The Journal of Experimental Medicine
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Published 22 February 2005. doi:10.1084/jem.20041367
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 4, 591-601
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ARTICLE

 Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy

Livia Casciola-Rosen1,2, Kanneboyina Nagaraju1, Paul Plotz6, Kondi Wang7, Stuart Levine1, Edward Gabrielson5, Andrea Corse4, and Antony Rosen1,3,5

1 Department of Medicine, Division of Rheumatology
2 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
3 Department Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, MD 21224
4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
5 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224
6 Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
7 Department of Neuropathology, Armed Forces Institute of Pathology, Washington DC 20306

CORRESPONDENCE Livia Casciola-Rosen: lcr{at}jhmi.edu

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.

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.


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