Topics covered on this page: Origin of the Autoimmune Response, Immunopathogenesis of MG, Antibody Mediated Mechanisms, Summary of Autoimmune Response

Origin of the Autoimmune Response

It is not certain how the autoimmune response originated, but one of the main theories is that the autoimmune process is initiated in the thymus. This would occur because of the location of myoid cells within the thymus. Myoid cells are muscle-like cells that bear acetylcholine receptors (AChR). In the thymus, these cells are surrounded by macrophages and helper T cells, which may make them vulnerable to immune attack. If there happened to be some alteration in the myoid cells, it may lead to an autoimmune response. There is also a hypothesis that myasthenia gravis could be triggered by a process known as "molecular mimicry". In this process, an immune response to an infectious agent that resembles the structure of an acetylcholine receptor would trigger the autoimmune response.

The fact that the autoimmune response originates in the thymus is supported by the evidence that 75% of myasthenic patients have thymic abnormalities. Of that 75%, 85% of the patients have hyperplasia and 15% have thymomas. It has also been found that genetic factors and various abnormalities of immune regulation can increase the likelihood of myasthenia gravis. Since many other autoimmune diseases have been found to occur in myasthenic patients and their relatives, the idea that a defect in immune regulation and the suggestion that there could be a heritable predisposition for this disease is supported.

Immunopathogenesis of Myasthenia Gravis

Myasthenia gravis is believed to be an antibody-mediated process because it satisfies a set of five criteria that are used to define an autoantibody-mediated process. First, 80-90% of patients with myasthenia gravis have antibodies to AChRs, supporting the idea that an antibody is present. Second, it has been demonstrated that these antibodies interact with the target antigen, the AChR, because the presence of IgG, the most abundant of circulating antibodies, has been detected at neuromuscular junctions. Third, the characteristic disease features can be reproduced by passive transfer. This was found when Serum IgG from myasthenic patients was injected into mice, and subsequently elicited the symptoms of the disease in the mice. Fourth, immunization with the antigen produces a model disease. This shows that an immune response directed against the AChRs could produce the same symptoms that are found in patients with myasthenia gravis. This model disease has been called Experimental Autoimmune Myasthenia Gravis. Research using this model disease has been very helpful in providing information about treatment of myasthenia gravis. Finally, a reduction of antibody levels cause the disease conditions to improve.

Antibody-Mediated Mechanisms:

Antibodies reduce the number of AChR by three principle mechanisms: accelerated endocytosis and degradation of AChR, functional blockade of the acetylcholine binding sites on the AChR, and complement-mediated damage to the AChRs.

Accelerated Degradation of AChR:

The ability of a patients IgG to speed the degradation of the AChRs depends on its ability to cross-link the receptors. This occurs when one Fab fragment (see diagram) of an antibody binds to one AChR, and the other Fab fragment binds to an adjacent AChR. These antibody-linked receptors are drawn together, rapidly endocytosed, (see diagram) which is a process that internalizes the AChRs, and then are degraded. Support for this mechanism can be seen in studies which have indicated that serum IgG from 90% of patients with myasthenia gravis caused a significant increase in the degradation of AChRs.

Blockade of AChR:

AChR antibodies can block the receptors for acetylcholine at the neuromuscular junction thereby rendering the AChR useless and, in a sense, eliminated. Since the AChR antibodies are bigger than the ACh binding-sites, it is thought that the blockage occurs because of steric hinderance. This means that the antibody is taking up a large space near the AChR, and therefore the ACh molecule cannot get in close enough to the receptor to bind to it and activate the receptor.

Damage to Neuromuscular Junctions:

Research has detected the presence of the membrane attack complex, or complement, at myasthenic junctions. This complement-mediated damage occurs by way of a cascade of enzymes from the attack complex, which work to create a hole in the postsynaptic membrane (where the AChRs lie). This hole causes an upset in the osmotic equilibrium of the cell, which in turn causes the cell to swell and burst.

AChR Antibodies:

There is a suggestion that antibodies may vary in their ability to produce myasthenic weakness, suggested by the evidence that the serum concentration of the AChR antibodies does not correlate with the severity of the disease. This is probably due to one or more of the following four factors. First, nonimmunological factors that affect neurological transmission can affect the clinical status of the myasthenic symptoms. Second, measurements of serum antibodies may not accurately reflect the antibody levels at the neuromuscular junction. Third, specific antibodies can bind to many different epitopes. Finally, AChR antibodies that block the two acetylcholine binding sites per receptor are more pathogenic. It follows then, that the functionality of the antibodies does correlate with the severity of myasthenia gravis. Those antibodies that have a high capacity for accelerated degradation produce a heightened severity of myasthenic weakness. It was found that some antibodies produce the effect of accelerating degradation of AChRs, while others have a greater effect on blockage of the AChRs. This is probably due to the fact that the antibodies are able to bind to different epitopes on the AChR. An epitope is simply a binding-site for an antibody.

It has been found that patients with myasthenia gravis have different types of AChR antibodies and there is a limited sharing of specificity between patients. Since the AChR is so large, it suggests that existing autoantibodies could bind to many different epitopes. The epitopes that they bind to are most likely recognized by their three-dimensional shape. Most of the antibodies that are involved in myasthenia gravis bind to the membrane near, but not within, the AChR. Therefore it is most likely that the antibodies have their blocking effect through steric hinderance.

Antibody-Negative Myasthenia Gravis:

The 10-20% of myasthenic patients who do not have detectable AChR antibodies, by normal means, are given the diagnoses of antibody-negative myasthenia gravis. However, support for the role of antibodies in this disease can be seen by passive transfer of IgG from these patients. Transfer to mice has been found to produce a loss of functional AChR. Also, immunoglobulin has been seen to bind to muscle cells and cause the accelerated degradation of the AChRs. These studies point to the fact that antibody-negative myasthenia gravis is indeed an antibody-mediated autoimmune disorder.

Summary of Autoimmune Response:

In the autoimmune response, when an invading microbe, having a structure resembling that of an AChR (as in the theory of molecular mimicry) enters the body, it is engulfed by a macrophage and broken down by the lysosome into its constituent parts. These peptides are then presented on the surface of the cell by the MHC Class II. The helper T cell can now recognize this foreign structure, and binds to the macrophage at the place where the MHC Class II is presenting the antigen which it learned to recognize (the TCR binds to the antigen that it is specialized to see). This activates the helper T cells and the immune response is initiated. B cells, which recognize certain antigens, also bind to another part of the antigen on the macrophage. The T cells then release lymphokines which cause the B cells to multiply and mature into plasma cells, which then make the antibodies that will mark the peptides for destruction. Because the initial invader closely resembled the AChR, the antibodies will bind to areas near AChRs and produce an affect in one of the following three ways: accelerated endocytosis and degradation of AChR, a functional blockade of the acetylcholine binding sites of the AChR, or complement-mediated damage to the AChRs. This antibody-mediated reduction of AChRs will then manifest into the disease that is known as myasthenia gravis.

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