What is Type II Hypersensitivity?

• Type II hypersensitivity, also known as cytotoxic hypersensitivity, is a type of immune response characterized by the destruction of healthy cells through antibody-mediated mechanisms. It falls under the classification system proposed by Gell and Coombs, which categorizes hypersensitivity reactions into four types. Type I, II, and III are immediate hypersensitivity reactions mediated by immunoglobulins, while Type IV is a delayed-type hypersensitivity reaction mediated by lymphoid cells.
• In Type II hypersensitivity, the immune response is primarily mediated by antibodies of the IgG or IgM classes, which are specific to one or more tissue antigens. Additionally, complement proteins, phagocytes, and K cells (natural killer cells) also play a role in this reaction. The response occurs within minutes to hours after exposure to the triggering antigen, making it an immediate hypersensitivity reaction.
• Type II hypersensitivity arises when the normal mechanisms of self-tolerance are compromised, leading to the activation of self-reactive immune cells that produce antibodies targeting antigens on host cells. These antigens can be intrinsic (endogenous), produced by the host tissue itself, or extrinsic (exogenous), referring to foreign substances attached to host tissues, such as drugs.
• In the Gell and Coombs classification, Type II hypersensitivity involves the production of IgG and IgM antibodies that specifically target antigens on cells, such as circulating red blood cells, or extracellular materials, such as the basement membrane. This antibody-antigen interaction triggers various mechanisms leading to cell lysis, tissue damage, or loss of function.
• The mechanisms involved in Type II hypersensitivity include the activation of the complement system via the classical complement pathway, antibody-dependent cellular cytotoxicity, and anti-receptor activity. Activation of the complement system results in opsonization, agglutination of red blood cells, cell lysis, and cell death.
• These reactions typically take between 2 and 24 hours to develop. The destruction of cells and tissues during Type II hypersensitivity can have significant clinical consequences, depending on the target cells involved and the affected organs or systems.

Definition of Type II Hypersensitivity

Type II hypersensitivity is an immune response characterized by the destruction of healthy cells mediated by antibodies, specifically IgG or IgM, targeting antigens on the surface of host cells. This antibody-mediated reaction can lead to cell lysis, tissue damage, or loss of function.

Mechanism of Type II Hypersensitivity

• The mechanism of Type II hypersensitivity reactions involves two phases: the sensitization phase and the effector phase.
• During the sensitization phase, antibodies are produced in response to substances or metabolites that accumulate in cellular membrane structures. These antibodies are specific to the antigens present on the surface of target cells.
• In the effector phase, the target cells become coated with these antibodies, which ultimately lead to cellular destruction. There are three main mechanisms by which the antibodies bound to surface antigens induce cell death.
• Firstly, the antibodies can bind to Fc receptors present on cells such as macrophages and neutrophils, initiating a process called antibody-dependent cell-mediated cytotoxicity (ADCC). This results in the phagocytosis of the antibody-bound cell.
• Secondly, IgG or IgM antibodies can activate the complement system via the classical pathway. This leads to the deposition of C3b, which can mediate phagocytosis by phagocytic cells. Additionally, complement activation results in the formation of the membrane attack complex (MAC), which creates pores in the cellular membrane, leading to cytolysis.
• Finally, IgG antibodies can bind to FcγRIII receptors on natural killer (NK) cells and macrophages, triggering the release of granzymes and perforin. This process induces cell death through apoptosis, known as antibody-dependent cellular cytotoxicity (ADCC).
• Alternatively, the antigen-antibody complex formed during Type II hypersensitivity may not directly cause cell lysis but instead impair the normal functioning of the cell by interrupting its receptor function. These antibodies are referred to as “antireceptor antibodies.”
• In summary, the mechanism of Type II hypersensitivity reactions involves the production of antibodies that recognize antigens on target cells, leading to cellular destruction through complement activation, ADCC, and phagocytosis. Additionally, the formation of antigen-antibody complexes can interfere with the normal functioning of cells by disrupting receptor function.

The killing of cell can occurs by one of the three mechanisms

They are-

1. Complement mediated cell lysis
2. Antibody dependent cell mediated cytotoxicity (ADCC)
3. Opsonization

1. Complement mediated lysis of cell

• Complement-mediated lysis of cells is a process in which the complement system, a group of lytic enzymes normally inactive in the blood, is activated and leads to the destruction of cells. This activation occurs when antigen-antibody complexes are formed.
• When antibodies bind to antigens, such as microorganisms or red blood cells (RBCs), they create antigen-antibody complexes. These complexes can activate the complement system through three different pathways: the classical pathway, the alternative pathway, and the lectin pathway.
• In the classical pathway, the antigen-antibody complex triggers the activation of complement enzymes. This pathway is initiated by the binding of the first component of complement, C1, to the Fc portion of the antibody in the antigen-antibody complex. This activates a cascade of complement proteins, leading to the formation of a membrane attack complex (MAC).
• The alternative pathway can be activated spontaneously or by certain molecules present on the surface of microorganisms. This pathway bypasses the antigen-antibody complex and directly activates complement enzymes. The lectin pathway is activated when specific proteins, called lectins, recognize and bind to carbohydrate molecules on the surface of microorganisms.
• Once the complement system is activated through any of these pathways, it proceeds in a cascade mechanism. Sequential activation of complement proteins leads to the formation of the MAC on the surface of the cell. The MAC creates pores or channels in the cell membrane, disrupting its integrity. This disruption allows for the influx of fluid and ions, resulting in osmotic lysis of the cell. In the case of red blood cells, this process is known as hemolysis.
• In summary, complement-mediated lysis of cells occurs when the complement system is activated by antigen-antibody complexes through various pathways. The activation of complement leads to a cascade of events that culminate in the formation of the membrane attack complex, causing cell lysis.

2. Antibody dependent cell mediated cytotoxicity (ADCC)

• Antibody-dependent cell-mediated cytotoxicity (ADCC) is a mechanism by which cytotoxic cells, such as natural killer (NK) cells and macrophages, kill target cells, such as microorganisms or red blood cells (RBCs), in the presence of specific antibodies.
• The process of ADCC begins with the binding of antibodies to antigens on the surface of target cells. The Fab portion of the antibody recognizes and binds to the antigen, while the Fc region of the antibody has receptors on cytotoxic cells. This cross-linking of the antibody-bound target cell with the cytotoxic cell promotes killing.
• Cytotoxic cells, including NK cells and macrophages, store hydrolytic and digestive enzymes. Upon contact with the target cell, these cytotoxic cells release their stored enzymes onto the surface of the target cell. The released enzymes cause damage to the target cell, leading to its destruction.
• It is important to note that the antibody itself does not directly kill or destroy the target cell. Instead, it acts as a mediator, presenting the antigen to the cytotoxic cell. The cytotoxic cell, in turn, depends on the presence of the antibody to bind to the antigen and initiate the killing process. This cooperative mechanism between the antibody and cytotoxic cells is why it is called antibody-dependent cell-mediated cytotoxicity.
• ADCC plays a crucial role in immune defense by enabling cytotoxic cells to specifically recognize and eliminate target cells that have been marked by antibodies. This mechanism is particularly important in fighting against infected cells, cancer cells, and cells coated with antibodies in certain autoimmune diseases.

3. Opsonization

• Opsonization is a process in which the binding of antibodies to antigens, such as microorganisms, red blood cells (RBCs), or target cells, enhances the rate of phagocytosis by phagocytic cells. This process is mediated by the interaction between the Fc region of antibodies and specific receptors on phagocytic cells, known as Fc receptors (FcRs).
• When an antigen enters the host body, antibodies are produced in response. The antibodies recognize and bind to the antigen through their Fab regions, leaving the Fc region free. Phagocytic cells, including neutrophils, macrophages, and monocytes, express Fc receptors on their surfaces. These Fc receptors have a high affinity for the Fc region of antibodies.
• In opsonization, the antibody molecules directly cross-link the antigen (microorganism, RBC, or target cell) with the phagocytic cells by binding to the Fc receptors. This cross-linkage activates the phagocytic cells, triggering the phagocytosis process. The engagement of the Fc receptors on phagocytic cells by the Fc region of antibodies enhances the recognition and engulfment of the target cells.
• Opsonization increases the efficiency and speed of phagocytosis by promoting the attachment and ingestion of opsonized particles by phagocytic cells. By coating the target cells with antibodies, opsonization facilitates their recognition by phagocytic cells and enhances the clearance of pathogens and cellular debris from the body.
• Overall, opsonization is an important immune mechanism that utilizes antibody-antigen interactions to enhance the recognition and engulfment of target cells by phagocytic cells, contributing to the elimination of pathogens and maintenance of immune homeostasis.

Examples of Type II Hypersensitivity

1. Rhesus incompatibility (Rh hemolytic disease)

• Rhesus incompatibility, also known as Rh hemolytic disease or Rh isoimmunization, is a condition that occurs when a Rh-negative mother becomes pregnant with a Rh-positive fetus. The Rhesus (Rh) system is a blood group system that includes the Rh antigen present on the surface of red blood cells (RBCs).
• During the first pregnancy with a Rh-positive fetus, there is a potential for the mixing of fetal Rh-positive RBCs with the mother’s Rh-negative blood. This exposure can stimulate the mother’s immune system to produce antibodies against the Rh antigen. However, in most cases, the initial pregnancy does not result in significant complications.
• The problem arises in subsequent pregnancies if the mother conceives another Rh-positive fetus. The memory response from the previous exposure triggers the production of IgG antibodies specific to the Rh antigen. These antibodies can cross the placenta and enter the fetal bloodstream.
• The Rh antibodies produced by the mother’s immune system can then attack and destroy the Rh-positive fetal erythrocytes. This immune response leads to the hemolysis, or destruction, of the fetal RBCs, causing hemolytic disease of the newborn (HDN) or erythroblastosis fetalis.
• The severity of Rh hemolytic disease can vary, ranging from mild to severe. In mild cases, the fetus may experience mild anemia, while in severe cases, it can result in significant fetal anemia, jaundice, edema, and even hydrops fetalis (excessive fluid accumulation in fetal tissues).
• To prevent Rh hemolytic disease, Rh-negative mothers who are at risk of Rh sensitization, such as those with a Rh-positive partner or a history of Rh-positive pregnancies, are typically given Rh immunoglobulin (RhIg) during pregnancy. RhIg helps prevent the mother’s immune system from producing antibodies against the Rh antigen, reducing the risk of Rh isoimmunization in future pregnancies.
• In summary, Rhesus incompatibility occurs when a Rh-negative mother carries a Rh-positive fetus. The mother’s immune system can produce antibodies against the fetal Rh antigen, leading to the destruction of fetal erythrocytes and causing hemolytic disease of the newborn. Rh immunoglobulin is commonly administered to prevent Rh sensitization in at-risk pregnancies.

2. Transfusion Reactions

• Transfusion reactions occur when incompatible blood is transfused into a recipient, leading to an immune response against the donor blood. One type of transfusion reaction can occur due to the presence of natural antibodies against major blood group antigens, namely ABO antigens (A and B).
• In individuals who lack the A antigen on their red blood cells (RBCs), they naturally produce antibodies against the A antigen, known as anti-A antibodies. Similarly, individuals lacking the B antigen on their RBCs produce anti-B antibodies. When transfused with blood that carries the corresponding antigen to which the recipient has preformed antibodies, a reaction can occur.
• When transfused erythrocytes carrying the target antigens (A or B) are exposed to the recipient’s corresponding antibodies, a process called agglutination occurs. The antibodies bind to the transfused RBCs, resulting in the clumping or agglutination of the RBCs. This can lead to a cascade of reactions, including the activation of complement proteins and subsequent destruction of the RBCs.
• The destruction of RBCs caused by the binding of natural antibodies to the transfused erythrocytes is known as hemolysis. Hemolysis refers to the rupture or lysis of RBCs, releasing their contents into the bloodstream. Massive hemolysis can occur, leading to a release of hemoglobin and its breakdown products into the circulation.
• The consequences of transfusion reactions can vary in severity, ranging from mild symptoms to life-threatening complications. Some common symptoms include fever, chills, back pain, hemoglobinuria (presence of hemoglobin in the urine), and acute kidney injury. Severe transfusion reactions can result in disseminated intravascular coagulation (DIC), kidney failure, and shock.
• To prevent transfusion reactions, careful blood typing and cross-matching are performed before transfusion to ensure compatibility between the donor and recipient. This involves testing both the donor’s and recipient’s blood for ABO blood group compatibility and for the presence of other clinically significant antigens.
• In summary, transfusion reactions can occur when natural antibodies against major blood group antigens bind to transfused erythrocytes carrying the corresponding antigens. This binding can result in agglutination and subsequent hemolysis of the transfused red blood cells. ABO blood typing and cross-m

3. Cell Destruction due to Autoantigens

• In certain autoimmune conditions, the immune system mistakenly produces antibodies that target and attack the body’s own tissues and cells. This phenomenon can lead to cell destruction due to autoantigens, where antibodies specifically recognize and bind to self-antigens, resulting in tissue-damaging reactions.
• Examples of autoimmune diseases that involve cell destruction due to autoantigens include Goodpasture’s syndrome, Myasthenia Gravis, and Autoimmune Hemolytic Anemia.
• In Goodpasture’s syndrome, antibodies are generated against the basement membranes of the lungs and kidneys. These antibodies recognize and bind to the self-antigens present in the basement membranes, triggering an immune response that results in tissue damage and inflammation in the lungs and kidneys. This can lead to symptoms such as lung hemorrhage and kidney dysfunction.
• Myasthenia Gravis is characterized by the production of antibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. These antibodies interfere with the normal functioning of the AChR, which is essential for the transmission of nerve impulses to the muscles. The binding of antibodies to the AChR disrupts this communication, resulting in muscle weakness and fatigue.
• In Autoimmune Hemolytic Anemia, antibodies are produced against erythrocytes (red blood cells). These antibodies recognize and bind to the self-antigens present on the surface of the erythrocytes, leading to their destruction. This can cause a decrease in the number of circulating red blood cells and result in anemia.
• The destruction of cells in these autoimmune conditions is primarily mediated by the binding of antibodies to their corresponding autoantigens. This interaction can trigger various immune mechanisms, including complement activation, phagocytosis by immune cells, and the recruitment of other components of the immune system. These processes collectively contribute to the destruction and damage of the targeted cells and tissues.
• Treatment approaches for cell destruction due to autoantigens in autoimmune diseases typically involve the use of immunosuppressive medications to modulate the immune response and reduce the production of autoantibodies. In some cases, specific therapies may be targeted towards neutralizing or removing the autoantibodies themselves.
• In summary, cell destruction due to autoantigens occurs when the immune system produces antibodies that target and attack the body’s own tissues and cells. This can result in tissue damage and dysfunction in autoimmune diseases such as Goodpasture’s syndrome, Myasthenia Gravis, and Autoimmune Hemolytic Anemia. Understanding the underlying mechanisms and developing targeted therapies are crucial for managing these autoimmune conditions.

4. Drug Induced Hemolytic Anemia

• Drug-induced hemolytic anemia is a condition that occurs as a result of certain drugs interacting with the surface of red blood cells (RBCs), leading to the formation of immune complexes and subsequent destruction of RBCs. This type of reaction is classified as a Type II hypersensitivity reaction.
• Certain drugs, such as penicillin, cephalosporin, and streptomycin, have the ability to bind non-specifically to proteins on the surface of RBCs. This binding forms complexes similar to hapten-carrier complexes. In some individuals, these drug-protein complexes can trigger an immune response, resulting in the production of antibodies specific to the drug.
• The antibodies produced in response to the drug-protein complexes bind to the drugs present on the surface of RBCs. This antibody-drug interaction can activate the complement system, which is a part of the immune system that plays a role in immune responses. Activation of the complement system leads to the lysis, or destruction, of the RBCs through a process called complement-mediated lysis.
• The progressive destruction of RBCs caused by the complement-mediated lysis leads to anemia, a condition characterized by a decrease in the number of circulating red blood cells. Anemia can result in symptoms such as fatigue, shortness of breath, pale skin, and rapid heartbeat.
• Drug-induced hemolytic anemia is an example of a Type II hypersensitivity reaction, also known as cytotoxic hypersensitivity. In this type of hypersensitivity reaction, antibodies directed against the drug-bound RBCs cause destruction of the cells. The reaction is mediated by antibodies of the IgG or IgM classes, and complement activation plays a significant role in the lysis of RBCs.
• Diagnosis of drug-induced hemolytic anemia involves a combination of clinical evaluation, laboratory tests, and identification of a potential association between drug exposure and the onset of anemia. Treatment typically involves discontinuation of the causative drug and supportive measures to manage anemia if necessary. In severe cases, immunosuppressive therapy may be required to suppress the immune response.
• In summary, drug-induced hemolytic anemia occurs when certain drugs form complexes with proteins on the surface of RBCs, triggering an immune response that leads to the production of antibodies. These antibodies bind to the drugs on RBCs and activate the complement system, resulting in the destruction of RBCs and the development of anemia. This condition is classified as a Type II hypersensitivity reaction. Prompt recognition and management of drug-induced hemolytic anemia are crucial to prevent complications and ensure patient well-being.

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.

FAQ

References

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