Chapter 24 Hypersensitivity (Type II)
• Type II hypersensitivity is mediated by antibodies binding to specific cells. Type II hypersensitivity reactions are caused by IgG, IgA, or IgM antibodies against cell surface and extracellular matrix antigens. The antibodies damage cells and tissues by activating complement, and by binding and activating effector cells carrying Fc γ receptors.
• Red blood cells (blood groups) must be cross-matched for transfusion. Transfusion reactions to erythrocytes are produced by antibodies to blood group antigens, which may occur naturally or may have been induced by previous contact with incompatible tissue or blood following transplantation, transfusion, or during pregnancy.
• Hemolytic disease of the newborn occurs when maternal antibodies to fetal blood group antigens cross the placenta and destroy the fetal erythrocytes.
• Type II hypersensitivity reactions may target tissues. Damage to tissues may be produced by autoantibodies to extracellular matrix, cell surface molecules, or intracellular proteins. Examples of diseases caused by these mechanisms are myasthenia gravis, pemphigus, and Goodpasture’s syndrome.
• The role of autoantibodies in disease is not always clear. Antibodies to intracellular components are not necessarily pathogenic, but they may be diagnostically useful.
Mechanisms of tissue damage
• antibodies directed against cell surface antigens are usually pathogenic;
• antibodies directed against internal antigens are usually not pathogenic.
Type II reactions therefore differ from type III reactions, which involve antibodies directed against soluble antigens in the serum, leading to the formation of circulating antigen–antibody complexes. Damage occurs when the complexes are deposited non-specifically onto tissues and/or organs (see Chapter 25).
Effector cells engage their targets using Fc and C3 receptors
In type II hypersensitivity, antibody directed against cell surface or tissue antigens interacts with the Fc receptors (FcR) on a variety of effector cells and can activate complement to bring about damage to the target cells (Fig. 24.1).
• complement fragments (C3a and C5a) generated by activation of complement attract macrophages and polymorphs to the site, and also stimulate mast cells and basophils to produce chemokines that attract and activate other effector cells;
• the classical complement pathway and activation loop lead to the deposition of C3b, C3bi, and C3d on the target cell membrane;
• the classical complement pathway and lytic pathway result in the production of the C5b–9 membrane attack complex (MAC) and insertion of the complex into the target cell membrane.
Effector cells – in this case macrophages, neutrophils, eosinophils, and NK cells – bind to either:
• the complexed antibody via their Fc receptors; or
• the membrane-bound C3b, C3bi, and C3d, via their C3 receptors (CR1, CR3, CR4).
Cells damage targets by releasing their normal immune effector molecules
The mechanisms by which neutrophils and macrophages damage target cells in type II hypersensitivity reactions reflect their normal methods of dealing with infectious pathogens (Fig. 24.2).
Normally pathogens would be internalized and then subjected to a barrage of microbicidal systems including defensins, reactive oxygen and nitrogen metabolites, hypohalites, enzymes, altered pH, and other agents that interfere with metabolism (see Chapters 7 and 14).
In some situations, such as the eosinophil reaction against schistosomes (see Chapter 15), exocytosis of granule contents is normal and beneficial. However, when the target is host tissue that has been sensitized by antibody, the result is damaging (Fig. 24.3).
The resistance of a target cell to damage varies. Susceptibility depends on:
• the amount of antigen expressed on the target cell’s surface; and
• the inherent ability of different target cells to sustain damage.
Type II reactions against blood cells and platelets
• incompatible blood transfusions, where the recipient becomes sensitized to antigens on the surface of the donor’s erythrocytes;
• hemolytic disease of the newborn, where a pregnant woman has become sensitized to the fetal erythrocytes;
• autoimmune hemolytic anemias, where the patient becomes sensitized to his or her own erythrocytes.
Transfusion reactions occur when a recipient has antibodies against donor erythrocytes
Some major human blood groups are listed in Figure 24.4.
The ABO blood group system is of primary importance
The epitopes of the ABO blood group system occur on many cell types in addition to erythrocytes and are located on the carbohydrate units of glycoproteins. The structure of these carbohydrates, and of those determining the related Lewis blood group system, is determined by genes coding for enzymes that transfer terminal sugars to a carbohydrate backbone (Fig. 24.5).
Transfusion reactions can be caused by minor blood groups
The related Ss system antigens are carried on glycophorin B.
The relationship of the blood groups to erythrocyte surface proteins is listed in Figure 24.w1.