Myasthenia Gravis: Prototype of the Antireceptor Autoimmune Diseases

S, Schönbeck; Chrestel, Susanne; Hohlfeld, Reinhard

doi:10.1016/s0074-7742(08)60583-8

Cited by 44 publications

(20 citation statements)

References 146 publications

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“…AChR from bovine muscle is a good substitute for the exceedingly scarce human muscle AChR because it can be purified in sufficient amounts (34) and is highly homologous to human AChR ( 14,30,37): the bovine y subunit is 92% identical to the human y subunit (30,37). Lines 2, 3, and 4 responded to 5 ,g/ml of FBAChR at least as strongly as to the highest concentration of y pool used (5 ,ug/ml ofeach peptide) whereas the response to FBAChR of line 1, although significant, was consistently lower than the response to the y pool.…”

Section: Resultsmentioning

confidence: 99%

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Myasthenia gravis. CD4+ T epitopes on the embryonic gamma subunit of human muscle acetylcholine receptor.

Protti¹,

Manfredi²,

Wu³

et al. 1992

J. Clin. Invest.

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In myasthenia gravis (MG) an autoimmune response against muscle acetylcholine receptor (AChR) occurs. Embryonic muscle AChR contains a y subunit, substituted in adult muscle by a homologous e subunit. Antibodies and CD4 + cells specific for embryonic AChR have been demonstrated in MG patients.We identified sequence segments of the human y subunit forming epitopes recognized by four embryonic AChR-specific CD4' T cell lines, propagated from MG patients' blood by stimulation with synthetic peptides corresponding to the human -y subunit sequence. Each line had an individual epitope repertoire, but two 20-residue sequence regions were recognized by three lines of different HLA haplotype. Most T epitope sequences were highly diverged between the y and the other AChR subunits, confirming the specificity of the T cells for embryonic AChR. These T cells may have been sensitized against AChR expressed by a tissue other than innervated skeletal muscle, possibly the thymus, which expresses an embryonic muscle AChR-like protein, containing a y subunit. Several sequence segments forming T epitopes are similar to regions of microbial and /or mammalian proteins unrelated to the AChR. These findings are consistent with the possibility that T cell cross-reactivity between unrelated proteins ("molecular mimicry"), proposed as a cause of autoimmune responses, is not a rare event. (J. Clin. Invest. 1992Invest. . 90:1558Invest. -1567

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Section: Resultsmentioning

confidence: 99%

“…In myasthenia gravis (MG) 1 an autoimmune response against muscle nicotinic acetylcholine receptor (AChR) occurs (1)(2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Myasthenia gravis. CD4+ T epitopes on the embryonic gamma subunit of human muscle acetylcholine receptor.

Protti¹,

Manfredi²,

Wu³

et al. 1992

J. Clin. Invest.

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“…In systemic lupus erythematosus, anti-dsDNA and anti-Sm autoantibodies can both serve as disease markers while only anti-dsDNA antibodies seem to have a pathogenic implication (1). In Graves' disease and myasthenia gravis, antibodies respectively targeting the thyroid-stimulating hormone and the acetylcholine receptors may actually drive the disease process (2,3). Conversely, antithyroglobulin, antimicrosomal thyroid peroxidase, and antistriated muscle autoantibodies appear to act only as disease markers.…”

Section: Introductionmentioning

confidence: 99%

Detection and expression of a cDNA clone that encodes a polypeptide containing two inhibitory domains of human calpastatin and its recognition by rheumatoid arthritis sera.

Després¹,

Talbot²,

Plouffe³

et al. 1995

J. Clin. Invest.

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RA is the most frequent and most destructive inflammatory arthropathy. Rheumatoid factors, in spite of their lack of disease specificity, are important serological markers for RA and appear important in its immunopathogenesis as well. In search of more disease-specific autoimmune systems, we have screened a human placenta Xgtll cDNA expression library using selected sera from patients with classical erosive RA. We have identified one clone (RA-1) that is recognized by three of five screening sera. The 950-bp insert shows a complete nucleotide sequence homology to the cDNA encoding the two COOH-terminal domains of calpastatin. The deduced open reading frame of the RA-1 cDNA predicts a 284-amino acid protein, with a calculated mol wt of 35.9 kD. Calpastatin is the natural inhibitor of calpains, which are members of the cysteine proteinases recently implicated in joint destruction in rheumatic diseases. The two domains encoded by the RA-1 clone each contain the structural features associated with the inhibitory activity of human calpastatin. By Western blotting, 45.5% or 21/44 RA sera specifically recognized both the fusion and the cleaved recombinant protein. This is in contrast to 4.7% (2/43) in nonrheumatoid sera and 0/10 in normal sera. Anticalpastatin autoantibodies could represent a diseaseassociated marker in chronic erosive arthritis of the rheumatoid type and could hypothetically play a dual pathogenic role, directly via an immune interference and indirectly through an immune complex mechanism. (J. Clin. Invest. 1995Invest. . 95:1891

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“…Myasthenia gravis (MG) is a debilitating autoimmune neuromuscular disease characterized by fluctuating muscle weakness and progressive deterioration of neuromotor function (Schonbeck et al, 1990). Symptoms affecting MG patients include drooping eyelids, double vision, difficulty eating or talking, and chronic fatigue.…”

Section: Neuromuscular Diseasementioning

confidence: 99%

Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

Soreq¹

2003

PsycEXTRA Dataset

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075REPORT Public reportinq burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing date sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect cif this collection of 'mormaton, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, andtotheOfficeof Vanaqement and Budget, Paperwork Reduction Project (0704-0188) soreq@shum.huji.ac.il SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUPPLEMENTARY NOTESReport contains color graphics. 12a. DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; Distribution unlimited 12b. DISTRIBUTION CODE ABSTRACT (Maximum 200 Words)To characterize neuropathological consequences of excess acetylcholinesterase (AChE), we employed transgenic mice developed under previous US Army support. These mice demonstrated association between such excess and adverse responses (in brain and intestine) to pyridostigmine and diisopropylfluorophosphonate. The stress-associated "readthrough" AChE-R variant was seen also in progenitor blood cells, suggesting its use as a surrogate marker for anti-AChE responses. Moreover, AChE-R accumulates in the brain following head injury, its pre-injury excess exacerbates damage, and its antisense suppression improves survival and recovery. Using a 2-hybrid yeast screen we discovered a previously unknown interaction of AChE-R with RACK1, a protein kinase cargo protein involved in signaling processes. Animals carrying a tetracycline-inducible anti-AChE antisense sequence are being characterized for further studies of these interactions. At the extended promoter of the ACHE gene, we found a 4 bp deletion that over-induces transcription and hypersensitivity to pyridostigmine through impairment of HNF3B interaction, and discovered a novel mutation that disrupts the glucocorticoid binding site. Finally, we found AChE-R-specific inhibitor interactions in mouse brain that reflect the specific increase in the AChE-R variant after psychological stress. ( The AChE-R variant thus emerges as the key scavenger and acetylcholine-hydrolyzing agent in several mammalian tissues under various stress insults. Table of contents 3 Introduction 4 Body task 1: characterize the sensory, cognitive and neuromotor consequences of a 5 transgenic excess in AChE variants. task 2: employ transgenic mouse models with up to 300-fold differences in 10 peripheral AChE levels for demonstration of direct correlation between AChE dosage and protection from stress and chemical warfare agents and to test their responses to pyridostigmine administration. task 3: develop RT-PCR tests in peripheral blood cells of model animals, and 12 additional surrogate markers, for follow-up of responses and protection task 5: emplo...

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Myasthenia Gravis: Prototype of the Antireceptor Autoimmune Diseases

Cited by 44 publications

References 146 publications

Myasthenia gravis. CD4+ T epitopes on the embryonic gamma subunit of human muscle acetylcholine receptor.

Myasthenia gravis. CD4+ T epitopes on the embryonic gamma subunit of human muscle acetylcholine receptor.

Detection and expression of a cDNA clone that encodes a polypeptide containing two inhibitory domains of human calpastatin and its recognition by rheumatoid arthritis sera.

Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

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