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Neurofilament is an autoantigenic determinant in myasthenia gravis
A Schultz1, V Hoffacker, A Wilisch
1Institute of Pathology, University of Würzburg, Germany.
Abstract:
Intratumorous expression of a 153-kd protein (p153), which contains an acetylcholine receptor-like epitope, is the only tumor marker described to date that significantly associates with thymoma in paraneoplastic myasthenia gravis (MG). Here, we report that p153 is identical to the midsize neurofilament, as verified by immunohistochemistry, immunofluorescence, and western blot analysis. Furthermore, the acetylcholine receptor-like epitope of the midsize neurofilament (NF-M) was identified by peptide epitope mapping. We also show, using T-cell proliferation assays, a significantly increased response of intratumorous T cells to a recombinant midsize neurofilament fragment in thymoma patients with MG compared with MG patients with thymic follicular hyperplasia or thymoma patients without MG. The T cells of thymic follicular hyperplasia and thymoma patients without MG seem to be unresponsive to NF-M. In contrast, we found increased T-cell responses to recombinant acetylcholine receptor fragments in MG patients in general compared with non-MG patients. Increased T-cell responses to NF-M in patients with paraneoplastic MG might be the result of an abnormal positive selection of immature T cells within thymomas, caused by the expression of NF-M in neoplastic thymic epithelial cells. Our results offer further evidence that NF-M expression in thymomas is an autoantigenic determinant in MG.
Insights
A 153-kd protein in thymoma, previously linked to paraneoplastic myasthenia gravis (MG), is identified as midsize neurofilament (NF-M). Intratumoral T cells in thymoma-associated MG patients show increased responses to NF-M, suggesting it
Area of Science:
- Immunology
- Neuroscience
- Oncology
Background:
- Paraneoplastic myasthenia gravis (MG) is often associated with thymoma.
- A 153-kd protein (p153) with an acetylcholine receptor-like epitope is the sole tumor marker linked to thymoma in paraneoplastic MG.
- The identity and role of p153 in MG pathogenesis remain unclear.
Purpose of the Study:
- To identify the 153-kd protein (p153) associated with thymoma and paraneoplastic myasthenia gravis (MG).
- To investigate the immunological response to this protein in patients with thymoma and MG.
- To elucidate the role of midsize neurofilament (NF-M) in the development of paraneoplastic MG.
Main Methods:
- Immunohistochemistry, immunofluorescence, and western blot analysis to identify p153.
- Peptide epitope mapping to locate the acetylcholine receptor-like epitope on NF-M.
- T-cell proliferation assays using recombinant NF-M fragments in patient cohorts.
Main Results:
- The 153-kd protein (p153) was identified as midsize neurofilament (NF-M).
- The acetylcholine receptor-like epitope was mapped to NF-M.
- T cells from thymoma patients with MG exhibited significantly increased proliferation in response to NF-M fragments compared to other groups.
- T cells from MG patients generally showed increased responses to acetylcholine receptor fragments.
Conclusions:
- Midsize neurofilament (NF-M) is the tumor marker p153 found in thymoma associated with paraneoplastic MG.
- NF-M expression in thymomas may trigger an autoimmune response in MG via T-cell activation.
- NF-M acts as an autoantigenic determinant in paraneoplastic MG, potentially due to abnormal T-cell selection in thymomas.