Abstract
Myasthenia gravis is (MG) a prototypic autoimmune disease; the immune effector mechanisms
and autoantigenic target have been delineated. However, the events that lead to the
abrogation of self-tolerance to neuromuscular acetylcholine receptors (nAChRs) remain
a mystery. The thymus gland has long been considered to hold the key to solving this
mystery, although the nature of its involvement remains to be elucidated. The nAChR
was one of the first self-proteins associated with a defined autoimmune disease that
was found to be expressed on thymic stromal populations. The studies described herein
represent our efforts to determine how this “promiscuous” autoantigen expression may
be involved in the immunopathogenesis of MG. We review our work, characterizing the
expression of the nAChR alpha subunit in the thymus, and advance a hypothesis and
experimental model, which explore how intrathymic expression of this autoantigen may
contribute to the immunopathogenesis of this autoimmune disease.
Keywords
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References
Levinson AI. Myasthenia Gravis. In: Rich R, et al., editors. Principles and Practice of Clinical Immunology. 4th edition. London, UK: Elsevier; in press.
- The thymus in myasthenia gravis: site of innate autoimmunity.Muscle Nerve. 2011; 44: 467-481
- Scenarios for autommunization of T and B cells in myasthenia gravis.Ann N Y Acad Sci. 2003; 998: 237-256
- Thymectomy as primary therapy in myasthenia gravis.Ann N Y Acad Sci. 1987; 505: 595-606
- Treatment strategies in myasthenia gravis.Ann N Y Acad Sci. 1993; 681: 603-608
- Comparative immunoglobulin synthesis by blood lymphocytes of myasthenics and normals.Ann N Y Acad Sci. 1981; 377: 385-392
- Phenotypic characterization of thymic B lymphocytes in myasthenia gravis.J Clin Immunol. 1989; 9: 242-247
- Pokeweed mitogen-induced immunoglobulin secretory responses of thymic B cells in myasthenia gravis: selective secretion of IgG vs. IgM cannot be explained by helper functions of thymic T cells.Clin Immunol Immunopathol. 1990; 57: 211-217
- Thymic B-cell activation in myasthenia gravis.Neurology. 1984; 34: 462-468
- Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes.N Engl J Med. 1981; 305: 1313-1318
- Antibodies to acetylcholine receptor and tetanus toxoid: in vitro synthesis by thymic lymphocytes.J Immunol. 1986; 137: 1221-1225
- Specific activation of lymphocytes against acetylcholine receptor in myasthenia gravis.J Immunol. 1986; 136: 887-891
- Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotine acetylcholine receptor from thymuses of myasthenic patients.J Clin Invest. 1988; 81: 902-908
- Myasthenic thymus and thymoma are selectively enriched in AChR-reactive T cells.Neurology. 1991; 41: 1270-1276
- Effector T lymphocyte cell line cells migrate to the thymus and persist there.Nature. 1982; 300: 262-264
- Immunohistological analysis of immigration of thymocyte-precursors into the thymus: evidence for immigration of peripheral T cells into the thymic medulla.Cell Immunol. 1989; 119: 160-170
- Rare peripheral T cells migrate to and persist in normal mouse thymus.J Exp Med. 1988; 168: 1929-1934
- Entry of antivirally active T lymphocytes into the thymus of virus-infected mice.J Immunol. 1991; 146: 293-297
- Reentry of T cells to the adult thymus is restricted to activated cells.J Exp Med. 1991; 173: 1039-1046
- Abrogation of tolerance to a chronic viral infection.J Immunol. 1991; 147: 3521-3529
- Regulatory and pathogenic mechanisms in human autoimmune myasthenia gravis.Ann N Y Acad Sci. 2008; 1132: 135
- Functional defect of regulatory CD4+ CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis.Blood. 2005; 105: 735-741
- Undiminished regulatory T cells in the thymus of patients with myasthenia gravis.Neurology. 2010; 74: 816-820
- In situ production of interleukins in hyperplastic thymus from myasthenia gravis patients.Hum Pathol. 1991; 22: 461-468
- The thymus is a source of B-cell-survival factors – APRIL and BAFF – in myasthenia gravis.J Neuroimmunol. 2006; 178: 161
- The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis.Blood. 2006; : 432-440
- CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia.Ann Neurol. 2009; 66: 521-531
- Intrathymic pathogenesis of myasthenia gravis: transient expression of acetylcholine receptors on thymus-derived myogenic cells.Eur J Immunol. 1978; 8: 579-582
- A central role for central tolerance.Annu Rev Immunol. 2006; 24: 571-606
- Thymic epithelial cells contain acetylcholine receptor.Lancet. 1977; 1: 1310-1311
- Thymic lymphocytes bear a surface antigen which cross-reacts with acetylcholine receptor.Nature. 1980; 287: 162-164
- Thymic muscle cells bear acetylcholine receptors: possible relation to myasthenia gravis.Science. 1977; 195: 74-75
- Acetylcholine in human thymic myoid cells in situ: an immunologic study.Ann Neurol. 1987; 22: 212-222
- Human helper T lymphocytes in myasthenia gravis recognize the nicotinic receptor a subunit.Proc Natl Acad Sci. 1987; 84: 5379-5383
- Immunologic heterogeneity of autoreactive T lymphocytes against the nicotinic acetylcholine receptor in myasthenic patients.Eur J Immunol. 1990; 20: 2577-2583
- Autoimmune T cell recognition of human acetylcholine receptor: the sites of T cell recognition in myasthenia gravis on the extracellular part of the α-subunit.Eur J Immunol. 1990; 20: 2563-2569
- Specificity of the T cell immune response to acetylcholine receptor in experimental autoimmune myasthenia gravis.J Immunol. 1988; 140: 1830-1837
- Molecular characterization of the nicotinic acetylcholine receptor alpha chain in mouse thymus.J Immunol. 1992; 148: 3105-3109
- Molecular analysis of intrathymic nicotinic acetylcholine receptor.Ann N Y Acad Sci. 1993; 681: 74-82
- Acetylcholine receptor alpha subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-γ.Clin Immunol. 1999; 1: 170-177
- Expression of acetylcholine receptor genes in human thymic epithelial cells. Implications for myasthenia gravis.J Immunol. 1998; 157: 3752-3760
- Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the δ subunit.Muscle Nerve. 2001; 24: 203-210
- Different patterns of nicotinic acetylcholine receptor subunit transcription in human thymus.J Neuroimmunol. 2004; 149: 147-159
- The human muscle nicotinic acetylcholine receptor α-subunit exists as two isoforms: a novel exon.EMBO. 1990; 9: 2101-2106
- Nicotinic acetylcholine receptor α-subunit variants in human myasthenia gravis: quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction.J Clin Invest. 1993; 94: 16
- IL-1, IL-4, and IFN-γ differentially regulate cytokine production and cell surface molecule expression in cultured human thymic epithelial cells.J Immunol. 1991; 47: 3823-3830
- Effects of cytokines on acetylcholine receptor expression: implications for myasthenia gravis.J Immunol. 2005; 174: 5941-5949
- Interferon-gamma modulates HLA class II antigen expression on cultured human thymic epithelial cells.J Immunol. 1985; 35: 1165-1171
- Antigen presentation in the thymus for positive selection and central tolerance.Nat Rev Immunol. 2009; 9: 833-844
- The anatomy of T-cell activation and tolerance.Proc Natl Acad Sci. 1996; 93: 2245-2252
- Roles of viruses in the loss of tolerance to self-antigens and in autoimmune diseases.Trends Microbiol. 1995; 3: 424-443
- A new model linking intrathymic acetylcholine receptor expression and the pathogenesis of myasthenia gravis. In myasthenia gravis and related disorders.Ann N Y Acad Sci. 2003; 998: 257-265
Article info
Publication history
Published online: January 18, 2013
Accepted:
December 21,
2012
Received in revised form:
December 13,
2012
Received:
September 14,
2012
Identification
Copyright
© 2012 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
