to trigger episodes of acute hemolysis. Extremities of these patients feel cold and turn blue and primary therapy is to avoid exposure to cold temperatures.  Alloimmune hemolytic anemias or Blood-transfusion reactions Read subsection on “Blood transfusions” from chapter 17 (pages 481-483). A large number of membrane proteins & glycoproteins of RBCs are encoded by different genes which have number of alternative alleles. An individual with one allelic form of a blood-group antigen can mount an antibody response to other allelic form of that gene in the transfused blood (foreign Ag). The blood type antigens (ABH) are carbohydrates, rather than proteins. Note that H Ag is present in all blood types. In case with ABO/ABH blood-group Ags, Abs are induced by natural exposure to similar antigenic determinants on a variety of microbes present in the gut as normal flora. TABLE 17-7 Blood Group Antigens and Antibodies Blood type of Genotype Sugar added Antigens on Anti-ABO Blood type of  Transfusion Reactions Abs to the A, B, & H Ags are called isohemagglutinins and they are of IgM isotype. Most adults possess IgM abs (isohemagglutinins) to those members of the ABH family they do not express as the Ag they express is recognized as self. If a type ‘A’ individual is transfused blood from a type ‘B’ individual, a ‘transfusion reaction’ occurs in which the anti-B isohemagglutinins bind to the B blood cells and mediate their destruction by complement-mediated lysis.  Transfusion Reactions Clinical manifestation of transfusion reaction occurs due to massive intravascular hemolysis of the transfused RBCs by Ab plus complement. These manifestations may either be immediate or delayed. Immediate hemolytic transfusion reactions: Mostly because of ABO blood-group incompatibilities. Symptoms: hemoglobinunuria, bilirubin build up, fever, chills, nausea, clotting within blood vessels, & pain in lower back. Treatment includes: Prompt termination of the transfusion & Maintenance of urine flow with diuretic as accumulation of hemoglobin in the kidney can cause tubular necrosis.  Transfusion Reactions Delayed hemolytic transfusion reactions: In adults, other blood group Ags such as Rh factor because of minor allelic differences may mediate Ab production upon repeated blood transfusion. These Abs are usually of IgG class. Develop 2-6 days after transfusion. As IgG Abs are less effective than IgM for complement activation., the complement mediated lysis of transfused RBCs is incomplete. Free hemoglobin is usually not detected in plasma or urine in these reactions as RBCs are usually destroyed at extravascular sites & removed by phagocytosis. Symptoms include fever, low hemoglobin, increased bilirubin, mild jaundice and anemia.  Hemolytic disease of the newborn Also called erythroblastosis fetalis (severe form).  Hemolytic disease of the newborn Erythroblastosis fetalis/hemolytic disease most commonly develops when an Rh+ fetus expresses an Rh antigen on its blood cells that Rh-mother does not express. Erythroblastosis fetalis develops when maternal IgG antibodies specific for fetal blood-group antigens cross the placenta and destroy fetal blood cells. Mild to severe anemia can develop in the fetus, sometime with fatal consequences. Conversion of hemoglobin to bilirubin (lipid-soluble) and its deposition in brain may cause brain damage. It can be prevented in a subsequent pregnancy by administrating Abs against Rh Ags (called Rhogam) to the mother at around 28 wks of pregnancy & within 24-48 hrs after first delivery.  Drug induced hemolytic anaemia Certain antibiotics (e.g. Penicillin, cephalosporin & streptomycin) & other drugs (ibuprofen & naproxen) can adsorb non-specifically to proteins on RBC membranes, forming a complex (similar to hapten-carrier complex). In some patients, such complexes cause production of Abs which bind to the adsorbed drug on RBCs and induce complement-mediated lysis & thus progressive anemia. When drug is withdrawn anemia Penicillin induced HS reactions disappears. Penicillin can induce all four types of hypersensitivities with various clinical manifestations.  Thrombocytopenias: Type II HS Thrombocytopenia patient has an abnormally low number of platelets in blood & exhibits impaired blood clotting. Thrombocytopenia is the most common cause of abnormal bleeding & is caused by decreased platelet production, increased platelet destruction or abnormal distribution of platelets within the body. Type II HS reactions mediated by antiplatelet Abs can contribute to increased platelet destruction & thus cause immune system-mediated thrombocytopenia. A prominent clinical feature of thrombocytopenia is the development of ‘purpura’, areas of purplish discoloration of the skin caused by leakage of blood into the skin layers. As with hemolytic anemias, type II HS thrombocytopenias may be either autoimmune or alloimmune in nature.  Other examples of Type II HS Ab-mediated rejection of solid tissue transplant: It occurs within minutes or hours of organ transplantation when the recipient has pre-existing alloantibodies directed against MHC molecules expressed on cells of donated organ. These Abs are present because of a previous pregnancy, organ or bone marrow transplant, or blood transfusion.  Other examples of Type II HS Goodpasture’s syndrome Is an autoimmune disease caused by autoantibodies that recognize a collagen protein found in the basement membranes of glomeruli in the kidney & alveoli in the lungs. Autoantibodies trigger classical complement activation that damages epithelial and endothelial cells in the target organs causing lung hemorrhage and inflammation of the renal glomeruli. Plate 18.3.  Other examples of Type II HS Pemphigus: Is an autoimmune disease characterized by potentially fatal blistering of the skin and mucosae that promotes dehydration and infection. This disorder is caused by autoantibodies (usually IgG or IgA) that attack adhesion proteins called desmogleins. Desmogleins glue keratanocytes together to form intact upper epidermal layers and do the same for mucosal epithelial cells to form mucosae. Autoantibody binding to desmogleins induces separation of epidermal or mucosal layers & it also allows release of protease that causes painful blisters. Corticosteroid administration is the Plate 18.4. Mouth standard treatment. blisters in pemphigus.  Immune complex-mediated Type III hypersensitivity Generally Ag-Ab immune complexes are formed as a normal part of an adaptive immune response and they facilitate the clearance of Ag by phagocytic cells & RBCs. In some cases, however, immune complexes are inefficiently cleared and may be deposited in the blood vessels or tissues. The presence of large numbers and network of immune complexes can lead to tissue-damaging type III hypersensitivity reactions.  Immune complex-mediated Type III hypersensitivity Deposition of complexes results in the recruitment of complement components and neutrophils & tissue damage is caused by granules released from these cells. The magnitude of the reaction depends on the quantity of immune complexes and their distribution within the body. Binding of immune-complexes to Fc and/or complement receptors of mast cells, neutrophils & macrophages trigger release of vasoactive mediators & inflammatory cytokines. These mediators interact with the capillary epithelium and increase the permeability of the blood vessels. Type III HS: Immune complex-mediated HS Large and insoluble immune complexes then move through the capillary wall & into the tissues where they are deposited and set up a localized inflammatory response. Complement fixation results in production of C3a & C5a anaphylatoxins which attract more neutrophils & macrophages. These cells are further activated by immune complexes binding to their Fc receptors to secrete pro-inflammatory chemokines & cytokines, prostaglandins and proteases. Proteases & oxygen free radicals released by neutrophils macrophages and NK cells cause tissue damage. Fig 18.6: Mechanism of action of Type III HS.  Type III hypersensitivity When complexes are formed & deposited: on blood vessel walls they cause vasculitis in synovial membrane of joints they cause arthritis in kidney they cause glomerulonephritis Can be localized or generalized. When Ag is injected (I/D or S/C), high level of circulating Abs form localized immune complexes which mediate localized reaction called ‘Arthus reaction’ within 4-8 hrs. Neutrophils migrate to the site of Development of a immune complexes deposition. localized Arthus reaction  Type III hypersensitivity In Arthus reaction a localized tissue & vascular damage results in pain, an accumulation of fluid (edema) & RBCs (erythema) at the site e.g. 4-8hrs after insect bite. Intrapulmonary Arthus-type reactions induced by bacterial spores/dried fecal proteins cause pneumonitis or alveolitis e.g. Farmer’s lung caused by moldy hay. Pigeon fancier’s disease from An Arthus reaction inhalation of dried pigeon feces. after injection of a drug for the second time. If immune complex mediated hypersensitivity is induced by single large bolus of Ag which is gradually cleared, then it can resolve spontaneously e.g. glomerulonephritis initiated following a streptococcal infection.  Type III hypersensitivity Generalized reactions: when large amount of Ag enter the blood stream & bind to Ab, circulating immune complexes are formed. When Ag>Ab, smaller complexes are formed which are not cleared by phagocytic cells & can cause tissue damage e.g. Serum sickness. Serum sickness develops days to weeks after administration of antitoxins containing foreign serum e.g. horse anti-tetanus or anti- diphtheria serum. Symptoms: fever, weakness, generalized vasculitis (rashes) with edema & erythema, lymphadenopathy, arthritis and sometime glomerulonephritis.  Type III hypersensitivity Serum sickness is most Examples of diseases commonly seen today after resulting from type III HS antibiotic treatment and reactions. certain vaccinations. Use of monoclonal Abs (produced in mouse) for treatment of cancer and other diseases can cause serum sickness (human anti-mouse antibody (HAMA) response); therefore, humanized antibodies are used for therapeutic purposes.  Type IV or delayed type HS (DTH) It is the only HS category that is purely cell mediated rather than Ab mediated. It results primarily from the tissue-damaging action of effector Th cells, CTLs & macrophages. It was first described by Robert Koch who observed that individuals infected with Mycobacterium tuberculosis developed a localized inflammatory response when injected in the skin with a filtrate from mycobacterial cultures. He named it as ‘tuberculin reaction’. Later, it was found that many other Ags could induce this cellular response.  Type IV or delayed type HS (DTH) Its name was changed to delayed–type or type IV hypersensitivity (DTH) because of its delayed onset or tissue damage only 24-72 hours after exposure of a sensitized individual to the antigen. When some activated CD4+ Th cells encounter certain Ags, they secrete cytokines that induce localized inflammatory reaction called delayed type hypersensitivity (DTH).  Type IV/delayed type hypersensitivity (DTH) DTH reaction is Intracellular pathogens and characterized by large contact antigens that induce number of nonspecific delayed type (type IV) HS. inflammatory cells, particularly macrophages. The term delayed type hypersensitivity is somewhat misleading that a DTH response is always detrimental. In some cases tissue damage is limited and response plays important role in defense against intracellular pathogens and contact Ags.  The DTH reponse Two phases of DTH response: Sensitization phase & effector phase. Sensitization phase: begins with an initial sensitization by Ag, followed by a period of at least 1-2 wks during which antigen-specific Th cells are activated & clonally expanded. Fig 18.7: Type IV HS: chronic DTH reaction.  Type IV hypersensitivity Effector Phase: It is induced by second exposure to a sensitizing antigen. In effector phase, TH1 cells (which in this context are called here TDTH cells) secrete a variety of cytokines & activate macrophages & other nonspecific inflammatory cells. By the time DTH response is fully developed, only about 5% of participating cells are antigen specific TH1 cells; the remaining cells are macrophages & other innate immune cells.  Type IV hypersensitivity A prolonged DTH response can lead to formation of a granuloma, a nodule like mass e.g. in tuberculosis. Lytic enzymes released from activated macrophages in a granuloma can cause extensive damage. The response to M. tuberculosis illustrates the double-edged nature of DTH response. The activated macrophages in tubercle or granuloma wall off the bacteria but lytic enzymes damage the lung tissue. Plate 13.2: Granuloma cross section- A central Corticosteroid treatment is most often zone of necrosis is surrounded by activated used to treat chronic DTH reactions. macrophages.  Type IV hypersensitivity The DTH reaction is detected with a skin test by injecting antigen intradermally. A characteristic skin lesion develop at the site of injection in positive cases. A positive skin test indicates that a individual has a population of sensitized TH1 cells specific for the test Ag. Example: Injection of PPD (protein from the cell wall of Mycobacterium tuberculosis) in a M. tuberculosis exposed individual leads to the development of a red, slightly swollen, firm lesion at the site between 48-72hrs later.  Type IV hypersensitivity Skin lesion is due to infiltration of cells to the site (80- 90% of these cells are macrophages). Positive skin test for M. tuberculosis does not allow to conclude whether the exposure was to a pathogenic form of M. tuberculosis or to a vaccine (BCG vaccine is used in certain part of the world but not in USA).  Contact hypersensitivity Contact HS (CHS) , sometime called ‘Contact dermatitis’ is a secondary immune response to a small, chemically reactive molecule that has bound covalently to self proteins in the uppermost layers of the skin. Examples: Poison ivy plant Poison oak Hair dyes Nickel salts Latex Drugs (Penicillin) Cosmetics Fig 18.8: Type IV HS: Contact hypersensitivity.