Pathogenese der Einschlusskörperchenmyositis: Stellenwert der Entzündung und Bedeutung für Therapiestrategien

Zusammenfassung

Die Einschlusskörperchenmyositis (sporadic Inclusion Body Myositis, sIBM) ist die häufigste entzündliche Myopathie bei älteren Patienten. Eine effektive Therapie ist nicht verfügbar, sodass es zu einem langsam fortschreitenden Gehverlust kommt. Die komplexe Pathogenese umfasst degenerative Mechanismen mit einer Akkumulation aberranter Moleküle, vor allem β-Amyloid. Es kommt daneben zu einer deutlichen Entzündungsreaktion im Muskel mit einer Infiltration durch zytotoxische T-Zellen. In dieser Übersicht werden neuere Arbeiten zu unterschiedlichen Pathomechanismen bei der sIBM zusammengefasst. Es konnte demonstriert werden, dass Makroautophagie an der Prozessierung von β-Amyloid beteiligt ist und in Relation zu antigenpräsentierenden Mechanismen steht. Bezüglich der zytotoxischen T-Zell-Infiltration gibt es Hinweise auf eine relevante Antigenpräsentation über sogenannte „nichtklassische”, kostimulatorische Moleküle. Des Weiteren konnte bei der sIBM eine spezifische Interaktion zwischen degenerationsassoziierten Molekülen und der Entzündung im Muskel belegt werden. Passend dazu fand sich in Muskelzellen eine Akkumulation von β-Amyloid, die durch IL-1β induziert werden konnte. Zusammengefasst belegen diese Arbeiten, dass entzündliche Pathomechanismen bei der sIBM von wesentlicher Bedeutung sind. Aktuelle Therapiestrategien umfassen eine gezielte antikörpervermittelte Blockade von T-Zellen (Alemtuzumab) und B-Zellen (Rituximab). Daneben sollte zukünftig auch die Blockierung entzündlicher Mediatoren wie IL-1β und CXCL-9 sowie von β-Amyloid-generierenden Mechanismen (BACE1, Autophagie) erwogen werden.

Abstract

Sporadic inclusion body myositis (sIBM) is the most common myopathy in older patients. An effective therapy is not available to halt the slowly progressive loss of ambulation. The complex pathology includes degenerative mechanisms with an accumulation of aberrant molecules, most of all β-amyloid. At the same time, a significant inflammation with an infiltration by cytotoxic T-cells occurs in the muscle. This review summarises recent work on different pathomechanisms of sIBM. It has been demonstrated that macroautophagy is involved in the processing of β-amyloid and related to antigen-presenting mechanisms. In view of the infiltration by cytotoxic T-cells, there is evidence of a relevant antigen presentation via so-called „non-classical” co-stimulatory molecules. Moreover, in sIBM there is a specific interrelationship between degeneration-associated molecules and inflammation in the muscle. In line with this, an accumulation of β-amyloid can be induced by IL-1β in muscle cells. Taken together, these studies demonstrate that inflammatory mechanisms are of crucial relevance to the pathology of sIBM. Current therapeutic strategies include an antibody-mediated depletion of T-cells (alemtuzumab) and B-cells (rituximab). In the future, blockade of inflammatory molecules such as IL-1β and CXCL-9 as well as of β-amyloid-associated mechanisms (BACE1, autophagy) should be taken into account.

Myositis - Myopathie - Autoimmunität

myositis - myopathy - autoimmunity

Literatur

• 1 Needham M, Corbett A, Day T. et al . Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis.  J Clin Neurosci. 2008;  15 1350-1353
• 2 Dalakas M C. Sporadic inclusion body myositis – diagnosis, pathogenesis and therapeutic strategies.  Nat Clin Pract Neurol. 2006;  2 437-447
• 3 Askanas V, Engel W K. Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer's and Parkinson's disease brains.  Acta Neuropathol. 2008;  116 583-595
• 4 Dalakas M C. Mechanisms of disease: signaling pathways and immunobiology of inflammatory myopathies.  Nat Clin Pract Rheumatol. 2006;  2 219-227
• 5 Askanas V, Engel W K. Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis.  Curr Opin Rheumatol. 2007;  19 550-559
• 6 Kumamoto T, Ueyama H, Tsumura H. et al . Expression of lysosome-related proteins and genes in the skeletal muscles of inclusion body myositis.  Acta Neuropathol. 2004;  107 59-65
• 7 Ventruti A, Cuervo A M. Autophagy and neurodegeneration.  Curr Neurol Neurosci Rep. 2007;  7 443-451
• 8 Lunemann J D, Schmidt J, Schmid D. et al . Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis.  Ann Neurol. 2007;  61 476-483
• 9 Maiuri M C, Zalckvar E, Kimchi A. et al . Self-eating and self-killing: crosstalk between autophagy and apoptosis.  Nat Rev Mol Cell Biol. 2007;  8 741-752
• 10 Wiendl H, Hohlfeld R, Kieseier B C. Immunobiology of muscle: advances in understanding an immunological microenvironment.  Trends Immunol. 2005;  26 373-380
• 11 Bradshaw E M, Orihuela A, McArdel S L. et al . A local antigen-driven humoral response is present in the inflammatory myopathies.  J Immunol. 2007;  178 547-556
• 12 Greenberg S A, Bradshaw E M, Pinkus J L. et al . Plasma cells in muscle in inclusion body myositis and polymyositis.  Neurology. 2005;  65 1782-1787
• 13 Tews D S, Goebel H H. Cytokine expression profile in idiopathic inflammatory myopathies.  J Neuropathol Exp Neurol. 1996;  55 342-347
• 14 De Paepe B, Creus K K, De Bleecker J L. Chemokines in idiopathic inflammatory myopathies.  Front Biosci. 2008;  13 2548-2577
• 15 Emslie-Smith A M, Arahata K, Engel A G. Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.  Hum Pathol. 1989;  20 224-231
• 16 Behrens L, Kerschensteiner M, Misgeld T. et al . 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
• 17 Greenwald R J, Freeman G J, Sharpe A H. The B7 family revisited.  Annu Rev Immunol. 2005;  23 515-548
• 18 Wiendl H, Mitsdoerffer M, Schneider D. et al . Muscle fibres and cultured muscle cells express the B7.1 / 2-related inducible co-stimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies.  Brain. 2003;  126 1026-1035
• 19 Schmidt J, Rakocevic G, Raju R. et al . Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8(+) T cell cytotoxicity.  Brain. 2004;  127 1182-1190
• 20 Goebels N, Michaelis D, Engelhardt M. et al . Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.  J Clin Invest. 1996;  97 2905-2910
• 21 Hohlfeld R, Engel A G. Coculture with autologous myotubes of cytotoxic T cells isolated from muscle in inflammatory myopathies.  Ann Neurol. 1991;  29 498-507
• 22 Waschbisch A, Wintterle S, Lochmuller H. et al . Human muscle cells express the costimulatory molecule B7-H3, which modulates muscle-immune interactions.  Arthritis Rheum. 2008;  58 3600-3608
• 23 Wiendl H, Mitsdoerffer M, Schneider D. et al . Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies.  FASEB J. 2003;  17 1892-1894
• 24 Schmidt J, Barthel K, Wrede A. et al . Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle.  Brain. 2008;  131 1228-1240
• 25 Nagaraju K, Raben N, Merritt G. et al . A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli.  Clin Exp Immunol. 1998;  113 407-414
• 26 Vattemi G, Engel W K, McFerrin J. et al . Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis.  Lancet. 2001;  358 1962-1964
• 27 Hong H S, Hwang E M, Sim H J. et al . Interferon gamma stimulates beta-secretase expression and sAPPbeta production in astrocytes.  Biochem Biophys Res Commun. 2003;  307 922-927
• 28 Kitazawa M, Trinh D N, LaFerla F M. Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta.  Ann Neurol. 2008;  64 15-24
• 29 Griggs R C. The current status of treatment for inclusion-body myositis.  Neurology. 2006;  66 S30-S32
• 30 Muscle Study Group . Randomized pilot trial of high-dose betaINF-1a in patients with inclusion body myositis.  Neurology. 2004;  63 718-720
• 31 Dalakas M C, Sonies B, Dambrosia J. et al . Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study.  Neurology. 1997;  48 712-716
• 32 Walter M C, Lochmuller H, Toepfer M. et al . High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study.  J Neurol. 2000;  247 22-28
• 33 van der Pas J, Hengstman G JD, ter Laak H J. et al . Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies.  J Neurol Neurosurg Psychiatry. 2004;  75 136-139
• 34 Chahin N, Engel A G. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM.  Neurology. 2008;  70 418-424
• 35 Lindberg C, Trysberg E, Tarkowski A. et al . Anti-T-lymphocyte globulin treatment in inclusion body myositis: a randomized pilot study.  Neurology. 2003;  61 260-262
• 36 Dalakas M C, Rakocevic G, McElroy B. et al . Alemtuzumab (CAMPATH 1-H) therapy in sporadic inclusion body myositis (sIBM) alters disease progression and suppresses endomysial inflammation.  Ann Neurol. 2007;  62 S60-S61
• 37 Greenberg S A. Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.  Neurology. 2007;  69 2008-2019
• 38 Dalakas M C. B cells as therapeutic targets in autoimmune neurological disorders.  Nat Clin Pract Neurol. 2008;  4 557-567