Hypersensitivity (Type II)

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 18/02/2015

Print this page

This article have been viewed 3581 times

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

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:

• 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).

Fig. 24.1 Antibody-dependent cytotoxicity

Effector cells – K cells, platelets, neutrophils, eosinophils, and cells of the mononuclear phagocyte series – all have receptors for Fc, which they use to engage antibody bound to target tissues. Activation of complement C3 can generate complement-mediated lytic damage to target cells directly, and also allows phagocytic cells to bind to their targets via C3b, C3bi, or C3d, which also activate the cells. (MAC, membrane attack complex.)

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:

• 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).

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.

Q. How do you interpret this observation?

A. These experiments indicate that phagocytosis of antibody-sensitized red cells depends on FcR-mediated binding to the phagocytes and is not dependent on opsonization by C3b deposited via the classical pathway.

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).

Fig. 24.2 Damage mechanisms

Neutrophil-mediated damage is a reflection of normal antibacterial action. (1) Neutrophils engage microbes with their Fc and C3 receptors. (2) The microbe is then phagocytosed and destroyed as lysosomes fuse to form the phagolysosome (3). In type II hypersensitivity reactions, individual host cells coated with antibody may be similarly phagocytosed, but where the target is large, for example a basement membrane (I), the neutrophils are frustrated in their attempt at phagocytosis (II). They exocytose their lysosomal contents, causing damage to cells in the vicinity (III).

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.

Q. What inflammatory mediators are synthesized from arachidonic acid?

A. This metabolite is the precursor of eicosanoids – prostaglandins and leukotrienes.

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).

Fig. 24.3 Phagocytes attacking a basement membrane

This electron micrograph shows a neutrophil (N) and three monocytes (M) binding to the capillary basement membrane (B) in the kidney of a rabbit containing anti-basement membrane antibody. × 3500. (P, podocyte.)

(Courtesy of Professor GA Andres.)

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:

• the amount of antigen expressed on the target cell’s surface; and

• the inherent ability of different target cells to sustain damage.

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.

Q. What molecules protect the surface of nucleated cells from complement-mediated damage?

A. Decay accelerating factor (CD55) and CD59.

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:

• 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.

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.

Fig. 24.4 Five major blood group systems involved in transfusion reactions

Not all blood groups are equally antigenic in transfusion reactions – thus RhD evokes a stronger reaction in an incompatible recipient than the other Rhesus antigens; and Fy^a is stronger than Fy^b. Frequencies stated are for Caucasian populations – other races have different gene frequencies.

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).

Fig. 24.5 ABO blood group antigens

The diagram shows how the ABO blood groups are constructed. The enzyme produced by the H gene attaches a fucose residue (Fuc) to the terminal galactose (Gal) of the precursor oligosaccharide. Individuals possessing the A gene now attach N-acetylgalactosamine (NAGA) to this galactose residue, whereas those with the B gene attach another galactose, producing A and B antigens, respectively. People with both genes make some of each. The table indicates the genotypes and antigens of the ABO system. Most people naturally make antibodies to the antigens they lack. (NAG, N-acetylglucosamine.)

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.

The Rhesus system is a major cause of hemolytic disease of the newborn

The Rhesus system is also of great importance because it is a major cause of hemolytic disease of the newborn (HDNB).

Rhesus antigens are associated with membrane proteins of 30 kDa, which are expressed at moderate levels on the erythrocyte surface. The antigens are encoded by two closely linked loci, RhD and RhCcEe, with 92% homology.

RhD is the most important clinically due to its high immunogenicity, but in RhD^– individuals the RhD locus is missing completely. The RhCcEe locus encodes a molecule that expresses the RhC/c and RhE/e epitopes.

Transfusion reactions can be caused by minor blood groups

A number of minor antigens can also induce transfusion reactions, but there is generally only a signficant risk if the person has been sensitized by previous blood transfusions.

MN system epitopes are expressed on the N-terminal glycosylated region of glycophorin A, a glycoprotein present on the erythrocyte surface. Antigenicity is determined by polymorphisms at amino acids 1 and 5.

The related Ss system antigens are carried on glycophorin B.

Proteins expressed on erythrocytes that display allelic variation can also act as blood group antigens. Examples of these include:

• the Kell antigen, a zinc endopeptidase;

• the Duffy antigen receptor for chemokines (DARC); and

• variants of decay accelerating factor (DAF).

The relationship of the blood groups to erythrocyte surface proteins is listed in Figure 24.w1.

Fig. 24.w1 Erythrocyte blood group antigens

Buy Membership for Allergy and Immunology Category to continue reading. Learn more here

Related

Immunology With Student Consult 8e