Type II (Cytotoxic) Hypersensitivity- Mechanism and Examples

Type II hypersensitivity reactions are also known as cytotoxic or antibody-mediated reactions. They involve the binding of antibodies to antigens on the surface of cells or tissues, leading to their destruction or dysfunction. The antibodies involved are usually of the IgG or IgM class, and they can activate the complement system or recruit other immune cells to cause damage. Type II hypersensitivity reactions can occur in various clinical settings, such as transfusion reactions, hemolytic disease of the newborn, autoimmune diseases, and drug-induced hemolytic anemia. In this article, we will explain the mechanism and examples of type II hypersensitivity reactions in detail.

The sensitization phase is the first step in type II hypersensitivity reactions. It occurs when an individual is exposed to an antigen that triggers an immune response. The antigen can be a foreign substance, such as a blood group antigen or a drug metabolite, or a self-antigen that is modified or expressed abnormally. The antigen binds to the surface of a cell, such as an erythrocyte, a platelet, or a tissue cell, and acts as a target for the immune system.

The sensitization phase involves the activation of B cells that recognize the antigen and produce antibodies against it. The antibodies belong to the IgG or IgM class and have high affinity and specificity for the antigen. The antibodies circulate in the blood and can bind to the antigen on the surface of the target cells. This leads to the formation of antigen-antibody complexes that mark the cells for destruction. The sensitization phase can take days or weeks to develop and depends on the dose and frequency of exposure to the antigen.

The sensitization phase sets the stage for the effector phase, which is responsible for the actual damage to the target cells. The effector phase can occur immediately after the sensitization phase or after a latent period of variable duration. The effector phase involves different mechanisms of cell death that are mediated by the antibodies and other components of the immune system. These mechanisms will be explained in detail in the next point.

The effector phase of type II hypersensitivity reactions occurs when antibodies bind to the antigens on the surface of target cells and trigger various mechanisms of cell destruction. The antibodies involved are usually IgG or IgM, which can activate the complement system, recruit phagocytic cells, or induce apoptosis. The effector phase can be divided into three subtypes based on the mechanism of cell death:

• Complement-mediated cytotoxicity: This occurs when antibodies activate the classical pathway of complement, leading to the formation of membrane attack complex (MAC) that creates pores in the cell membrane and causes osmotic lysis. The complement fragments C3b and C4b also act as opsonins that enhance phagocytosis by macrophages and neutrophils. Examples of diseases caused by this mechanism include hemolytic anemia, transfusion reactions, and hemolytic disease of the newborn.
• Antibody-dependent cell-mediated cytotoxicity (ADCC): This occurs when antibodies bind to Fc receptors on natural killer (NK) cells or macrophages and trigger the release of cytotoxic granules that contain perforin and granzymes. Perforin forms pores in the cell membrane and allows granzymes to enter and induce apoptosis. Examples of diseases caused by this mechanism include chronic granulomatous disease, autoimmune thyroiditis, and viral hepatitis.
• Opsonization and phagocytosis: This occurs when antibodies bind to Fc receptors on macrophages or neutrophils and facilitate the ingestion and degradation of target cells. Examples of diseases caused by this mechanism include bacterial infections, systemic lupus erythematosus, and rheumatoid arthritis.

The effector phase of type II hypersensitivity reactions can also impair the normal function of target cells without causing cell death. This happens when antibodies bind to cell surface receptors and interfere with their signaling or activity. These antibodies are called antireceptor antibodies and can cause diseases such as myasthenia gravis, Graves` disease, and insulin-resistant diabetes.

Antibody bound to a cell-surface antigen can induce death of the antibody-bound cell by three distinct mechanisms:

• Complement activation: IgG or IgM antibodies can activate the complement system via the classical pathway, leading to the formation of membrane attack complex (MAC) that creates pores in the cell membrane and causes cytolysis. Complement activation also results in the deposition of C3b on the cell surface, which acts as an opsonin and facilitates phagocytosis by macrophages and neutrophils.
• Antibody-dependent cellular cytotoxicity (ADCC): IgG antibodies can bind to Fc receptors (FcγRIII) on natural killer (NK) cells and macrophages, triggering the release of cytotoxic granules that contain perforin and granzymes. Perforin forms pores in the cell membrane, allowing granzymes to enter and induce apoptosis.
• Opsonization and phagocytosis: IgG or IgM antibodies can bind to Fc receptors (FcγRI or FcγRII) on macrophages and neutrophils, enhancing the uptake and destruction of the antibody-coated cells.

These mechanisms can result in tissue damage and loss of function in various organs and systems. Some examples of diseases caused by type II hypersensitivity reactions are discussed below.

Antireceptor antibodies are a type of autoantibodies that bind to specific receptors on the surface of target cells and interfere with their normal function. Antireceptor antibodies can cause either stimulation or inhibition of the receptor-mediated signaling, depending on the nature and location of the receptor.

Some examples of antireceptor antibodies are:

• Anti-acetylcholine receptor (AChR) antibodies: These antibodies bind to the AChR on the postsynaptic membrane of neuromuscular junctions and block the binding of acetylcholine, a neurotransmitter that stimulates muscle contraction. This leads to muscle weakness and fatigue, a condition known as myasthenia gravis.
• Anti-TSH receptor antibodies: These antibodies bind to the thyroid-stimulating hormone (TSH) receptor on the thyroid gland and mimic the action of TSH, causing excessive production of thyroid hormones. This leads to hyperthyroidism, a condition characterized by increased metabolism, weight loss, nervousness, and heat intolerance. This condition is also called Graves` disease.
• Anti-insulin receptor antibodies: These antibodies bind to the insulin receptor on various cells and either block or enhance the binding of insulin, a hormone that regulates glucose uptake and metabolism. This leads to either insulin resistance or hypoglycemia, depending on whether the antibodies inhibit or stimulate the receptor. Insulin resistance can cause type 2 diabetes mellitus, while hypoglycemia can cause seizures, coma, and death.
• Anti-platelet antibodies: These antibodies bind to various receptors on platelets, such as glycoprotein IIb/IIIa, and either activate or inhibit platelet aggregation. This leads to either thrombosis or bleeding, depending on whether the antibodies induce or prevent clot formation. Thrombosis can cause stroke, heart attack, and pulmonary embolism, while bleeding can cause hemorrhage and anemia.

Antireceptor antibodies can be detected by various methods, such as radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), and immunoprecipitation (IP). The treatment of antireceptor antibody-mediated diseases depends on the type and severity of the condition but may include immunosuppressive drugs, plasmapheresis, intravenous immunoglobulin (IVIG), and monoclonal antibody therapy.

Rhesus incompatibility (Rh hemolytic disease) is a type of type II hypersensitivity reaction that occurs when a pregnant woman who is Rh-negative carries a fetus who is Rh-positive. The Rh factor is an antigen that is present on the surface of red blood cells (RBCs) in most people. People who have the Rh factor are called Rh-positive, and those who do not have it are called Rh-negative.

The first pregnancy of an Rh-negative woman with an Rh-positive fetus usually does not cause any problems because the maternal and fetal blood do not mix much during pregnancy. However, during delivery, some of the fetal blood may enter the maternal circulation and expose the mother to the Rh antigen. This can trigger an immune response in the mother, who may produce antibodies against the Rh antigen. These antibodies are of the IgG class, which can cross the placenta and reach the fetal blood.

In subsequent pregnancies, if the mother conceives another Rh-positive fetus, the maternal anti-Rh antibodies can bind to the fetal RBCs and cause their destruction. This can lead to hemolytic disease of the newborn (HDN), a condition characterized by anemia, jaundice, edema, and sometimes death in severe cases. The risk of HDN increases with each subsequent pregnancy with an Rh-positive fetus.

Rhesus incompatibility can be prevented by administering anti-Rh immunoglobulin (RhIg) to the mother within 72 hours after the delivery of an Rh-positive baby. This can prevent the mother from developing anti-Rh antibodies and protect future pregnancies from HDN. RhIg can also be given to the mother after a miscarriage, abortion, or ectopic pregnancy involving an Rh-positive fetus.

Rhesus incompatibility is an example of how antibodies can cause cell destruction by activating complement and inducing phagocytosis. It also illustrates how maternal-fetal immunological interactions can affect the health of both the mother and the baby.

Transfusion reactions are a type of type II hypersensitivity reaction that occurs when a person receives blood that is incompatible with their own blood type. The most common cause of transfusion reactions is mismatched ABO blood group antigens. A person`s blood type is determined by the presence or absence of two antigens, A and B, on the surface of their red blood cells (RBCs). A person can have one of four blood types: A, B, AB, or O. A person also has antibodies in their plasma that recognize and bind to the antigens that they do not have on their own RBCs. For example, a person with blood type A has anti-B antibodies, and a person with blood type O has both anti-A and anti-B antibodies.

When a person receives blood that has antigens that are different from their own, their antibodies will bind to the foreign RBCs and activate the complement system. This leads to hemolysis, or the destruction of the RBCs, and the release of hemoglobin and other substances into the bloodstream. Hemolysis can cause various symptoms and complications, such as fever, chills, nausea, vomiting, pain, jaundice, kidney failure, shock, and even death.

To prevent transfusion reactions, blood donors and recipients are carefully matched for their ABO and Rh blood types. Rh is another antigen that can cause transfusion reactions if it is present on the donor RBCs but not on the recipient`s. Rh incompatibility can also cause hemolytic disease of the newborn (HDN), as discussed in point 6. In addition to ABO and Rh typing, other minor blood group antigens are also screened for compatibility before transfusion.

Transfusion reactions are an example of how type II hypersensitivity reactions can have serious consequences for human health. They illustrate how antibodies can mediate cell destruction by activating the complement system and causing hemolysis. They also show how important it is to match blood types before transfusion to avoid adverse reactions.

Drug-induced hemolytic anemia is a type of type II hypersensitivity reaction that occurs when certain drugs bind to the surface of red blood cells and trigger an immune response against them. The drugs act as haptens, which are small molecules that can elicit an immune response only when attached to a larger carrier protein. The drugs bind to red blood cell membrane proteins and form drug-protein complexes that are recognized as foreign by the immune system. The antibodies produced against these complexes can cause red blood cell destruction by different mechanisms, such as complement activation, phagocytosis, or ADCC.

Some examples of drugs that can cause drug-induced hemolytic anemia are:

• Penicillin and related antibiotics: These drugs can bind covalently to red blood cell membrane proteins and induce IgG-mediated hemolysis. The antibodies can also cross-react with platelets and cause thrombocytopenia.
• Cephalosporin and related antibiotics: These drugs can bind non-covalently to red blood cell membrane proteins and induce IgM-mediated hemolysis. The antibodies can activate complement and cause intravascular hemolysis.
• Quinidine and related anti-malarial drugs: These drugs can bind non-covalently to red blood cell membrane proteins and induce IgG-mediated hemolysis. The antibodies can also cross-react with other tissues and cause systemic lupus erythematosus-like symptoms.
• Methyldopa and related anti-hypertensive drugs: These drugs can induce autoantibodies against the Rh antigen on red blood cells and cause IgG-mediated hemolysis. The antibodies can also cross-react with other tissues and cause hemolytic anemia with a positive direct antiglobulin test (DAT).

The diagnosis of drug-induced hemolytic anemia is based on the clinical history, laboratory tests, and drug withdrawal. The laboratory tests include a complete blood count (CBC), peripheral blood smear, serum bilirubin, lactate dehydrogenase (LDH), haptoglobin, reticulocyte count, and DAT. The DAT detects the presence of antibodies or complement on the surface of red blood cells. A positive DAT indicates that the red blood cells are coated with immune complexes and are prone to hemolysis.

The treatment of drug-induced hemolytic anemia involves stopping the offending drug, transfusing compatible blood if needed, and administering corticosteroids or immunosuppressive agents in severe cases. The prognosis depends on the severity of the hemolysis, the underlying condition of the patient, and the response to treatment.

Drug-induced hemolytic anemia (DIHA) is a rare but serious condition that occurs when a drug triggers the immune system to attack the red blood cells (RBCs), causing them to break down prematurely. This leads to anemia, jaundice, and sometimes kidney failure or shock.

There are different types of DIHA, depending on the mechanism of the drug-induced antibody formation and the type of antibody involved. The most common types are:

• Drug-dependent antibodies: These antibodies can only bind to RBCs in the presence of the drug or its metabolite. They can be IgG, IgM, or IgA and can activate complement or cause phagocytosis or antibody-dependent cellular cytotoxicity (ADCC). Examples of drugs that can cause this type of DIHA are penicillin, cephalosporins, quinine, and quinidine.
• Drug-independent antibodies: These antibodies can bind to RBCs even in the absence of the drug. They are usually IgG and can cause extravascular hemolysis by phagocytosis or ADCC. Examples of drugs that can cause this type of DIHA are methyldopa, levodopa, and procainamide.
• Autoimmune hemolytic anemia: Some drugs can induce autoantibodies that react with RBCs regardless of the drug exposure. They are usually IgG and can cause warm autoimmune hemolytic anemia (WAIHA) or cold agglutinin disease (CAD). Examples of drugs that can cause WAIHA are fludarabine, oxaliplatin, and immune checkpoint inhibitors. Examples of drugs that can cause CAD are interferon-alpha, rituximab, and nivolumab.

The diagnosis of DIHA is based on clinical history, laboratory tests, and direct antiglobulin test (DAT). The DAT detects antibodies or complement components on the surface of RBCs. A positive DAT indicates immune-mediated hemolysis, but it does not identify the specific drug or antibody involved. Therefore, additional tests may be needed to confirm the diagnosis, such as elution studies, drug-dependent antibody tests, or drug-independent antibody tests.

The treatment of DIHA depends on the severity of hemolysis and the type of antibody involved. The mainstay of treatment is to stop the offending drug and provide supportive care, such as transfusions, fluids, and steroids. In some cases, immunosuppressive agents, plasma exchange, or splenectomy may be required. The prognosis of DIHA varies depending on the underlying cause and the response to treatment.

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