title: Required role of apoptotic myogenic precursors and toll-like receptor stimulation for the establishment of autoimmune myositis in experimental murine models.
abstract: OBJECTIVE
  Muscle regeneration is a hallmark of the idiopathic inflammatory myopathies (IIMs), a group of autoimmune disorders that are characterized by leukocyte infiltration and dysfunction of the skeletal muscle. Despite detailed studies describing the clinical and histopathologic features of IIMs, the immunopathogenesis of these disorders remains undefined. The aim of this study was to investigate the immunopathologic processes of autoimmune myositis in experimental murine models.
  
  
  METHODS
  Expression of the autoantigen histidyl-transfer RNA synthetase (HisRS) was analyzed in mice with acutely injured or dystrophic muscles, in inflammatory leukocytes, and in purified satellite cells. Anti-HisRS antibodies and myositis induction were assessed in mice after muscle injury and immunization with apoptotic satellite cells or C2C12 myoblasts, in the presence or absence of the Toll-like receptor 7 (TLR-7) agonist R848.
  
  
  RESULTS
  Muscle necrosis, leukocyte infiltration, and myofiber regeneration induced by toxic agents (cardiotoxin or glycerol) or promoted by genetic disruption of the α-sarcoglycan/dystrophin complex in mice were uniformly associated with up-regulated expression of HisRS. Although regenerating myofibers and purified satellite cells are known to show increased expression of HisRS in these settings, anti-HisRS antibodies were not detectable. However, intramuscular immunization with ultraviolet B-irradiated, HisRS-expressing apoptotic myoblasts in the presence of R848 triggered the production of anti-HisRS IgG antibodies as well as persistent lymphocyte infiltration and prolonged/delayed muscle regeneration. Conversely, intramuscular administration of R848 alone or in combination with living or postapoptotic/necrotic myoblasts failed to generate this myositis phenotype.
  
  
  CONCLUSIONS
  In the presence of TLR/adjuvant signals and underlying muscle injury, apoptotic myogenic precursors expressing high levels of autoantigen can provoke autoantibody formation and lymphocytic infiltration of muscle tissue, effectively replicating the features of IIM.
authors.affiliation: San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Sciorati
authors.forename: Antonella
authors.initials: A
authors.lastname: Monno
authors.forename: Dana P
authors.initials: DP
authors.lastname: Ascherman
authors.forename: Elena
authors.initials: E
authors.lastname: Seletti
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
mesh_terms: D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology*; D015153:Blotting, Western; D005434:Flow Cytometry; D006643:Histidine-tRNA Ligase / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology*; D020721:Nervous System Autoimmune Disease, Experimental / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D006643:Histidine-tRNA Ligase