Hypersensitivity (Type II)

Chapter 24 Hypersensitivity (Type II)





Mechanisms of tissue damage


Type II hypersensitivity reactions are mediated by IgG and IgM antibodies binding to specific cells or components of the extracellular matrix. The damage caused is therefore restricted to the specific cells or tissues bearing the antigens. In general:



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).



Once the antibody has attached itself to the surface of the cell or tissue, it can bind and activate complement component C1, with the following consequences:



Effector cells – in this case macrophages, neutrophils, eosinophils, and NK cells – bind to either:



The mechanisms by which these antibodies trigger cytotoxic reactions in vivo have been investigated in FcR-deficient mice. Anti-red blood cell antibodies trigger erythrophagocytosis of IgG-opsonized red blood cells in an FcR-dependent manner. Fc receptor γ chain-deficient mice were protected from the pathogenic effect of these antibodies whereas complement-deficient mice were indistinguishable from wild-type animals in their ability to clear the targeted red cells.




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).


If the target is too large to be phagocytosed, the granule and lysosome contents are released in apposition to the sensitized target in a process referred to as exocytosis. Cross-linking of the Fc and C3 receptors during this process causes activation of the phagocyte with production of reactive oxygen intermediates, as well as activation of phospholipase A2 with consequent release of arachidonic acid from membrane phospholipids.



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).



Antibodies may also mediate hypersensitivity by NK cells. In this case, however, the nature of the target, and whether it can inhibit the NK cells’ cytotoxic actions, are as important as the presence of the sensitizing antibody.


The resistance of a target cell to damage varies. Susceptibility depends on:



For example, an erythrocyte may be lysed by a single active C5 convertase site, whereas it takes many such sites to destroy most nucleated cells – their ion-pumping capacity and ability to maintain membrane integrity with anti-complementary defenses is so much greater.



We now examine some instances where type II hypersensitivity reactions are thought to be of prime importance in causing target cell destruction or immunopathological damage.



Type II reactions against blood cells and platelets


Some of the most clearcut examples of type II reactions are seen in the responses to erythrocytes. Important examples are:



Reactions to platelets can cause thrombocytopenia, and reactions to neutrophils and lymphocytes have been associated with systemic lupus erythematosus (SLE).



Transfusion reactions occur when a recipient has antibodies against donor erythrocytes


More than 20 blood group systems, generating over 200 genetic variants of erythrocyte antigens, have been identified in humans.


A blood group system consists of a gene locus that specifies an antigen on the surface of blood cells (usually, but not always, erythrocytes).


Within each system there may be two or more phenotypes. In the ABO system, for example, there are four phenotypes (A, B, AB, and O), and therefore four possible blood groups.


An individual with a particular blood group can recognize erythrocytes carrying allogeneic (non-self) blood group antigens, and will produce antibodies against them. However, for some blood group antigens such antibodies can also be produced ‘naturally’ (i.e. without previous sensitization by foreign erythrocytes).


Some blood group systems (e.g. ABO and Rhesus) are characterized by antigens that are relatively strong immunogens; such antigens are more likely to induce antibodies.


When planning a blood transfusion, it is important to ensure that donor and recipient blood types are compatible with respect to these major blood groups, otherwise transfusion reactions will occur.


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).



Most individuals develop antibodies to allogeneic specificities of the ABO system without previous sensitization by foreign erythrocytes. This sensitization occurs through contact with identical epitopes, coincidentally expressed on a wide variety of microorganisms.


Antibodies to ABO antigens are therefore extremely common, making it particularly important to match donor blood to the recipient for this system. However, all people are tolerant to the O antigen, so O individuals are universal donors with respect to the ABO system.



Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Hypersensitivity (Type II)

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