Type II (Cytotoxic) Hypersensitivity

What is Type II Hypersensitivity?

• A type II hypersensitivity is considered to occur when cellular lysis triggered by the direct binding of antibody to cell surface antigens causes harm to the host’s tissues.
• Antibodies implicated in type I HS are of the IgE isotype, whereas antibodies involved in type II HS are predominantly of the IgM or IgG isotype.
• In certain instances of type II HS, the pathogenic antibodies target leukocytes or red blood cells, referred to as “mobile cells.”
• In some instances, antibodies bind to cells that are “fixed” within a solid tissue. Regarding the antigenic specificity of the pathogenic antibody, some recognise a foreign substance that has “gotten stuck” on the surface of a host cell.
• Others may be autoantibodies that are free to bind to self-epitopes on host cells in the periphery due to a lack of tolerance mechanisms.
• Some forms of anaemia, blood transfusion reactions, some platelet problems, and certain types of tissue transplant rejection are examples of type II HS.
• Additionally, Type II HS responses are often components of autoimmune disorders.
• As with other hypersensitivities, certain type II HS reactions are drug-induced.

Mechanism of Type II Hypersensitivity

• Similar mechanisms of cell lysis and tissue damage are induced in type II HS when IgG or IgM antibodies bind to cellular invaders.
• ADCC, complement activation, and opsonized phagocytosis are all detrimental processes. To summarise briefly: ADCC of a target cell is induced by the binding of the Fab portion of the pathogenic antibody to the target cells, followed by the binding of the Fc section of the pathological antibody to FcR-bearing cytotoxic cells, including NK cells, neutrophils, eosinophils, and macrophages.
• Activation of the classical complement is triggered by the binding of the pathogenic antibody to the antigen on the target cells.
• C3b is deposited, which allows either opsonized phagocytosis by CR1-containing cells such as macrophages or neutrophils, or MAC assembly and lysis of the target cell as a result of hole development. In hypersensitive individuals, the RCA proteins attempting to defend the cell surface from MAC assembly are likely overwhelmed.
• Intriguingly, the damage caused by opsonization differs depending on whether the target cell is mobile or immobile within a tissue.
• When the target is mobile, the phagocyte can sometimes successfully phagocytose the cell “on the spot.” Alternatively, the antibody-bound target cell travels to the liver or spleen to undergo phagocytosis.
• If the target cell is a fixed component of a bigger tissue or organ, phagocytes may be unable to ingest it.
• The “frustrated” phagocyte then releases its lysosome contents externally, resulting in localised tissue injury.
• NK cells contribute to the killing of antibody-bound target cells by beginning ADCC.
• This damage is increased by the local presence of C3a and C5a, which are byproducts of complement activation.
• These anaphylatoxins generate a chemotactic gradient that attracts extra neutrophils to the afflicted location and stimulates basophils and mast cells to degranulate, causing further tissue damage.

Examples Of Type II Hypersensitivity: Cytotoxicity Against Mobile Cells

1. Hemolytic Anemias

• Anemia is the broad term for any condition in which a person’s red blood cell count is below normal.
• Numerous instances of anaemia are secondary effects of non-immunological sickness.
• In contrast, when a pathogenic antibody mediates the lytic destruction of erythrocytes in a type II HS reaction, the resulting condition is known as hemolytic anaemia or immune hemolytic anaemia.
• Actual hemolysis frequently occurs extravascularly, with the site defined by the predominant antibody isotype.
• In the case of RBCs coated with IgG antibodies, the cells are killed by FcR-carrying phagocytes in the spleen, and intravascular complement activation is activated to a negligible degree.
• When IgM antibodies are present, however, complement is readily triggered through the classical pathway, resulting in “on-the-spot” lysis of certain RBCs and minimal intravascular hemolysis.
• IgM-bound RBCs with surface C3b and iC3b acquired during complement activation are typically transported to the liver, where they are killed by CR-containing Kupffer cells.

a. Alloimmune hemolytic anemias

• When an individual is exposed to allogeneic erythrocytes, antibodies directed against the foreign RBC antigens are produced, resulting in alloimmune hemolytic anaemia.
• If the interaction between these antibodies and the foreign antigen induces an excessively robust inflammatory response, the resulting tissue damage is a type II HS reaction.
• The transfusion reaction, which occurs when a patient is transfused with ABO-incompatible donor blood, and Rh disease (also known as hemolytic disease of the newborn or erythroblastosis fetalis), which occurs when Rh-positive RBCs of a foetus are destroyed by maternal anti-Rh IgG antibodies, are the best-known examples of type II HS.

b. Autoimmune hemolytic anemias

• An individual develops autoimmune hemolytic anaemia when antibodies directed towards RBC epitopes are produced. The antibodies are categorised as “warm” or “cold” based on the temperature at which they exhibit maximal affinity and reactivity in vitro.
• Cold autoantibodies only bind efficiently at temperatures below 37 °C, whereas warm autoantibodies are most potent at 37 °C and have diminished effects at lower temperatures. This distinction in molecular behaviour manifests itself in vivo as well.
• 50 to 70% of autoimmune hemolytic anemias are caused by autoantibodies that are heated. The existence of these antibodies is frequently secondary to an autoimmune or lymphoproliferative illness, and the prevalence of concomitant hemolytic anaemia increases with age.
• The onset of anaemia can be either gradual or sudden. In situations with gradual onset, symptoms such as weariness, dizziness, weakness, and trouble breathing with effort develop initially. Also possible are fever, coughing, abdominal pain, and weight loss.
• In such instances, the severity of the symptoms frequently varies over time. Acute onset anaemia is characterised by an abrupt, potentially lethal onset. The patient undergoes a severe wave of hemolysis that causes the aforementioned symptoms as well as jaundice, pallor, edoema, hemoglobinuria (haemoglobin in the urine), and spleen, liver, and lymph node enlargement.
• Kidney poisoning may develop from the release of excessive quantities of haemoglobin into the circulation. To decrease the inflammatory response, glucocorticoids are commonly used to treat warm autoimmune hemolytic anemias.
• In addition, these illnesses frequently involve antibodies of the IgG isotype; splenectomy may be effective in cases when medication treatment has failed. (Splenectomy eliminates the primary organ responsible for extravascular hemolysis.)
• Clinically, there are two major kinds of cold autoimmune hemolytic anaemia: cold agglutinin syndrome (CAS), also known as cold hemagglutinin disease (CHD), and paroxysmal cold hemoglobinuria (PCH) (PCH). 20–30% of all autoimmune hemolytic anemias are caused by CAS, whereas PCH accounts for less than 10%. The majority of people with CAS are approximately 70 years of age.
• Because of the nature of the cold autoantibodies implicated, the strength of symptoms changes with the ambient temperature. In temperate environments or seasons, for instance, patients may merely be pale and have mild weariness, whereas the transfer to more northern regions or the advent of winter may provoke episodes of severe hemolysis.
• Anatomically, the intensity of symptoms also differs. Due to the susceptibility of extremity blood to temperature changes, antibody-mediated RBC destruction may be more widespread in the fingers, toes, wrists, and ankles. Due to the decreased amount of RBCs available to transport oxygen, these anatomical tissues may feel exceedingly chilly and develop a bluish hue.
• The primary treatment for CAS is avoiding exposure to cold temperatures. Immunosuppressants are only administered in the most extreme instances. In contrast to IgG-mediated warm autoimmune hemolytic anemias, splenectomy is often ineffective for CAS, which is caused by IgM autoantibodies that promote liver hemolysis.
• In situations of CAS, treatment with rituximab (anti-CD20 antibody; see Ch.26) can be beneficial. This therapeutic mAb attaches to the surfaces of B cells (including those that produce pathogenic antibodies) and promotes their death via complement-mediated lysis and ADCC.
• In contrast to CAS, PCH mostly affects children and is one of the most common causes of hemolytic anaemia in this age range. When PCH was initially characterised in 1904, 90% of cases were related to syphilis infection, making it a chronic, recurrent adult condition.
• After the discovery of efficient antibiotics for syphilis, the epidemiology of PCH altered substantially, and the disease became an acute, nonrecurrent ailment affecting nearly entirely children. After an infection with the measles, mumps, EBV, varicella, or influenza virus, children often experience an acute type of PCH that comes and goes.
• Exposure to frigid temperatures may also precipitate PCH. Common symptoms include sudden high fever, chills, back and leg discomfort, abdominal cramping, and hemoglobinuria, with headache, nausea, vomiting, and diarrhoea occurring less commonly.
• In most circumstances, a PCH attack fades within hours; however, in certain instances, the severity of hemolysis can be so life-threatening that the patient requires several weeks to recover.
• Donath-Landsteiner antibody is the IgG autoantibody responsible for PCH. In vitro, this antibody binds at low temperatures to a polysaccharide P antigen on RBCs and subsequently activates complement when the cells are restored to 37 °C.
• Patients subjected to cold and then warm conditions have a similar reaction. The treatment for PCH consists on keeping the patient warm (to prevent autoantibody binding) and symptom management.
• Plasmapheresis can be used to eliminate autoantibodies and minimise the severity of hemolysis in severe cases.

2. Thrombocytopenia

• A patient suffering from thrombocytopenia has an abnormally low platelet count. The most prevalent cause of irregular bleeding is thrombocytopenia, which is caused by decreased platelet production, accelerated platelet breakdown, or aberrant platelet distribution in the body.
• Type II HS responses can contribute to increased platelet destruction, resulting in thrombocytopenia mediated by the immune system. As is the case with hemolytic anaemia, type II HS thrombocytopenia may be caused by alloimmune or autoimmunity-related antibodies.

a. Alloimmune thrombocytopenia

• Neonatal thrombocytopenia and post-transfusion purpura (PTP) are termed type II HS thrombocytopenia. Both diseases are induced by platelet surface antigen PLA1-specific alloantibodies.
• In neonatal thrombocytopenia, a pregnant, PLA1-negative woman gets sensitised by her bearing a PLA1-positive foetus. The mother produces PLA1-specific IgG antibodies that can cross the placenta and damage foetal platelets, resulting in foetal and newborn thrombocytopenia.
• Fortunately, due to the fact that 98% of individuals are PLA1, newborn thrombocytopenia is uncommon and happens once in every 5000 births. Affected newborns acquire patches of purplish or brownish-red skin discoloration (purpura) due to bleeding into the skin layers.
• Additionally, little red patches known as petechia may be visible. While these symptoms are modest and non-permanent, intracranial haemorrhage that affects the brain is a potentially fatal condition. Standard treatment for newborn thrombocytopenia often consists of steroid administration to decrease inflammation and limit the function of phagocytic cells.
• Platelet transfusion may also be utilised to alleviate symptoms and decrease the likelihood of cerebral bleeding. In addition, if neonatal thrombocytopenia is discovered during pregnancy, caesarean section delivery may be recommended to reduce the baby’s exposure to the harmful alloantibodies.
• PTP occurs when PLA1 people get PLA1 Platelets via therapeutic blood or blood product transfusion. PTP occurs more frequently in patients who have undergone numerous pregnancies or many transfusions, despite the fact that some PLA1 persons possess natural antibodies detecting PLA1.
• Anti-PLA1 antibodies initiate platelet destruction in the patient, leading to an abrupt onset of thrombocytopenia. In addition to purpura and petechiae on the skin and mucosa, there may be bleeding from the nasal, gingival, gastrointestinal, or urogenital tracts.
• As with newborn thrombocytopenia, cerebral bleeding is a worry with PTP, but the condition is typically self-limiting. When necessary, PTP is treated with steroids or plasmapheresis.

b. Autoimmune thrombocytopenia

• The cause of autoimmune thrombocytopenia is an autoantibody attack on one’s own platelets. The condition may be acute or persistent. In both instances, platelet death via phagocytosis is triggered by the binding of autoantibodies against platelet antigens.
• In patients with autoimmune thrombocytopenia, both IgG and IgM bind to platelets, although IgG tends to predominate. IgG autoantibodies cause the lysis of platelets in the spleen, similar to hemolytic anemias, whereas IgM autoantibodies target platelets for destruction in the liver.
• Acute autoimmune thrombocytopenia (AAT) is most prevalent in young children and young adults. In 80% of patients, a recent viral infection with EBV, rubella, varicella, or rubeola, or one of numerous respiratory viruses, has been documented.
• Indeed, the incidence of AAT coincides with that of other viral infections, peaking in the winter and spring. Symptoms are similar to those previously described for PTP, with abnormal bleeding in the skin and other mucosal surfaces serving as the defining characteristic.
• In around 90% of acute cases, symptoms disappear without treatment within six months. Although cerebral bleeding is a potentially life-threatening consequence, it occurs in less than 1% of acute cases.
• Chronic autoimmune thrombocytopenia (CAT) primarily affects adults but can also affect children older than 8 years. Although symptoms resemble those of acute AAT, the duration of this syndrome exceeds six months.
• Patients suffer from intermittent bleeding, with each episode lasting days or weeks. CAT is not related with previous viral infections, unlike AAT. When necessary, steroids are the mainstay of treatment, however splenectomy is an option if the patient does not react to drugs after many weeks.

Examples Of Type II Hypersensitivity: Cytotoxicity Against Fixed Tissues

1. Antibody-Mediated Rejection of Solid Tissue Transplants

• Graft rejection is a well-known example of type II HS against a fixed cellular target.
• HAR occurs within minutes or hours of organ donation when the recipient has preexisting alloantibodies directed against donor MHC in his or her circulation.
• Patients who have been exposed to allogeneic cells during past pregnancies, organ or bone marrow transplantation procedures, or blood transfusions are most likely to have these preexisting alloantibodies.
• As shown, during HAR, alloantibody-mediated degradation of transplanted tissue occurs rapidly and irreversibly. In variable degrees, antibody-mediated killing of fixed cells also occurs in acute humoral graft rejection and chronic graft rejection, while T cell-mediated damage is typically contemporaneous.
• These relatively delayed forms of graft rejection are thus examples of type II and type IV HS responses occurring simultaneously.

2. Goodpasture’s Syndrome

• Goodpasture’s syndrome (GS) is brought on by autoantibodies that identify the C-terminal domain of the collagen IV protein in the basement membranes of lung and kidney cells (Plate 28-4).
• These autoantibodies trigger a type II HS reaction, which destroys the epithelia and endothelia of the lungs and kidneys, resulting in pulmonary bleeding and glomerulonephritis (inflammation of the renal glomeruli).
• Nephritis is frequently severe and progressive, and, if left untreated, may culminate in renal failure within weeks. A patient suffering with both GS and a renal infection may undergo a rapid decline in kidney function within hours or days.
• Plasmapheresis, injection of cyclophosphamide, and corticosteroid therapy are typically utilised in the treatment of GS. Since the autoantibodies that cause GS are produced for a relatively short length of time, the immunosuppression essential to overcome GS is provided by a therapy term of around three months.

3. Pemphigus

• Pemphigus is an autoimmune disorder marked by potentially lethal blistering of the skin and mucous membranes. This condition is brought on by autoantibodies (often IgG or IgA) that attack the numerous cadherin-like proteins involved in epithelial cell adhesion.
• Specifically, desmoglein proteins appear to be targeted. Autoantibody binding to desmogleins causes epithelial cells to lose contact with one another and with the lamina propria, resulting in the separation of huge regions of cells (acantholysis).
• Although pemphigus mostly affects the skin, blisters can also be observed on the mucosal tissues of the mouth, nose, conjunctiva, genital region, and throat. Typically, patients are middle-aged or older.
• Systemic immunosuppression is typically necessary to treat this condition, with corticosteroids serving as the gold standard. In fact, prior to the discovery of corticosteroids, the most prevalent form of the disease (pemphigus vulgaris) was almost always fatal due to dehydration and infections caused by blistering.
• With treatment, this disease’s death rate is now below 10%. Other immunosuppressants such as azathioprine or cyclophosphamide may be beneficial in the most severe situations.
• These complexes are too big to be phagocytosed, therefore instead of being eliminated, the ICs are deposited at a single site or multiple sites throughout the body (often in the walls of vessels).
• Localized pain, edoema, and inflammation result from the presence of ICs in the tissues, which trigger immunological responses that damage neighbouring cells. Histologically, type III HS is characterised by the increase of neutrophils at the site of tissue injury 4–6 hours after antigen exposure.
• Throughout an adaptive immune response, antigen and antibody spontaneously combine to produce immune complexes. Typically, these complexes do not become big and insoluble because the Fc portions of the antibodies promote complement C1q binding.
• In addition to initiating the traditional complement cascade that results in the clearance of the antibody-bound antigen, the binding of C1q inhibits the formation of the antigen–antibody lattice. Thus, the ICs are kept at a size that is soluble in the circulation.
• When do ICs become a problem that induces hypersensitive responses? Some type III HS reactions occur when a complement deficit leads to poor clearance of immune complexes (ICs).
• In other instances, when an individual’s immune system is otherwise healthy, the sheer quantity of antibodies and antigens present may cause harmful ICs. Numerous bacteria, parasites, and viruses produce antigens that persist after the primary pathogen threat has been eliminated; these “persistent antigens” trigger type III HS reactions.
• The ICs generated by the persistent antigen and anti-pathogen antibodies circulate in the blood and are deposited in many organs, resulting in symptoms distinct from those caused by the pathogen.
• In these instances, the type III HS reaction represents a pathogen-related clinical consequence. Similarly, some cancer patients produce antibodies to tumour antigens secreted by cancer cells into the blood.
• Unless the tumour spontaneously disappears or is compelled to do so by medical intervention, exposure to these antigens is constant and relatively prolonged. Thus, ICs may develop between the antibodies and tumour antigens, causing symptoms of type III HS.
• Some medication “allergies” may be caused by type III HS responses as well. In this instance, the symptoms persist for as long as the individual’s medication creates the offending antibodies.
• Type III HS is very frequently observed in people with autoantibodies. The autoantibodies bind to particular autoantigens, which may be proteins, glycoproteins, or even DNA, that are always present. The formation of large ICs results in inflammatory autoimmunity.

Briefly describe the Pathogenesis of Type II Hypersensitivity?

Several causes can account for the binding of antibodies to host tissues. Once binding occurs, the antibody can result in a variety of pathogenic effects.

Antibody Binding

• Antibodies that bind self-antigens, commonly referred to as auto-antibodies, may be created by auto-reactive B-cells that evaded normal mechanisms of negative selection during B-cell Development, as described in Autoimmune Disease.
• Alternately, certain medicines may adsorb onto host proteins, creating unique antigenic epitopes that are identified by typically chosen B-cells, which then activate and make antibodies that bind the drug-host protein combination.

Complement Activation

• Remember that ordinarily, cross-linked antibodies trigger the Classical Pathway of the Complement Cascade. This generates the membrane-disrupting “Membrane Attack Complex” or opsonizes the material with C3, which stimulates other immune cells to phagocytose the opsonized material.
• When antibodies target host cells, complement activation can cause direct damage to the host cells and also generate powerful inflammation and phagocytic host tissue death.

Antibody-mediated Cell-mediated Cytotoxicity (ADCC)

• The Fc Region of an antibody generally engages phagocytic immune cells such as macrophages and neutrophils, which are then activated to phagocytose the opsonized material after cross-linking with antigen.
• When antibodies attack host membranes, severe inflammation and phagocytic death of host tissues may ensue.

Antibody-mediated Cellular Dysfunction

• Antibody binding frequently interferes with the normal function of the bound protein. If the host protein that the antibody targets has a significant regulatory or enzymatic function, the protein’s function may become significantly aberrant, leading to dysregulation of the host tissue.

References

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