Skip to main content

Advertisement

Log in

Advances in the immunobiology and treatment of inflammatory myopathies

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

The clinical spectrum and immunopathogenesis of inflammatory myopathies are summarized with an update on possible triggering factors, cell degeneration, and emerging new therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Dalakas MC: Polymyositis, dermatomyositis and inclusionbody myositis. N Engl J Med 1991, 325:1487–1498.

    Article  PubMed  CAS  Google Scholar 

  2. Engel AG, Hohlfeld R: The polymyositis and dermatomyositis syndromes. In Myology, 3rd edn. Edited by Engel AG, Franzini-Armstrong C. New York: McGraw-Hill Book Co.; 2004:1321–1366.

    Google Scholar 

  3. Mastaglia FL, Phillips BA: Idiopathic inflammatory myopathies: epidemiology, classification and diagnostic criteria. Rheum Dis Clin N Am 2002, 28:723–741.

    Article  Google Scholar 

  4. Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis. Lancet 2003, 362:971–982.

    Article  PubMed  CAS  Google Scholar 

  5. Hilton-Jones D: Inflammatory myopathies. Curr Opin Neurol 2001, 14:591–596.

    Article  PubMed  CAS  Google Scholar 

  6. Dalakas MC: Mechanisms of disease: signaling pathways and immunobiology of inflammatory myopathies. Nat Clin Pract Rheumatol 2006, 2:219–227.

    Article  PubMed  CAS  Google Scholar 

  7. Dalakas MC: Sporadic inclusion body myositis—diagnosis, pathogenesis and therapeutic strategies. Nat Clin Pract Neurol 2006, 2:437–447.

    Article  PubMed  CAS  Google Scholar 

  8. Dalakas MC: Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol 1998, 55:1509–1512.

    Article  PubMed  CAS  Google Scholar 

  9. Brunn A, Schroder R, Deckert M: The inflammatory reaction pattern distinguishes primary dysferlinopathies from idiopathic inflammatory myopathies: an important role for the membrane attack complex. Acta Neuropathol (Berl) 2006, 112:325–332.

    Article  CAS  Google Scholar 

  10. Dorph C, Englund P, Nennesmo I, Lundberg IE: Signs of inflammation in both symptomatic and asymptomatic muscles from patients with polymyositis and dermatomyositis. Ann Rheum Dis 2006, 65:1565–1571.

    Article  PubMed  CAS  Google Scholar 

  11. Prayson RA: Diagnostic yield associates with multiple simultaneous skeletal muscle biopsies. Am J Clin Pathol 2006, 126:843–848.

    PubMed  Google Scholar 

  12. Kissel JT, Mendell JR, Rammohan KW: Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986, 314:329–334.

    Article  PubMed  CAS  Google Scholar 

  13. Emslie-Smith AM, Engel AG: Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 1990, 27:343–356.

    Article  PubMed  CAS  Google Scholar 

  14. Dalakas MC: Immunopathogenesis of inflammatory myopathies. Ann Neurol 1995, 37(Suppl 1):S74–S86.

    Article  PubMed  Google Scholar 

  15. Dalakas MC, Illa I, Dambrosia JM, et al.: A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 1993, 329:1993–2000.

    Article  PubMed  CAS  Google Scholar 

  16. Gallardo E, de Andres I, Illa I: Cathepsins are upregulated by IFN-gamma/STAT1 in human muscle culture: a possible active factor in dermatomyositis. J Neuropathol Exp Neurol 2001, 60:847–855.

    PubMed  CAS  Google Scholar 

  17. Illa I, Gallardo E, Gimeno R, et al.: Signal transducer and activator of transcription 1 in human muscle: implications in inflammatory myopathies. Am J Pathol 1997, 151:81–88.

    PubMed  CAS  Google Scholar 

  18. Greenberg SA, Pinkus JL, Pinkus GS, et al.: Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 2005, 57:664–678.

    Article  PubMed  CAS  Google Scholar 

  19. O’Connor KA, Abbott KA, Sabin B, et al.: MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: association with muscle involvement. Clin Immunol 2006, 120:319–325.

    Article  PubMed  CAS  Google Scholar 

  20. Tezak Z, Hoffman EP, Lutz JL, et al.: Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis. J Immunol 2002, 168:4154–4163.

    PubMed  CAS  Google Scholar 

  21. Raju R, Dalakas MC: Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain 2005, 128:1887–1896.

    Article  PubMed  Google Scholar 

  22. Nagaraju K, Rider LG, Fan C, et al.: Endothelial cell activation and neovascularization are prominent in dermatomyositis. J Autoimmune Dis 2006, 3:2.

    Article  PubMed  CAS  Google Scholar 

  23. Hohlfeld R, Engel AG: The immunobiology of muscle. Immunol Today 1994, 15:269–274.

    Article  PubMed  CAS  Google Scholar 

  24. Wiendl H, Hohlfeld R, Kieseier BC: Immunobiology of muscle: advances in understanding an immunological microenvironment. Trends Immunol 2005, 26:373–380.

    Article  PubMed  CAS  Google Scholar 

  25. Arahata K, Engel AG: Monoclonal antibody analysis of mononuclear cells in myopathies. II. Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984, 16:209–215.

    Article  PubMed  Google Scholar 

  26. Karpati G, Pouliot Y, Carpenter S: Expression of immunoreactive major histocompatibility complex products in human skeletal muscles. Ann Neurol 1988, 23:64–72.

    Article  PubMed  CAS  Google Scholar 

  27. Emslie-Smith AM, Arahata K, Engel AG: Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes and T-cell-mediated cytotoxicity in myopathies. Hum Pathol 1989, 20:224–231.

    Article  PubMed  CAS  Google Scholar 

  28. Michaelis D, Goebels N, Hohlfeld R: Constitutive and cytokine-induced expression of human leukocyte antigens and cell adhesion molecules by human myotubes. Am J Pathol 1993, 143:1142–1149.

    PubMed  CAS  Google Scholar 

  29. Goebels N, Michaelis D, Engelhardt M, et al.: Differential expression of perforin in muscle-infiltrating T cell in polymyositis and dermatomyositis. J Clin Invest 1996, 97:2905.

    Article  PubMed  CAS  Google Scholar 

  30. Schmidt J, Rakocevic G, Raju R, Dalakas MC: Upregulated inducible costimulator and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T-cell cytotoxicity. Brain 2004, 127:1182–1190.

    Article  PubMed  Google Scholar 

  31. Ikezoe K, Ohshima S, Osoegawa M, et al.: Expression of granulysin in polymyositis and inclusion-body myositis. J Neurol Neurosurg Psychiatry 2006, 77:1187–1190.

    Article  PubMed  CAS  Google Scholar 

  32. O’Hanlon TP, Dalakas MC, Plotz PH, Miller FW: Predominant T cell receptor variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies. J Immunol 1994, 152:2 569–2 576.

    CAS  Google Scholar 

  33. Bender A, Behrens L, Engel AG, Hohlfeld R: T-cell heterogeneity in muscle lesions of inclusion body myositis. J Neuroimmunol 1998, 84:86–91.

    Article  PubMed  CAS  Google Scholar 

  34. Fyhr IM, Moslemi AR, Mosavi AA, et al.: Oligoclonal expansion of muscle infiltrating T cells in inclusion body myositis. J Neuroimmunol 1997, 79:185–189.

    Article  PubMed  CAS  Google Scholar 

  35. Benveniste O, Cherin P, Maisonobe T, et al.: Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomyositis patients. J Immunol 2001, 167:3521–3529.

    PubMed  CAS  Google Scholar 

  36. Nishio J, Suzuki M, Miyasaka N, Kohsaka H: Clonal biases of peripheral CD8 T cell repertoire directly reflect local inflammation in polymyositis. J Immunol 2001, 167:4051–4058.

    PubMed  CAS  Google Scholar 

  37. Amemiya K, Granger RP, Dalakas MC: Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time: studies in repeated muscle biopsies. Brain 2000, 123:2030–2039.

    Article  PubMed  Google Scholar 

  38. Muntzing K, Lindberg C, Moslemi AR, Oldfors A: Inclusion body myositis: clonal expansions of muscle-infiltrating T cells persist over time. Scand J Immunol 2003, 58:195–200.

    Article  PubMed  CAS  Google Scholar 

  39. Hofbauer M, Wiesener S, Babbe H, et al.: Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR and CDR3 spectratype analysis. Proc Natl Acad Sci U S A 2003, 100:4090–4095.

    Article  PubMed  CAS  Google Scholar 

  40. Dimitri D, Benveniste O, Dubourg O, et al.: Shared blood and muscle CD8+ T-cell expansions in inclusion body myositis. Brain 2006, 129(Pt 4):986–995.

    Article  PubMed  Google Scholar 

  41. Salajegheh M, Rakocevic G, Goldfarb L, Dalakas MC: T cell spectratyping in IBM: In situ clonal expansion. Neurology 2007, in press.

  42. Behrens L, Kerschensteiner M, Misgeld T: Human muscle cells express a functional costimulatory molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in inflammatory lesions. J Immunol 1998, 161:5943–5951.

    PubMed  CAS  Google Scholar 

  43. Murata K, Dalakas MC: Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28 and their mRNA in inflammatory myopathies. Am J Pathol 1999, 155:453–460.

    PubMed  CAS  Google Scholar 

  44. Wiendl H, Mitsdoerffer M, Schneider D, et al.: Muscle fibers and cultured muscle or cells express the B7.1/2 related costimulatory molecule ICOSL: implications for the pathogenesis of inflammatory myopathies. Brain 2003, 126:1026–1035.

    Article  PubMed  Google Scholar 

  45. Sugiura T, Kawaguchi Y, Harigai M, et al.: Increased CD40 expression on muscle cells of polymyositis and dermatomyositis: role of CD40-CD40 ligand interaction in IL-6, IL-8, IL-15 and monocyte chemoattractant protein-1 production. J Immunol 2000, 164:6593–6600.

    PubMed  CAS  Google Scholar 

  46. Howard OM, Dong HF, Yang D, et al.: Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med 2002, 196:781–791.

    Article  PubMed  CAS  Google Scholar 

  47. Greenberg SA, Pinkus GS, Amato AA, Pinkus JL: Myeloid dendritic cells in inclusion-body myositis and polymyiositis. Muscle Nerve 2007, 35:17–23.

    Article  PubMed  CAS  Google Scholar 

  48. Bradshaw EM, Orihuela A, McArdel SL, et al.: A local antigen-driven humoral response is present in the inflammatory myopathies. J Immunol 2007, 178:547–556.

    PubMed  CAS  Google Scholar 

  49. Figarella-Branger D, Civate M, Bartoli C, Pellissier JF: Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve 2003, 28:659–682.

    Article  PubMed  CAS  Google Scholar 

  50. De Bleecker JL, De Paepe B, Vanwalleghem IE, Schroder JM: Differential expression of chemokines in inflammatory myopathies. Neurology 2002, 58:1779–1785.

    PubMed  Google Scholar 

  51. Raju R, Vasconcelos OM, Semino-Mora C, et al.: Expression of interferon-gamma inducible chemokines in the muscles of patients with inclusion body myositis. J Neuroimmunol 2003, 141:125–131.

    Article  PubMed  CAS  Google Scholar 

  52. Confalonieri P, Bernasconi P, Megna P, et al.: Increased expression of beta-chemokines in muscle of patients with inflammatory myopathies. J Neuropathol Exp Neurol 2000, 59:164–169.

    PubMed  CAS  Google Scholar 

  53. Choi YC, Dalakas MC: Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies. Neurology 2000, 54:65–71.

    PubMed  CAS  Google Scholar 

  54. Amemiya K, Semino-Mora C, Granger RP, Dalakas MC: Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol 2000, 94:99–104.

    Article  PubMed  CAS  Google Scholar 

  55. Grundtman C, Salomonsson S, Dorph C, et al.: Immunolocalization of interleukin-1 receptors in the sarcolemma and nuclei of skeletal muscle in patients with idiopathic inflammatory myopathies. Arthritis Rheum 2007, 56:674–687.

    Article  PubMed  Google Scholar 

  56. Dehmel T, Janke A, Hartung HP, et al.: The cell-specific expression of metalloproteinase-sisintegrins (ADAMs) in inflammatory myopathies. Neurobiol Dis 2007, 25:665–674.

    Article  PubMed  CAS  Google Scholar 

  57. Leff RL, Love LA, Miller FW, et al.: Viruses in the idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle. Lancet 1992, 339:1192–1195.

    Article  PubMed  CAS  Google Scholar 

  58. Leon-Monzon M, Dalakas MC: Absence of persistent infection with enteroviruses in muscles of patients with inflammatory myopathies. Ann Neurol 1992, 32:219–222.

    Article  PubMed  CAS  Google Scholar 

  59. Dalakas MC, Pezeshkpour GH, Gravell M, Sever JL: Polymyositis in patients with AIDS. JAMA 1986, 256:2381–2383.

    Article  PubMed  CAS  Google Scholar 

  60. Cupler EJ, Leon-Monzon M, Miller J: Inclusion body myositis in HIV-I and HTLV-I infected patients. Brain 1996, 119:1887–1893.

    Article  PubMed  Google Scholar 

  61. Dalakas MC: Autoimmune and viral aspects of inclusion body myositis. Neurology 2006, 66(2 Suppl 1):S33–38.

    PubMed  CAS  Google Scholar 

  62. Dalakas MC, Rakocevic G, Shatunov A, et al.: Inclusion body myositis with human immunodeficiency virus infection: four cases with HIV infection and clonal expansion of viralspecific T cells. Ann Neurol 2007, 61:466–475.

    Article  PubMed  CAS  Google Scholar 

  63. Ozden S, Cochet M, Mikol J, et al.: Direct evidence for a chronic CD8+-T-cell-mediated immune reaction to tax within the muscle of a human T-cell leukemia/lymphoma virus type 1-infected patient with sporadic inclusion body myositis. J Virol 2004, 78:10320–10327.

    Article  PubMed  CAS  Google Scholar 

  64. Ozden S, Gessain A, Gout O, Mikol J: Sporadic inclusion body myositis in a patient with human T-cell leukemia virus type 1-associated myelopathy. Clin Infect Dis 2001, 32:510–514.

    Article  PubMed  CAS  Google Scholar 

  65. Saito M, Higuchi I, Saito A, et al.: Molecular analysis of T cell clonotypes in muscle-infiltrating lymphocytes from patients with human T lymphotropic virus type 1 polymyositis. J Infect Dis 2002, 186:1231–1241.

    Article  PubMed  CAS  Google Scholar 

  66. Illa I, Nath A, Dalakas MC: Immunocytochemical and virological characteristics of HIV-associated inflammatory myopathies: similarities with seronegative polymyositis. Ann Neurol 1991, 29:474–481.

    Article  PubMed  CAS  Google Scholar 

  67. Leon-Monzon M, Illa I, Dalakas MC: Polymyositis in patients infected with HTLV-I: the role of the virus in the cause of the disease. Ann Neurol 1994, 36:643–649.

    Article  PubMed  CAS  Google Scholar 

  68. Nyberg P, Wikman AL, Nennesmo I, Lundberg I: Increased expression of interleukin 1alpha and MHC class I in muscle tissue of patients with chronic, inactive polymyositis and dermatomyositis. J Rheumatol 2000, 27:940–948.

    PubMed  CAS  Google Scholar 

  69. Williams A, Peh CA, Elliott T: The cell biology of MHC class I antigen presentation. Tissue Antigens 2002, 59:3–17.

    Article  PubMed  CAS  Google Scholar 

  70. Grandea AG 3rd, Van Kaer L: Tapasin: an ER chaperone that controls MHC class I assembly with peptide. Trends Immunol 2001, 22:194–199.

    Article  PubMed  CAS  Google Scholar 

  71. Lehner PJ, Cresswell P: Recent developments in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 2004, 16:82–89.

    Article  PubMed  CAS  Google Scholar 

  72. Hughes EA, Hammond C, Cresswell P: Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. Proc Natl Acad Sci U S A 1997, 94:1896–1901.

    Article  PubMed  CAS  Google Scholar 

  73. Nagaraju K, Casciola-Rosen L, Lundberg I, et al.: Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 2005, 52:1824–1835.

    Article  PubMed  CAS  Google Scholar 

  74. Ferrer I, Martin B, Castano JG: Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis. J Neuropathol Exp Neurol 2004, 63:484–498.

    PubMed  CAS  Google Scholar 

  75. Vattemi G, Engel WK, McFerrin J, et al.: Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle. Am J Pathol 2004, 164:1–7.

    PubMed  CAS  Google Scholar 

  76. Fratta P, Engel WK, McFerrin J, et al.: Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-beta precursor protein-overexpressing cultured human muscle fibers. Am J Pathol 2005, 167:517–526.

    PubMed  CAS  Google Scholar 

  77. Pahl HL, Baeuerle PA: The ER-overload response: activation of NF-kappa B. Trends Biochem Sci 1997, 22:63–67.

    Article  PubMed  CAS  Google Scholar 

  78. Banwell BL, Engel AG: AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 2000, 54:1033–1041.

    PubMed  CAS  Google Scholar 

  79. Ferrer I, Carmona M, Blanco R, et al.: Involvement of clusterin and the aggresome in abnormal protein deposits in myofibrillar myopathies and inclusion body myositis. Brain Pathol 2005, 15:101–108.

    Article  PubMed  CAS  Google Scholar 

  80. Nagaraju K, Raben N, Loeffler L, et al.: Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci U S A 2000, 97:9209–9214.

    Article  PubMed  CAS  Google Scholar 

  81. Dalakas MC: Therapeutic approaches in patients with inflammatory myopathies. Sem Neurology 2003, 23:199–206.

    Article  Google Scholar 

  82. Hohlfeld R, Dalakas MC: Basic principles of immunotherapy in neurological diseases. Sem Neurol 2003, 23:121–132.

    Article  Google Scholar 

  83. Dalakas MC: Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscul Disord 2006, 16:223–236.

    Article  PubMed  Google Scholar 

  84. Dalakas MC: B cell in the pathophysiology of autoimmune neurological disorders: a credible therapeutic target. Pharmacol Ther 2006, 112:57–70.

    Article  PubMed  CAS  Google Scholar 

  85. Efthimiou P, Schwartzman S, Kagen LJ: Possible role for tumour necrosis factor inhibitors in the treatment of resistant dermatomyositis and polymyositis: a retrospective study of eight patients. Ann Rheum Dis 2006, 65:1233–1236.

    Article  PubMed  CAS  Google Scholar 

  86. Noss EH, Hausner-Sypek DL, Weinblatt ME: Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol 2006, 33:1021–1026.

    PubMed  Google Scholar 

  87. Bronner IM, van der Meulen MF, de Visser M, et al.: Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis 2006, 65:1456–1461.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marinos C. Dalakas MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalakas, M.C. Advances in the immunobiology and treatment of inflammatory myopathies. Curr Rheumatol Rep 9, 291–297 (2007). https://doi.org/10.1007/s11926-007-0047-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-007-0047-5

Keywords

Navigation