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Chapter 9 : Cytotoxic and Cytolytic Reactions

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Cytotoxic and Cytolytic Reactions, Page 1 of 2

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Abstract:

Cytotoxic or cytolytic reactions occur when antibody reacts with either an antigenic component of a cell membrane or an antigen that has become intimately associated with a cell. The reaction of antibody with the cell activates two complement-mediated pathways of cell death or lysis: (i) activation of the complete cascade with insertion of membrane attack complexes and lysis of the target cell, or (ii) aggregated immunoglobulin Fc and/or C3b receptor binding produces “immune adherence” of antibody-coated cells to phagocytic cells and phagocytosis. Antibody-mediated cytolytic reactions are protective when the affected cell is an invading organism but destructive when it occurs to an individual's own blood cells. Cytotoxic or cytolytic reactions are initiated by immunoglobulin M (IgM) or those IgG immunoglobulin subclasses that have the capacity to activate complement. The cells usually affected are circulating blood cells: red blood cells (RBCs, erythrocytes), white blood cells, and platelets. The resulting diseases are hemolytic anemia, agranulocytosis, and thrombocytopenia; they are grouped together as immunohematologic diseases. Disease conditions arising from the immune destruction of RBCs result from loss of erythrocyte function, from the damaging effects of the released cell contents, and from toxic effects due to antigen-antibody complexes formed. These disorders include transfusion reactions, erythroblastosis fetalis, acquired autoimmune hemolytic diseases, hemolytic reactions to drugs, and some infectious diseases, such as malaria. The role of cytotoxic reactions in malaria is summarized in this chapter.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.1
Figure 9.1

Cytotoxic or cytolytic reactions. These reactions most often affect cellular elements in intimate contact with circulating plasma, such as erythrocytes, leukocytes, or platelets. Circulating humoral antibody reacts with antigens present on cell membranes. In vitro, through action of the complement system, the integrity of cell membrane is compromised and the cell is lysed. The osmotic difference in intracellular and extracellular fluids causes release of intracellular fluids. In vivo, the cells coated with immunoglobulin antibody or complement are subject to phagocytosis and sequestration in the spleen and liver.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.2
Figure 9.2

Experimental model of acute hemolytic reaction. (i) Rat red blood cells (RBCs) are injected into a rabbit to produce antibodies to rat RBCs. (ii) In vitro, this antiserum will lyse rat RBCs in the presence of complement. If the antiserum is decomplemented, agglutination of the cells, but not lysis, occurs. (iii) In vivo injection of the rabbit anti-rat RBC serum into rats results in a rapid drop in the hematocrit (the percentage of the blood made up of red cells) and increasing red color in the plasma due to hemoglobin released from destroyed cells. Death of the injected rat occurs at doses sufficient to reduce the hematocrit below 20%. In the dead rat, the organs are congested with RBCs, particularly the liver and spleen.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.3
Figure 9.3

Hemolytic reactions. Shown are four types of hemolytic reactions caused by antibody-mediated complement activation in relation to the origin of the antibody and the source of the antigen. (I) Transfusion reactions (exogenous antigen and endogenous antibody). Erythrocytes from a donor (A+) that are antigenic for a recipient whose serum contains antibody to the donor's erythrocyte antigen (O anti-A) will be lysed upon transfusion, resulting in release of hemoglobin and a clinical syndrome known as a transfusion reaction. (II) Erythroblastosis fetalis (endogenous antigen and exogenous antibody). Rh+ erythrocytes cross the placenta and stimulate the production of antibody to Rh if the mother is not Rh+. These antibodies will cross back through the placenta to attack fetal erythrocytes. (III) Autoimmune hemolytic anemia (endogenous antigen and endogenous antibody). An individual becomes sensitized to the antigens of his or her own erythrocytes (autoantibody). (IV) Reverse transfusion reaction (endogenous antigen and exogenous antibody). Antibodies are transfused from a donor to a recipient whose red cells contain the antigen. This passively transferred antibody causes lysis of recipient red cells.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.4
Figure 9.4

Chemistry of the ABO blood group system. ABO blood group identification depends upon the presence of carbohydrate antigenic specificities on surfaces of red cells. Blood group characteristics are inherited according to simple Mendelian laws. ABO blood group antigens have been characterized by analysis of purified blood group substances. They contain about 85% carbohydrate and 15% amino acids. The peptide component contains 15 amino acids and is the same for each blood group substance. Antigenic specificity is determined by carbohydrate structures and linkages. Individuals with type O blood who do not have A or B group specificity have a specificity now recognized as H, which consists of three sugar groups attached to a peptide. Addition of a fourth sugar group to the basic H structure produces A or B specificity. If the additional sugar is O-α--galactose, specificity is B; if it is O-α-N-acetyl-D-galactose, specificity is A. Formation of H substance is controlled by a pair of alleles, H and h. H gene gives rise to production of H specificity. H-active material is converted to A- or B-activate substances under the influence of galactosyl transferases determined by the A or B genes. Rare individuals lack A, B, and H reactivity, presumably because of an inability to form normal precursor for H substance. (Modified from W. M. Watkins, Science 152:172, 1966.)

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Figure 9.5

Erythroblastosis fetalis. During the first pregnancy of an Rh- mother carrying an Rh+ fetus, sensitization occurs during delivery when immunizing numbers of fetal RBC enter the maternal circulation. During subsequent pregnancies of a sensitized mother carrying an Rh+ fetus, anti-Rh antibodies may cross the placenta and react with fetal RBCs. During the first pregnancy, small numbers of Rh+ fetal erythrocytes, usually insufficient for sensitization, cross the placenta. However, at delivery, a substantial number of Rh+ erythrocytes are released into maternal circulation. In a small percentage of Rh-incompatible pregnancies, this is sufficient to immunize the mother if the mother is not treated with passively administered anti- Rh antibody. During a second pregnancy, the small number of erythrocytes that reach the maternal circulation will induce a secondary antibody response in the mother to the Rh antigen. The maternal antibody is IgG and crosses the placenta to the fetus, where it acts on fetal erythrocytes, causing their destruction.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.6
Figure 9.6

Prevention of Rh immunization by passive antibody. (Top) Naturally occurring situation when an ABO and Rh incompatibility are combined; sensitization of the mother to Rh+ antigens is significantly less than when there is an Rh incompatibility but no ABO incompatibility. The presence of antibody to fetal red cell A+ antigen in the non-A mother prevents sensitization to the Rh+ antigen, whereas the mother with no anti-A becomes sensitized to the Rh system. This observation was used as a rationale for passively transferring antibody to Rh to mothers who were Rh- and were carrying an Rh+ fetus. (Bottom) Administration of anti-Rh at delivery significantly reduces the incidence of sensitization of the mother to the Rh system; erythroblastosis fetalis has thus become a preventable disease through the application of immunoprophylaxis.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.7
Figure 9.7

Mechanisms of drug-induced hemolytic drug reactions. (See text for details.)

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.8
Figure 9.8

Coombs' antiglobulin tests. Coombs' test for incomplete antibody to erythrocytes is carried out in two forms: direct and indirect. In the direct test, cells taken from the patient are coated with antibody in vivo and are agglutinated by the addition of anti-Ig, which reacts with the antibodies coating the cells. In the indirect test, the patient's serum contains free antibody that binds to but does not agglutinate erythrocytes added in vitro. Agglutination is accomplished by addition of a second antibody, which reacts with the first antibody (anti-Ig).

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.9
Figure 9.9

Immune mechanisms in malaria. Malaria is transmitted from the salivary glands of a mosquito to the blood of an animal by sporozoites that enter host liver cells and develop into intracellular stages. Merozoites are released into the circulation and reinfect other liver cells and RBCs. Micro- and macrogametes are produced and are taken up by mosquitoes, where they develop after fusion of micro- and macrogametes and formation of an oocyst in the stomach into sporozoites. Malaria antigens are found not only in organisms but also on the surface of infected cells. Antibodies to these antigens are able to lyse organisms or infected cells, producing anemia or liver cell necrosis. Soluble antibody-antigen complexes formed may produce immune complex lesions (glomerulonephritis). The production of large numbers of opsonized red cells and particulate antigen results in accumulation of phagocytosed material in macrophages (hemozoin pigment), reticuloendothelial blockade, and immune dysfunction. Malarial organisms are able to change antigens expressed on the cell surface, avoid destruction by antibody, and set up another cycle of infection (antigenic variation). Protective immunity may be effected by antibodies to sporozoites, which prevent infection. Protective immunity could be mediated by antibody directed to extracellular stages [(i) sporozoites, (ii) merozoites, or (iii) zygotes] or by TCTL cells directed to infected hepatocytes.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.10
Figure 9.10

TCTL-cell immunity in malaria. Sporozoite antigen is presented to TCTL-cell precursors complexed to class I major histocompatibility complex cell surface markers on infected hepatocytes, leading to the proliferation of a population of TCTL cells that can recognize and destroy hepatocytes expressing sporozoite antigens. Since the sporozoite antigen is expressed before infective merozoites are released, preexisting specific TCTL cells may be able to destroy infected cells before systemic infection is established or prevent spread of infection from liver cells to RBCs.

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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Image of Figure 9.11
Figure 9.11

(A) Circumsporate protein of the malaria parasite. The middle third of the protein contains a set of repetitions of two short sequences of amino acids (Asn-Ala-Asn-Pro or Asn-Val-Asp-Pro), as well as a polymorphic region (Th2R) and two pairs of cysteine residues. Hydrophobic regions at the C terminus may anchor the protein in the plasma membrane of the sporozoite. The repetitive sequences constitute epitopes that are recognized by all known antibodies against Plasmodium strains. (B) Multiple-antigen peptide is a synthetic molecule in which a lysine core provides “mooring posts” for B-cell epitopes that can be processed by macrophages for presentation to T cells. In this example, all eight arms of the lysine core hold the same B-cell epitope (Asn-Ala-Asn-Pro). (Modified from V. Nussenzweig and R. S. Nussenzweig, Hosp. Pract. 25:41, 1990.)

Citation: Sell S. 2001. Cytotoxic and Cytolytic Reactions, p 276-301. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch9
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