Marjorie E. Seybold

Antibody to acetylcholine receptor in myasthenia gravis Prevalence, clinical correlates, and diagnostic value

Elevated amounts of antibodies specific for acetylcholine receptors were detected in 87 percent of sera from 71 patients with myasthenia gravis but not in 175 sera from individuals without myasthenia gravis, including those with other neurologic or autoimmune diseases. Antireceptor antibodies were not directed at the acetylcholine binding site of the receptor. Presence or titer of antibody did not appear to correlate with age, sex, steroid therapy, or duration of symptoms. Myasthenia gravis patients with only ocular symptoms had lower antibody titers, while the majority of titers in myasthenia gravis patients with thymoma exceeded the median titer of the myasthenia gravis group as a whole. Assay of antireceptor antibody should prove a useful test in the diagnosis of myasthenia gravis.

EXPERIMENTAL AUTOIMMUNE MYASTHENIA GRAVIS AND MYASTHENIA GRAVIS: BIOCHEMICAL AND IMMUNOCHEMICAL ASPECTS

Stucture of acetylcholine receptor protein (AChR) purified from Electrophorus electricus (eel) by affinity chromatography is described. AChR is detected in extracts from human muscle, rat muscle, and rat thymus. Rats immunized with eel AChR develop humoral antibodies, a small fraction of which recognize AChR from rat muscle. Rats immunized with AChR exhibit myasthenia, but those immunized with denatured AChR do not. Immunoglobulin fraction of antisera to eel AChR can block the activity of AChR in electroplaques. Sera from patients with myasthenia gravis contain antibodies to AChR from human muscle detectabe at an average value 300-fold the background level in sera from nonmyasthenics. Relationship of thymoma and disease intensity to antibody titer is examined. The chronic phase of EAMG appears a good model of MG, since in both cases similar concentrations of 7-S immunoglobulin against determinants on muscle AChR other than the toxin binding site are found. Assay of anti-AChR antibody in sera from MG patients using AChR from rat muscle gives titers 10%-15% of those obtained using AChR from human muscle, and using AChR from eel gives negligible titers. The assay method described for assaying antibodies against AChR from human muscle is suggested as a diagnostic test for MG.

The spectrum and diagnosis of acid maltase deficiency

P o m p e ’ i n 1932 described generalized glycogenosis as a disease fatal in infancy. However, the recognition of acid maltase deficiency (AMD) in this disease by Hers’ in 1963 has led to the diagnosis of less severely affected cases (cases cited in Discussion). In these patients, symptoms may occur after infancy and the prognosis is better, The late-onset form of the disease may simulate, and is often misdiagnosed as, other myopathies. This paper compares the infantile, childhood and adult cases of AMD and considers the diagnostic methods.

Experimental autoimmune myasthenia gravis: cellular and humoral immune responses.

Rats inoculated intradermally with eel acetylcholine receptor protein(AChR) with adjuvants developed autoimmunity to skeletal muscle AChR. This is evidenced clinically as two episodes of experimental autoimmune myasthenia gravis (EAMG), an acute phase that occurs early (8 days) and is transient, and a chronic phase (30 days) that is usually progressive. Positive delayed cutaneous reactivity appeared at day 4 and serum antibody to eel AChR was detectable by day 7 postinoculation. After day 25 the titer of antibody to syngeneic muscle AChR rose abruptly. Antibody to muscle AChR sedimented as 7S. Lymph node cells from rats sensitized to AChR were capable of transferring EAMG to normal recipients. Thymectomy after the onset of EAMG had no effect. Early treatment in vivo with antithymocyte serum suppressed acute but not chronic phase EAMG. Experiments combining thymectomy, x-irradiation and reconstitution with distinct populations of lymphocytes indicated athat thymus-derived lymphocytes are required for induction of EAMG and antibody to AChR. These data suggest that both cellular and humoral responses to AChR, either sequentially or in combination, contribute to the pathogenesis of EAMG.

PATTERNS OF ACETYLCHOLINE RECEPTOR ANTIBODY FLUCTUATION IN MY ASTHENIA GRAVIS

Serial acetylcholine receptor antibody (AChR-ab) titers have been followed in 32 patients with myasthenia gravis (MG) for an average of 43 months (range 12-81 months). Seventeen patients became asymptomatic or markedly improved during the study, 12 of whom showed AChR-ab decreases of greater than 50% sustained for 12 months. Only three of 15 patients showing no substantial clinical improvement had AChR-ab decreases greater than 50%. Steroids were more often associated with AChR-ab suppression than was thymectomy. The differences in AChR-ab suppressibility among identically treated patients were not predictable by any clinical characteristics studied. The study indicates a strong relationship between clinical course and AChR-ab in the individual patient when sustained improvement over 12 months and AChR-ab decreases greater than 50% are examined.

EXPERIMENTAL AUTOIMMUNE MYASTHENIA: CLINICAL, NEUROPHYSIOLOGIC, AND PHARMACOLOGIC ASPECTS*

It has been suggested by several authors 1, that an autoimmune response against acetylcholine receptor ( AChR) could account for the symptoms of myasthenia gravis (MG) . Testing of this theory in vivo required the use of purified AChR and was therefore delayed until the techniques for the isolation of receptor could be perfected. In 1973 Patrick and Lindstrom3 reported the development of weakness in rabbits immunized with purified AChR from the electric eel (Electrophorus electricus). The character of the weakness and the improvement following anticholinesterase administration suggested a similarity to human MG. Our present work is an attempt to verify and extend these observations and to evaluate the usefulness of this disorder as an experimental model for MG. This paper reports the clinical and electrophysiological characteristics of the disorder in animals immunized with purified receptor and compares the disorder with human MG.

Myasthenia gravis in infancy

Symptoms of myasthenia gravis in infancy may occur from passive transfer of maternal disease, acquired autoimmune disease, or nonautoimmune hereditary disease. Of nine patients with infantile-onset myasthenia who were not born to mothers with the disease, two had detectable antibody to acetylcholine receptor. Patients with or without antibodies were clinically indistinguishable, except for the occurrence of similar disease in siblings of patients without antibody. Differentiation of autoimmune and hereditary myasthenia in infancy is necessary for appropriate therapeutic measures and genetic counseling. Antibody determinations provide a useful aid in this differentiation.

Pupillary abnormalities associated with tumors of the pineal region

NEOPLASMS OF THE PINEAL BODY or other tumors in the same region-the superior collicular and pretectal areas-often produce eye symptoms and signs that include paralysis of conjugate upward gaze, retraction nystagmus, papilledema, and abnormalities of the pupils. The abnormalities include dilatation, absence of constriction on light stimulation, and preservation of the near reflex. Ocular abnormalities of these types, especially when associated with evidence of increased intracranial pressure, allow a presumptive clinical diagnosis of tumor in the pineal region. When air-contrast studies demonstrate a mass lesion in this region, even without histologic verification, the diagnosis is presumed to be that of a pinealoma. The object of this paper is to report on the pupillary abnormalities recorded by electronic infrared pupillography in patients with ocular disturbances associated with tumors in the pineal region.

Immunopathology of acetylcholine receptors in myasthenia gravis

SummaryIt is now clear that the muscular weakness and fatigability seen in MG result from an antibody-mediated immune response to AChR. The mechanisms by which antibodies impair transmission are moderately well understood and detection of antibodies in patients sera is a reliable diagnostic test for the disease. The spectrum of antibody specificities produced in MG is also beginning to be understood, largely through the use of antibodies produced in the experimental model EAMG. Treatment for MG continues to rely heavily on the symptomatic relief afforded by acetylcholinesterase inhibitors. However, the recent recognition of the autoimmune nature of MG has led to increased emphasis on immunosuppression and antibody removal with some beneficial effects. Despite all that has been learned, the level of ignorance has just been pushed back one step -from the neuromuscular junction to the immune system. What initiates the immune response to AChR in MG and how to specifically suppress this aberrant response remain completely unknown.

Myasthenia gravis: In vitro immunoglobulin production with pokeweed mitogen challenge and B- and T-lymphocyte competence

Abstract Myasthenia gravis (MG) is an autoimmune disorder associated with the production of antibodies to the acetlycholine receptor (AChR). To learn whether the autoimmune abnormalities involved the failure of suppressor cells to regulate excessive and aberrant immunoglobulin (Ig) production, we studied the numbers of T suppressor cells and their ability to regulate B-cell responses in MG patients. The percentage of T cells bearing receptors for the Fc portion of IgG (T G cells) from patients with MG and from healthy controls were compared. Lymphocytes from 7 of the 13 MG patients examined showed abnormal levels of T G cells; some values were higher and some lower than normal. Possible activation of suppressor cells in vivo was evaluated by comparing the abilities of irradiated and unirradiated T cells from MG patients to provide help for B cells producing Ig in a pokeweed mitogen (PWM) assay. In this respect, responses by the MG patient group equaled those of healthy controls. In contrast, PBLs from patients with multiple sclerosis undergoing acute exacerbation, and tested for comparison, contained activated suppressor cells.