A Novel Therapy for Myasthenia Gravis by Reducing the Endocytosis of Acetylcholine Receptorsa

Kuncl, Ralph W.; Wittstein, Ilan S.; Adams, Robert N.; Wiggins, Winston W.; Avila, Orlando; Pestronk, Alan; McIntosh, Kevin R.; Lucas, Donna P.; DeSilva, Shari; Lehar, Mohamed; Drachman, Daniel B.

doi:10.1111/j.1749-6632.1993.tb22900.x

Cited by 12 publications

(10 citation statements)

References 5 publications

(1 reference statement)

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“…Since c~Ado acts as both inhibitor and substrate of AdoHcyase the metabolic consequences of c3Ado treatment are both Hcy depletion, build up of Sadenosylhomocysteine (AdoHcy) and formation of 3-deazaadenosylhomocysteine (c3AdoHcy) [54]. c3AdoHcy is a potent inhibitor of transmethylation reactions and it has been claimed that phospholipid methyla-tion alters the properties of the cytoplasmic membrane [27,32]. c3AdoHcy is a potent inhibitor of transmethylation reactions and it has been claimed that phospholipid methyla-tion alters the properties of the cytoplasmic membrane [27,32].…”

Section: Discussionmentioning

confidence: 99%

Morphological modifications of apoptosis in HL-60 cells: effects of homocysteine and cytochalasins on apoptosis initiated by 3-deazaadenosine

Endresen

Aarbakke

Fandrem

et al. 1995

Vichows Archiv A Pathol Anat

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Using electron microscopy, confocal laser scanning microscopy and measurements of intact DNA we have studied the morphology and DNA degradation of human leukaemia HL-60 cells undergoing drug initiated apoptosis. Apoptosis was initiated by 100 microM 3-deazaadenosine (c3Ado), 25 microM c3Ado plus 1 mM homocysteine thiolactone (Hcy) and 100 microM c3Ado plus 5 micrograms/ml cytochalasin B (CB). Two different phenotypes of apoptotic cells (APC), blebbed and non-blebbed, were present in the cultures. Blebbed APC dominated in cultures exposed to c3Ado, whereas most APC in cultures treated with c3Ado plus Hcy and all the APC in cultures treated with c3Ado plus CB displayed a non-blebbed phenotype. A more pronounced reduction of the chromatin/cytoplasm ratio, lower volume fractions of uncondensed chromatin and higher volume fractions of highly condensed chromatin (micronuclei) were found in cultures exposed to c3Ado and c3Ado plus Hcy when compared with cultures exposed to c3Ado plus CB. A partial inhibition of c3Ado apoptosis by CB was confirmed by measurements of intact DNA. The inhibitory effect of CB was not reproducible by CE, indicating that CB exerts its effect by an actin independent mechanism. Both blebbed and non-blebbed APC displayed nuclear fragmentation, segregation of organelles and cytoplasmic vesiculation, suggesting that the differences between the phenotypes were restricted to the cytoplasmic membrane. We were not able to demonstrate the presence of F-actin by fluorescein isothiocyanate-phalloidin staining in blebbed APC nor in non-blebbed APC in cultures treated with c3Ado plus Hcy. Non-blebbed APC in cultures treated with c3Ado plus CB displayed foci of F-actin at the internal part of the cytoplasmic membrane. This suggests that F-actin is preserved by the mechanism by which CB inhibits blebbing, and may indicate that blebbing of the cytoplasmic membrane during apoptosis is associated with F-actin deficiency rather than a result of actin-myosin interactions.

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Section: Discussionmentioning

confidence: 99%

Morphological modifications of apoptosis in HL-60 cells: effects of homocysteine and cytochalasins on apoptosis initiated by 3-deazaadenosine

Endresen

Aarbakke

Fandrem

et al. 1995

Vichows Archiv A Pathol Anat

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“…Anti-AChR Abs are found in ϳ90% of MG patients (23), and are suggested to play an important role in functional loss by blocking the receptor (24), by increasing receptor endocytosis (25), or by activating the complement-mediated inflammatory destruction of the NMJ (26). It is uncertain whether Abs could cause clinical symptoms without the aid of the complement system.…”

Section: Discussionmentioning

confidence: 99%

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

Tüzün

Scott

Goluszko

et al. 2003

The Journal of Immunology

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Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3−/−, C4−/−, C3+/−, and C4+/− mice and their control littermates (C3+/+ and C4+/+ mice) with AChR in CFA. C3−/− and C4−/− mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3−/− and C4−/− mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3−/− mice was significantly suppressed. Both C3−/− and C4−/− mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3−/− and C4−/− mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

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“…MAC and lytic pore formation at NMJs cause AChR destruction 7. There is increasing evidence that changes in complement concentration can influence the severity of MG: (1) depletion of complement protects animals from developing experimental autoimmune MG (EAMG)8; (2) administration of antibodies that block complement component C6 or soluble complement receptor 1 protect rodents from EAMG9; and (3) mice with reduced complement function due to a genetic defect are resistant or less susceptible to EAMG than mice with normal amounts of complement 10. These findings suggest that complement activation at NMJs is the primary cause of AChR loss and failure of neuromuscular transmission.…”

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confidence: 99%

Correlation of C3 level with severity of generalized myasthenia gravis

et al. 2009

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Acute exacerbation of generalized myasthenia gravis (GMG) can cause swallowing impairment, respiratory failure, or death. It is important to identify immunological factors that might be regarded reliably as an index of the patient's clinical condition, response to treatment, and measure of certain immune aberrations of MG. In this study we investigated correlations between complement component C3, acetylcholine receptor antibody (AChRab) titer, and clinical severity of GMG. AChRab titer and C3 concentration were determined by radioimmunoassay and nephelometry, respectively. The clinical severity of GMG was assessed by the quantitative MG score (QMGS) according to Besinger and colleagues. Our findings indicate that the C3 level correlates with clinical severity of AChRab-positive GMG.

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A Novel Therapy for Myasthenia Gravis by Reducing the Endocytosis of Acetylcholine Receptorsa

Cited by 12 publications

References 5 publications

Morphological modifications of apoptosis in HL-60 cells: effects of homocysteine and cytochalasins on apoptosis initiated by 3-deazaadenosine

Morphological modifications of apoptosis in HL-60 cells: effects of homocysteine and cytochalasins on apoptosis initiated by 3-deazaadenosine

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

Correlation of C3 level with severity of generalized myasthenia gravis

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