Biomedical subjects
M A Agius
Publications and source records attributed to M A Agius.
Myasthenia gravis: pathogenesis and treatment.
Much is known about the pathogenesis of MG. This information has provided a rational basis for treatment of the disease, which is very effective. On the other hand, present treatments are limited by significant adverse effects. Our knowledge of pathogenesis also provides clues for the development of new, effective, but less toxic treatments. In addition, knowledge of the autoimmune mechanisms in MG may be useful in devising better treatments for the many human autoimmune diseases that are less well understood.
Acquired myasthenia gravis. Immunopathology.
Much of the remarkable advance in our understanding of the immunopathology of MG relates to the availability of two gifts of nature that permit the ready purification of the antigen, AChR. Immunization of experimental animals with AChR has led to the development of the extremely faithful animal model, EAMG. Analysis of both EAMG and MG has revealed that the effector agents in this autoimmune disease are anti-AChR antibodies, whose production is regulated by anti-AChR CD4+ T cells. The pathogenic effects on neuromuscular transmission are mediated by antibody-induced antigenic modulation of end-plate AChR, end-plate membrane destruction through complement fixation and recruitment of inflammatory cells, and antibody-induced blockade of the function of the remaining AChR molecules. The origin of MG remains unknown. One theory proposes that dysregulation of the thymic control of tolerance plays an important role. An alternative hypothesis is that tolerance is broken as the result of a vigorous immune response directed against an invading microorganism that expresses a molecule that is similar to AChR, so-called molecular mimicry. This "normal" response eventually cross-reacts with self-AChR, resulting in the autoimmune damage. Our current knowledge of MG has suggested a number of possible sites of therapeutic intervention that are under active study. Future information concerning the origin of the disease will likely be useful in the design of more effective treatment for this and other related autoimmune diseases.
Effector mechanisms of myasthenic antibodies.
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Molecular structure of a monoclonal antiacetylcholine receptor antibody and of a corresponding monoclonal antiidiotopic antibody.
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Noninflammatory immune mechanisms in diseases of the nervous system.
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Monoclonal anti-idiotopic antibodies against myasthenia-inducing anti-acetylcholine receptor monoclonal antibodies. Preponderance of nonparatope-directed antibodies affecting antigen binding.
To analyze components of the idiotypic network in experimental autoimmune disease, we produced 17 isogeneic anti-idiotopic monoclonal antibodies (anti-Id) against two experimental autoimmune myasthenia gravis-producing anti-acetylcholine receptor (anti-AChR) monoclonal antibodies. We studied the binding of five of the anti-Id to the anti-AChR monoclonal antibodies bearing the complementary idiotopes (Id-mAb). They bound with Kd values ranging from 0.06 to 0.86 nM, values comparable to those of Id-mAb:AChR complexes (0.26 and 0.34 nM). All of the anti-Id tested moderately inhibited the binding of AChR to Id-mAb, whereas for each anti-Id, AChR either strongly inhibited anti-Id binding or had no effect on anti-Id binding. Hence, the inhibition of Id-mAb:AChR binding by anti-Id was not reciprocal with the inhibition of anti-Id:Id-mAb binding by AChR. For each anti-Id, the relative affinities of anti-Id and AChR for Id-mAb together with the lack of symmetry of inhibition by anti-Id compared to inhibition by AChR indicate that these two "ligands" are not competitive inhibitors. Consequently, anti-Id and AChR do not bind to overlapping sites on the Id-mAb, suggesting that the observed inhibition is mediated allosterically. This may be a common mechanism of anti-Id:Id binding, which would have important implications for the mechanism of anti-Id-induced suppression.
Refractoriness to a second episode of experimental myasthenia gravis. Correlation with AChR concentration and morphologic appearance of the postsynaptic membrane.
Rats injected with anti-acetylcholine receptor (anti-AChR)2 monoclonal antibodies (mAb) develop the acute phase of experimental autoimmune myasthenia gravis characterized by a macrophage inflammation of muscle endplates (EP). These animals are subsequently refractory to induction of a second such episode up to 8 wk after the initial injection. Analysis of this phenomenon to date has shown that mechanisms such as anti-idiotypic regulation, epitopic modulation, and cellular suppression or deletion are not significantly involved. In the present study, animals reinjected from 11 wk on developed a second episode of cellular EP inflammation. This renewed susceptibility correlated temporally with an increase in postsynaptic membrane length and AChR content. When the second injection of anti-AChR mAb was given at 8 wk, mAb bound to muscle EP caused a small reduction in AChR content in the absence of cellular inflammation. These observations suggested that total inaccessibility of AChR to mAb is not responsible for the refractoriness to cellular EP inflammation. More likely, a certain AChR concentration or density is necessary to bind a critical amount or density of antibody to activate complement and set in motion the events leading to a cellular inflammatory response. In human myasthenia gravis, in which initially damaged EP are continuously exposed to anti-AChR antibodies, this critical AChR concentration or density may not be reached again because of continuous complement-mediated lysis and/or increased AChR turnover. Hence, these data may explain the infrequency of cellular EP inflammation in motor point muscle biopsies in this disease.
Human x human hybridomas from patients with myasthenia gravis: possible tools for idiotypic therapy for myasthenia.
Hybridomas secreting monoclonal antibodies directed against the nicotinic acetylcholine receptor have been developed from rats with experimental autoimmune myasthenia gravis and from a patient with myasthenia gravis. Rat monoclonal antibodies were characterized by their ability to bind to electroblotted acetylcholine receptor subunits. Of 34 tested, 22 bound to the alpha subunit. Three bound to other subunits, and the remainder appeared to bind only to the native molecule. The human monoclonal antibodies were analyzed with respect to their binding to membrane-bound and solubilized acetylcholine receptor. Many bound with greater affinity to the membrane-bound form of the antigen. Two rat monoclonal antibodies capable of passively transferring experimental autoimmune myasthenia gravis, and with reactivities to the alpha subunit of the acetylcholine receptor, were employed to produce isogeneic monoclonal antiidiotypic antibodies. When they were injected prior to immunization with acetylcholine receptor, two of the antiidiotypic antibodies directed against framework determinants prevented the development of experimental autoimmune myasthenia gravis. This observation raises the possibility that the human monoclonal antibodies will be useful in the development of idiotypic treatment of the human disease.
Suppression of development of experimental autoimmune myasthenia gravis with isogeneic monoclonal anti-idiotopic antibody.
We have made use of isogeneic anti-idiotopic (anti-Id) monoclonal antibodies (mAb to modify experimental autoimmune myasthenia gravis (EAMG) in Lewis rats. High-avidity anti-Id mAb HC-4A (Kd = 0.1 nM) and HC-29 (Kd = 0.1 nM) were produced against an anti-acetylcholine receptor (anti-AChR) Lewis-rat mAb 132A (Kd = 0.34 nM) that is capable of inducing passive-transfer EAMG. mAb HC-4A and HC-29 define separate framework Id cross-reactive with anti-AChR mAb recognizing different AChR epitopes. Animals were preinjected i.p. with either anti-Id mAb or with control mAb and then were actively immunized 2 wk later with purified AChR. All animals had elevated total serum anti-AChR antibody titers, despite the absence of weakness or decremental electromyographic findings. Animals preinjected with control mAb developed serum anti-AChR titers of 1.34 +/- 0.29 microM (mean +/- SEM) and reduced muscle AChR content to 30 percent of normal. Animals injected with 0.5 mg/kg of either anti-Id had significantly lower serum anti-AChR titers, 0.55 +/- 0.1, p less than 0.05, and normal muscle AChR content. Both the 132A Id and the anti-Id complementary to 132A were detected in the serum of all of the animals preinjected with this dose of either anti-Id HC-29 or HC-4A, whereas both were detected in a much smaller percentage of the animals receiving control mAb. These results show that pretreatment with anti-Id not only perturbs this Id-anti-Id network, but also suppresses the overall polyclonal anti-AChR response with resultant protection of actively immunized animals from EAMG.