title: Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism.
abstract: OBJECTIVE
  The etiopathogenesis of primary Sjögren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system.
  
  
  METHODS
  Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNalpha-producing cells and measurable IFNalpha levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNalpha production in normal peripheral blood mononuclear cells was examined. The IFNalpha inducer was characterized, and IFNalpha-producing cells were identified. Clinical data were correlated with the IFNalpha-inducing capacity of primary SS sera.
  
  
  RESULTS
  Numerous IFNalpha-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNalpha levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNalpha production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcgamma receptor IIa. The IFNalpha-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score >/=1) and with dermatologic, hematologic, and pulmonary manifestations.
  
  
  CONCLUSIONS
  Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNalpha synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNalpha production at the tissue level. This IFNalpha promotes the autoimmune process by a vicious circle-like mechanism, with increased autoantibody production and formation of more endogenous IFNalpha inducers.
authors.affiliation: Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Ullvi
authors.initials: U
authors.lastname: Båve
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Tanja
authors.initials: T
authors.lastname: Lövgren
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.forename: Stefan
authors.initials: S
authors.lastname: Cajander
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.forename: Gunnar V
authors.initials: GV
authors.lastname: Alm
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
mesh_terms: D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D006528:Carcinoma, Hepatocellular; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007369:Interferon Inducers / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D009336:Necrosis / Q000276:immunology; D016601:RNA-Binding Proteins / Q000276:immunology; D012470:Salivary Glands, Minor / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012859:Sjogren's Syndrome / Q000097:blood / Q000276:immunology* / Q000473:pathology; D020298:U937 Cells
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007369:Interferon Inducers; D016898:Interferon-alpha; D016601:RNA-Binding Proteins