The preferential involvement of extraocular muscles by myasthenia gravis

Ubogu, Eroboghene E.; Kaminski, Henry J.

doi:10.1076/noph.25.4.219.8061

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…A hallmark of human MG is the propensity for involvement of the extraocular muscles (34). In the mouse, gene expression profiling by DNA microarray has shown that Daf1 gene expression is five-to sevenfold lower in extraocular muscles than in other skeletal muscles (35).…”

Section: Discussionmentioning

confidence: 99%

Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection

Lin¹,

Kaminski²,

Conti‐Fine³

et al. 2002

J. Clin. Invest.

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Myasthenia gravis (MG) is an autoimmune neuromuscular transmission disorder characterized by loss of acetylcholine receptors (AChR's) due primarily to the production of anti-AChR autoantibodies. In this study we investigated whether the presence of decay-accelerating factor (DAF or CD55), an intrinsic complement regulator, protects against the development of disease. Experimental autoimmune MG was induced in Daf1 -/-mice (devoid of neuromuscular DAF protein) and their Daf1 +/+ littermates by injection of rat anti-AChR mAb McAb-3. After twenty-four hours, grip strength assessment revealed that Daf1 -/-mice exhibited hold times of less than 30 seconds, compared with more than 8 minutes for the Daf1 +/+ controls. The weakness was reversed by edrophonium, consistent with a myasthenic disorder. Immunohistochemistry revealed greatly augmented C3b deposition localized at postsynaptic junctions, and radioimmunoassays showed more profound reductions in AChR levels. Electron microscopy demonstrated markedly greater junctional damage in the Daf1 -/-mice compared with the Daf1 +/+ littermates. Control studies showed equivalent levels of other cell surface regulators, i.e., Crry and CD59. The results demonstrate that mice that lack DAF are markedly more susceptible to anti-AChR-induced MG, which simulates the primary mechanism in the human disease, and strongly suggest that in disease flares complement inhibitors might have therapeutic value.

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Section: Discussionmentioning

confidence: 99%

Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection

Lin¹,

Kaminski²,

Conti‐Fine³

et al. 2002

J. Clin. Invest.

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“…84 One of the authors (H.J.K.) has recently provided detailed reviews of the preferential involvement of the EOM by MG, 85,86 and the arguments are briefly summarized here.…”

Section: The Differential Involvement Of Muscle Groups By Mgmentioning

confidence: 99%

Pathophysiology of Myasthenia Gravis

2004

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Myasthenia gravis (MG) is arguably the best understood autoimmune disease, and its study has also led to fundamental appreciation of mechanisms of neuromuscular transmission. MG is caused by antibodies against the acetylcholine receptor (AChR), which produce a compromise in the end-plate potential, reducing the safety factor for effective synaptic transmission. It is clear that AChR antibody destruction of the postsynaptic surface is dependent on complement activation. A muscle-specific kinase has been recently found to be an antigenic target in MG patients without antibodies against the AChR. Autoantibody production in MG is a T-cell-dependent process, but how a breakdown in tolerance occurs is not known. In MG there is an interesting differential involvement of muscle groups, in particular, the extraocular muscles. This article reviews normal neuromuscular transmission, mechanisms of the autoimmune process of MG, and differential susceptibility of eye muscles to MG.

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“…Weaknesses of the EOM and the levator palpebrae are the initial signs of MG in the majority of patients, ultimately occurring in nearly all patients, and may remain restricted to these muscles in 10–15% of patients 29. The apparent preferential clinical involvement of EOM to MG could have a simple explanation 30,31. Their dysfunction leads to the dramatic symptom of double or blurred vision 3.…”

Section: Susceptibility To Myasthenia Gravismentioning

confidence: 99%

Susceptibility of Ocular Tissues to Autoimmune Diseases

Kaminski

Richmonds

et al. 2003

Annals of the New York Academy of Sciences

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The orbital tissues may form a unique immunological environment, as evidenced by autoimmune disorders that specifically target orbital tissues, particularly myasthenia gravis (MG) and Graves' ophthalmopathy (GO). The reasons for the preferential susceptibility are likely to be multiple, based on the interplay of molecular and physiological properties of extraocular muscles (EOM), the unique requirements of the ocular motor system, and the specific autoimmune pathology. Of general importance, even a minor loss of EOM force generation will sufficiently misalign the visual axes to produce dramatic symptoms, and proprioceptive feedback is limited to overcome such a deficit. Particular to MG, EOM synapses appear susceptible to neuromuscular blockade, the autoimmune pathology differs between ocular and generalized MG patients, and the influence of complement regulatory factors may be less prominent in preventing damage at EOM neuromuscular junctions. GO pathogenesis is poorly understood, but shared epitopes of orbital fibroblasts, EOM, and thyroid could lead to specific autoimmune targeting of these tissues. The differential response of orbital fibroblasts to cytokines may be a key factor in disease development. Greater appreciation of the immunologic environment of orbital tissues may lead to therapies specifically designed for orbital autoimmune diseases.

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The preferential involvement of extraocular muscles by myasthenia gravis

Cited by 10 publications

References 36 publications

Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection

Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection

Pathophysiology of Myasthenia Gravis

Susceptibility of Ocular Tissues to Autoimmune Diseases

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