IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 24. Hypersensitivity - Type II

REACTIONS AGAINST TISSUE ANTIGENS

There are A number of autoimmune diseases in which autoantibodies directed against tissue Antigens damage Tissues via type II hypersensitivity mechanisms. In these cases, the antigens are located extracellularly, specifically on structural tissue Proteins or on The Cell surface. Examples of such conditions—Goodpasture's syndrome, Pemphigus, and myasthenia gravis—are discussed below.

Antibodies against intracellular antigens of various Cells can also frequently be detected, but their role in type II hypersensitivity mechanisms is less well understood. In such instances, the interaction of the antigen with T cells is likely of greater importance, with autoantibodies being formed secondarily.

Goodpasture's nephritis is caused by antibodies to the basement membrane

In many patients with nephritis, antibodies to the basement membrane glycoprotein of glomerular capillaries are detected. Typically, these antibodies belong to the IgG Class and, in at least 50% of patients, they are capable of fixing Complement. Such nephritis is generally characterized by glomerular necrosis accompanied by fibrin deposition.

Goodpasture first described the association of this type of nephritis with pulmonary hemorrhages (hence "Goodpasture's syndrome"). Although pulmonary symptoms do not occur in all patients, the combination of lung and Kidney damage is driven by the presence of cross-reacting autoantigens in both of these tissues.

Several EXPERIMENTAL MODELS OF Goodpasture's syndrome exist. For example, administering heterologous antibodies against renal glomerular basement membrane to rats or rabbits induces nephrotoxic nephritis [Masugi Glomerulonephritis] in the animals. The administered antibodies deposit on the basement membranes, followed by the deposition of host antibodies onto these initial antibody deposits, thereby triggering acute nephritis. The Development of nephritis and proteinuria is driven by the accumulation of neutrophils, which bind via complement-dependent and complement-independent mechanisms. Similar damage can be induced by immunizing animals with heterologous basement membranes [Steblay model].

Another disease model [Heymann nephritis], which resembles human membranous glomerulonephritis, is reproduced in animals by inducing autoantibodies against the brush border protein of glomerular capillary epithelial cells. In this case, the damage is primarily mediated by complement: complement depletion in the animals reduces disease severity.

Pemphigus is caused by autoantibodies to a Cell adhesion molecule

Pemphigus vulgaris is a severe disorder characterized by The formation of blisters on the Skin and mucous membranes. Patients produce autoantibodies to desmoglein-3, a component of desmosomes that form Intercellular junctions between epidermal cells (Fig. 24.15). These antibodies disrupt Cell-to-Cell Adhesion, leading to a loss of epidermal integrity. The disease correlates with the presence of IgG4 antibodies directed against various Regions of the desmoglein-3 molecule. Pemphigus is closely associated with the rare HLA-DR4 haplotype (DRB1*0402), and it has been established that this molecule, unlike other DR4 subtypes, presents a desmoglein-3 peptide. Thus, pemphigus serves as a clear example of an autoimmune disease in which the pathological process is linked to type II hypersensitivity mechanisms.

Fig. 24.15. In pemphigus, autoantibodies are detected at sites of intercellular junctions (immunofluorescence assay). The antigen is a component of desmosomes, which mediate cell adhesion. Immunofluorescence of human skin stained with anti-IgA. (Micrograph kindly provided by Dr. R. Mirakian and Mr. P. Collins.)

Myasthenia gravis and Lambert-Eaton syndrome are caused by antibodies that reduce acetylcholine availability at motor neuron end-plates

In myasthenia gravis—a disease characterized by profound Muscle weakness—antibodies are produced against acetylcholine receptors On the surface of muscle membranes. Acetylcholine receptors are located at the end-plate of the muscle fiber, precisely where the motor neuron contacts the muscle. The transmission of impulses from nerve to muscle occurs via the release of acetylcholine from the nerve terminal and its diffusion across the synaptic cleft to the muscle fiber.

Immunization with a purified preparation of the Acetylcholine Receptor induces a state of muscle weakness in experimental animals that resembles human myasthenia; this observation led to the hypothesis that antibodies to the acetylcholine receptor play a role in the Pathogenesis of the disease. Analysis of muscle pathology in myasthenia has shown that neither acetylcholine synthesis nor its release in response to a Nerve Impulse is impaired; rather, the released acetylcholine appears to depolarize the muscle membrane less effectively (Fig. 24.16).

Fig. 24.16. A nerve impulse traveling along a neuron normally reaches the end-plate and triggers the release of acetylcholine (ACh). The latter diffuses across the neuromuscular synapse, binds to muscle acetylcholine receptors, and causes Ion Channels in the muscle membrane to open, thereby initiating Muscle contraction. In myasthenia gravis, receptor antibodies block the binding of the neurotransmitter (acetylcholine). Consequently, the functional impact of acetylcholine released from vesicles is diminished, and the muscle becomes severely weak. This is likely only one of the factors contributing to the pathogenesis of the disease.

Immunochemical examination of Neuromuscular Junction end-plates has revealed the presence of IgG and complement proteins C3 and C9 on the folds of the postsynaptic muscle membrane (Fig. 24.17). (Further Evidence for the pathogenic role of IgG in this disease comes from the finding of transient muscle weakness in newborns born to myasthenic mothers. This is a compelling argument, as IgG is known to cross the Placenta into the Fetal Circulation.) It is believed that IgG and complement act through two mechanisms: by increasing the turnover rate of acetylcholine receptors and by partially blocking acetylcholine binding. Cellular infiltration of the end-plates is rarely observed in myasthenia, suggesting that effector cells do not participate in the Development of the pathological process.

Fig. 24.17. Electron micrographs showing the localization of IgG autoantibodies (1) and the C9 complement component at the motor neuron end-plate in myasthenia gravis. The top photo shows discrete deposits of IgG (G) on the postsynaptic membrane (P), x13,000. The bottom photo shows a postsynaptic region devoid of a nerve terminal; it is represented by debris and degenerating folds (D). These disintegrating fragments react strongly when stained for C9 (C). (M, muscle fiber) x9,000. (Photographs kindly provided by Dr. A. G. Engel.)

In a similar condition, Lambert-Eaton syndrome, muscle weakness results from impaired release of acetylcholine from Neurons. Administration of serum or IgG from patients with this syndrome to mice induces a comparable condition, indicating the presence of autoantibodies in the patients. These autoantibodies interact with components of voltage-gated calcium channels or the synaptic vesicle protein synaptotagmin. It is believed that Various Forms of the syndrome are caused by autoantibodies to different antigens, as well as by different classes and titers of antibodies. Both of these disorders serve as examples of conditions in which receptor autoantibodies block normal function. However, There are also diseases in which autoantibodies exert the opposite effect. For instance, in certain forms of autoimmune thyroid disease, antibodies to TSH (thyroid-stimulating hormone) receptors mimic the action of TSH itself, thereby stimulating thyroid function (see Chapter 27).

Autoantibodies to tissue antigens do not necessarily cause a type II hypersensitivity reaction

Although numerous autoantibodies interact with tissue antigens, their significance as drivers of tissue pathology in vivo is not always obvious. For example, in the serum of some diabetes patients, in vitro autoantibodies to pancreatic islet cells can be detected (Fig. 24.18), yet the primary immunopathological processes in autoimmune diabetes appear to be driven by autoreactive T cells.

Fig. 24.18. Islet cell autoantibodies. Immunofluorescence Microscopy reveals autoantibodies against pancreatic cells in Diabetes Mellitus. They have diagnostic and, potentially, pathogenetic significance. (Micrograph kindly provided by Dr. W. Dean.)

Until recently, it was widely believed that autoantibodies to intracellular antigens generally do not trigger immunopathological processes because they cannot come into contact with their target antigen within a living cell. However, recent studies have shown that certain antibodies, such as anti-RNP and anti-DNA, can penetrate even into cell nuclei and alter cellular function. In some cases, they may induce apoptosis. Although the precise role of such antibodies in cell damage remains controversial, they often serve as reliable disease markers, as they are frequently detected even before the onset of the immunopathological process.

Questions for Review

■ Which effector cells of The Immune System are activated during type II hypersensitivity reactions?

■ What happens to allogeneic erythrocytes upon their first or subsequent transfusion into a human completely lacking the complement component C5?

■ Why do antibodies directed against cell surface antigens frequently elicit pathological reactions, whereas antibodies to intracellular antigens typically do not?

■ Why does hemolytic disease of the newborn (HDN) occur in only about 1 out of every 20 Rhesus-incompatible mother-fetus pairs?

Introduction/47.html">Further Reading

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