Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.
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21 February 2005
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February 22 2005
Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy
Livia Casciola-Rosen,
Livia Casciola-Rosen
1Department of Medicine, Division of Rheumatology
2Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
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Kanneboyina Nagaraju,
Kanneboyina Nagaraju
1Department of Medicine, Division of Rheumatology
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Paul Plotz,
Paul Plotz
6Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
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Kondi Wang,
Kondi Wang
7Department of Neuropathology, Armed Forces Institute of Pathology, Washington DC 20306
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Stuart Levine,
Stuart Levine
1Department of Medicine, Division of Rheumatology
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Edward Gabrielson,
Edward Gabrielson
5Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
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Andrea Corse,
Andrea Corse
4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
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Antony Rosen
Antony Rosen
1Department of Medicine, Division of Rheumatology
3Department Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, MD 21224
5Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
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Livia Casciola-Rosen
1Department of Medicine, Division of Rheumatology
2Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
Kanneboyina Nagaraju
1Department of Medicine, Division of Rheumatology
Paul Plotz
6Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
Kondi Wang
7Department of Neuropathology, Armed Forces Institute of Pathology, Washington DC 20306
Stuart Levine
1Department of Medicine, Division of Rheumatology
Edward Gabrielson
5Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
Andrea Corse
4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
Antony Rosen
1Department of Medicine, Division of Rheumatology
3Department Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, MD 21224
5Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
CORRESPONDENCE Livia Casciola-Rosen: [email protected]
Abbreviations used: DM, dermatomyositis; DNA-PKcs, catalytic subunit of DNA-dependent protein kinase; HRS, histidyl tRNA synthetase; NCAM, neural cell adhesion molecule; NOVA, neuro-oncological ventral antigen; PARP, poly(ADP ribose polymerase); PCNA, proliferating cell nuclear antigen; PM, polymyositis; SLE, systemic lupus erythematosus.
Received:
July 08 2004
Accepted:
November 23 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 201 (4): 591–601.
Article history
Received:
July 08 2004
Accepted:
November 23 2004
Citation
Livia Casciola-Rosen, Kanneboyina Nagaraju, Paul Plotz, Kondi Wang, Stuart Levine, Edward Gabrielson, Andrea Corse, Antony Rosen; Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy . J Exp Med 21 February 2005; 201 (4): 591–601. doi: https://doi.org/10.1084/jem.20041367
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