Kanneboyina Nagaraju

Rabin N,Loeffler L,Parker T,Rochon P,Le E,Danning C

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Abstract

In the human inflammatory myopathies (polymyositis and dermatomyositis), the early, widespread appearance of MHC class I on the surface of muscle cells and the occurrence of certain myositis-specific autoantibodies are striking features. We have used a controllable muscle-specific promoter system to up-regulate MHC class I in the skeletal muscles of young mice. These mice develop clinical, biochemical, histological, and immunological features very similar to human myositis. The disease is inflammatory, limited to skeletal muscles, self-sustaining, more severe in females, and often accompanied by autoantibodies, including, in some mice, autoantibodies to histidyl-tRNA synthetase, the most common specificity found in the spontaneous human disease, anti-Jo-1. This model suggests that an autoimmune disease may unfold in a highly specific pattern as the consequence of an apparently nonspecific event—the sustained up-regulation of MHC class I in a tissue—and that the specificity of the autoantibodies derives not from the specificity of the stimulus, but from the context, location, and probably the duration of the stimulus. This model further suggests that the presumed order of events as an autoimmune disease develops needs to be reconsidered.

In many autoimmune diseases, not only is the inflammatory destruction limited to particular target cells, but the associated autoantibodies are often highly disease specific. In myositis, for example, muscle cells are the target, and the autoantibodies against aminoacyl-tRNA synthetases, the signal recognition particle, or the Mi-2 nuclear protein (which are components of all cells) that occur in a significant proportion of cases are highly specific for myositis (1). In primary biliary cirrhosis, the inflammation affects intrahepatic biliary ducts, and the associated antimitochondrial autoantibodies, directed against the pyruvate dehydrogenase complex, occur in most cases and only rarely in other diseases (2). Such tight relationships naturally have fostered the view that a specific inciting agent is responsible for both the target cell injury and the autoantibodies. It has been generally assumed that the high specificity of target tissue damage and disease-specific autoantibodies derive from the structure of the inciting agent, but direct evidence for such a model has been sparse. Although much evidence suggests a role for inciting environmental agents as well as genetic factors in the development of autoimmune diseases, there are few, if any, persuasive examples connecting particular inciting agents to the later immunopathogenetic events (3), and although cross-reactivity with an inciting antigen would provide a convenient explanation for the breaking of tolerance, some carefully studied cases suggest that the endogenous target protein rather than a foreign antigen drives the autoantibody response (4).

The overexpression of MHC class I molecules is an early event in many autoimmune diseases, particularly in tissues which, like muscle, pancreatic β cells, and thyroid, have low or absent constitutive expression (5–7). The overexpression can occur in the absence of an inflammatory infiltrate, suggesting that it may be independent of and precede the effects of cytokines released from infiltrating mononuclear cells. Transgenic overexpression of MHC class I in several tissues has resulted in the destruction of the target tissue leading to insulin-dependent diabetes, a shivering phenotype with severe demyelination of the central nervous system, and Graves' disease in the absence of lymphocyte infiltration (8–10). In these mice, the transgenic MHC class I expression was driven by the respective tissue-specific promoters during the development of immune system in utero, with uncertain effects on tolerance. In a recently described mouse illness strongly resembling rheumatoid arthritis, the disease is genetically determined, both T and B cells are required, and an apparently driving antigen has been identified, but the reason that the inflammation is confined to the joints is not yet clear (11–13). Furthermore, in none of these models have the autoantibodies characteristic of the corresponding human disease been described. In another set of models of autoimmunity, such as knockout of transforming growth factor β (TGF-β) apoptosis inhibition, or graft-versus-host disease, generalized dysregulation of immunity leads to widespread inflammation and considerable nonspecific humoral autoimmunity (14–16).

In the human idiopathic inflammatory myopathies, the early, widespread appearance of MHC class I on the surface of muscle cells, even distant from lymphocytic infiltration, is a striking feature (17). Skeletal muscle cells do not constitutively express or display MHC class I molecules, although they can be induced to do so by proinflammatory cytokines such as IFN-γ and tumor necrosis factor α (18). The presence of proinflammatory cytokines in the affected tissue is inconstant (19, 20) and appears to be inadequate to account for the up-regulation. Because many events can up-regulate MHC class I on cell surfaces, we considered the possibility that the prolonged expression of MHC class I on the surface of muscle cells could itself be the inciting event of myositis, independent of a specific inciting stimulus. To avoid the possible effects of MHC class I on fetal development and present it to animals with a mature immune system, we used tetracycline regulation to control its expression.

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PNAS

9209–9214, doi: 10.1073/pnas.97.16.9209

2000

http://www.pnas.org/content/97/16/9209.long