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. 2000 Aug 1;97(16):9209-14.
doi: 10.1073/pnas.97.16.9209.

Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies

K Nagaraju  1 , N Raben, L Loeffler, T Parker, P J Rochon, E Lee, C Danning, R Wada, C Thompson, G Bahtiyar, J Craft, R Hooft Van Huijsduijnen, P Plotz
Affiliations

Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies

K Nagaraju et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
(A) Schematic outline of the tetracycline regulatory system showing the MCK-tTA and TRE-H-2Kb transgenes. (B) Southern analysis of transgenic mice by using both tTA and TRE probes. (C) Northern analysis of mRNA from skeletal muscle of H+ T+ and H+ mice with (+) or without (−) doxycycline administration.
Figure 2
Figure 2
(A) Clinical phenotype of an H+ T+ female mouse at 5 months of age (Lower) showing significantly smaller size and lower back muscle wasting compared with a female H+ littermate (Upper). (B) Locomotor activity in pairs of mice at 3.5 months after the induction of the transgene. Total distance P < 0.001; vertical activity P < 0.0001. (C) Serum creatine phosphokinase (CK), P < 0.01; and glutamic-oxaloacetic transaminase (GOT) levels P < 0.01 (n = 8 per group); H+ T+ (filled bars) and control H+ or T+ female littermates (empty bars).
Figure 3
Figure 3
Hematoxylin-eosin staining of formalin-fixed sections at different stages of the disease. (A) 1.5 months of age H+ T+ mice; (B) 3.5 months of age H+ T+ mice; (C) 5.5 months of age H+ T+ mice; and (D) 5.5 months of age, single transgenic T+ littermate. (Scale bar: A–D, 100 μm.)
Figure 4
Figure 4
Immunohistological findings in 5.5-month-old H+ T+ female (Right) and T+ female littermate (Left). Immunohistochemistry for H-2Kb (A and B), ICAM-1 (C and D), MOMA-2 for monocyte/macrophage lineage cells (E and F), and I-Ab (G and H). No reactivity was found for the above antibodies in single transgenic control mice except for the occasional presence of I-Ab positive mononuclear cells (data not shown). [Scale bars and magnifications: (A–D) 100 μm and ×100 and (E–H) 50 μm and ×200.]
Figure 5
Figure 5
Immunofluorescent staining on Hep2 cells to detect autoantibodies. Sera from a T+ female mouse (A) and an H+ T+ female mouse (B). The H+ T+ serum shows fine cytoplasmic staining condensed around the nucleus, which diminishes toward the periphery.
Figure 6
Figure 6
The readministration of doxycycline to H+ T+ mice manifesting disease. (A) Hematoxylin-eosin staining of skeletal muscle; (1) T+ mouse at 9 months of age; (2) H+ T+ mouse without doxycycline at 9 months of age; and (3) H+ T+ mouse retreated with doxycycline for 5 months after 4 months without doxycycline. (B) Locomotor activity (total distance and vertical activity); lane 1, T+ mice (white bar); lanes 2 and 3, H+ T+ mice without doxycycline (black bar); and H+ T+ mice retreated with doxycycline for 5 months after 4 months of disease (red bar). (C) Northern blot analysis of skeletal muscle mRNA for endogenous H-2Kb and ICAM-1. Control T+ (lane 1) and H+ T+ mice before and after readministration of doxycycline (lanes 2 and 3).
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Comment in

  • B cells in autoimmunity.
    Mitchison NA, Wedderburn LR. Mitchison NA, et al. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8750-1. doi: 10.1073/pnas.97.16.8750. Proc Natl Acad Sci U S A. 2000. PMID: 10922029 Free PMC article. No abstract available.

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