Thymic Myogenesis, T‐lymphocytes and the Pathogenesis of Myasthenia Gravis*

Wekerle, Hartmut; Hohlfeld, Reinhard; Ketelsen, Uwe‐Peter; Kalden, J. R.; Kalies, I.

doi:10.1111/j.1749-6632.1981.tb33753.x

Cited by 78 publications

(16 citation statements)

References 62 publications

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“…This finding has ramifications for the pathogenesis of MG, because it has been proposed that the anti-AChR sensitization in MG may originate within the thymus (20): the existence of MG patients of Th cells specific for embryonic AChR strongly supports this hypothesis. Further, antibodies specific for embryonic muscle AChR are frequently present in MG patients (21,22).…”

Section: Introductionsupporting

confidence: 55%

“…Because embryonic AChR is not expressed by adult innervated muscle, this finding lends credence to the proposed origin ofthe anti-AChR sensitization in MG within the thymus (20), which expresses an AChR similar or identical to embryonic muscle AChR, containing a y subunit (18) . Because the thymus AChR also contains a, ,B, and 6 subunits (18), T cells sensitized against epitopes formed by subunit present also in the more abundant muscle AChR may be preferentially expanded.…”

Section: Discussionmentioning

confidence: 60%

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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: Introductionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 60%

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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“…Although all responders recognized one or more epitopes on all three AChR subunits, including the embryonic y subunit, the relative contribution of each subunit to the repertoire of antiAChR Th cells was characteristic for each patient. Therefore, several AChR epitopes are involved in Th sensitization in any (36,37) may be due to removal ofa reservoir of embryonic AChR in a tissue rich in antigen-presenting cells.…”

Section: Discussionmentioning

confidence: 99%

“…The embryonic -y subunit is a likely candidate as the EOM-specific structure recognized in MG. The y subunit is expressed in normal thymus (35), further supporting the involvement ofan embryonic AChR in MG pathogenesis, since the anti-AChR sensitization might originate within the thymus (36), which in MG patients is frequently hypertrophic or contains a thymoma (37), and contains anti-AChR T and B cells (10,(38)(39)(40).…”

mentioning

confidence: 99%

T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits.

et al. 1993

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We tested the response of CD4' cells and/or total lymphocytes from the blood of 22 myasthenic patients and 10 healthy controls to overlapping synthetic peptides, 20 residues long, to screen the sequence of the y and 5 subunits of human muscle acetylcholine receptor (AChR). The oy subunit is part of the AChR expressed in embryonic muscle and is substituted in the AChRs of most adult muscles by an e subunit. The 5 subunit is present in both embryonic and adult AChRs. Adult extrinsic ocular muscles, which are preferentially and sometimes uniquely affected by myasthenic symptoms, and thymus, which has a still obscure but important role in the pathogenesis of myasthenia gravis, express the embryonic 'y subunit. AntiAChR CD4+ responses were more easily detected after CD8+ depletion. All responders recognized epitopes on both the y and a subunits and had severe symptoms. In four patients the CD4 + cell response was tested twice, when the symptoms were severe and during a period of remission. Consistently, the response was only detectable, or larger, when the patients were severely affected. (J. Clin. Invest. 1993. 92:1055-1067

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“…In addition to these clinical observations, strong experimental evidence implies the thymus as the primary site of a pathogenic autoimmune response against the neuromuscular acetylcholine receptor (AchR). Thymic myogenic precursor cells are inducible to differentiate in vitro into AchR-expressing myotubes (4)(5)(6)(7). In fact, AchR is expressed on thymic "myoid cells" (8), rare muscle-like, HLA-DR-negative cells concentrated at the cortico-medullary junction and in the thymic medulla (9,10).…”

Section: Introductionmentioning

confidence: 99%

Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis.

S¹,

Padberg²,

Hohlfeld³

et al. 1992

J. Clin. Invest.

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To study the role of the thymus in the cellular pathogenesis of myasthenia gravis (MG) we transplanted thymus tissue fragments from MG thymuses beneath the kidney capsule of severe combined immunodeficiency (SCID) mice. Immunocytochemical studies documented that the human thymus tissues are accepted as long-term grafts in the host SCID mice, with human lymphocytes, thymic stroma, and thymic myoid cells demonstrable in transplanted thymus for at least 15 weeks after transplantation. Human anti-acetylcholine receptor antibodies became detectable 1 to 2 weeks after transplantation, and in most chimeras the titers increased over at least 11 weeks to reach levels typically found in severe human MG. Human Ig deposits were detected at skeletal muscle end-plates, demonstrating that the human (auto)antibodies bound to murine acetylcholine receptor. In contrast, transfers of dissociated thymus cells only lead to a transient increase of anti-acetylcholine receptor antibodies. Our data prove that myasthenia gravis thymus is able to induce and maintain autoantibody production in immunodeprived host animals, and that this tissue contains all cellular components required for autoantibody production. Transplantation of solid thymus tissue seems to transfer an autoimmune microenvironment, which will allow direct studies ofthe mechanism of autosensitization inside the thymus. (J. Clin. Invest. 1992. 90:245-250.)

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Thymic Myogenesis, T‐lymphocytes and the Pathogenesis of Myasthenia Gravis*

Cited by 78 publications

References 62 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.

T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits.

Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis.

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