title: Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis.
abstract: OBJECTIVE
  IgG4-related disease is a recently recognized entity affecting multiple organs, including the pancreas, biliary tracts, and salivary glands. Although IgG4-related disease is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells, the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. The aim of this study was to clarify the innate immune responses leading to IgG4 antibody production.
  
  
  METHODS
  IgG4 and cytokine responses to various nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) and Toll-like receptor (TLR) ligands were examined using peripheral blood mononuclear cells (PBMCs) from healthy control subjects and patients with IgG4-related autoimmune pancreatitis.
  
  
  RESULTS
  Activation of NOD-2 in monocytes from healthy control subjects induced IgG4 production by B cells in a BAFF-dependent and T cell-independent manner. In addition, PBMCs from patients with IgG4-related disease produced a large amount of IgG4 upon stimulation with NLR and TLR ligands; this enhanced IgG4 production was associated with the induction of BAFF by NLR and TLR ligands. Monocytes from patients with IgG4-related disease induced IgG4 production by B cells from healthy control subjects upon stimulation with NLR and TLR ligands.
  
  
  CONCLUSIONS
  The results of these studies suggest that abnormal innate immune responses against microbial antigens may underlie the immunopathogenesis of IgG4-related disease.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. tmhrwtnb@kuhp.kyoto-u.ac.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamashita
authors.forename: Saori
authors.initials: S
authors.lastname: Fujikawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shiokawa
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Kazushige
authors.initials: K
authors.lastname: Uchida
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D053473:Nod2 Signaling Adaptor Protein / Q000096:biosynthesis*; D010195:Pancreatitis / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis*
chemical_list: D000942:Antigens, Bacterial; D007074:Immunoglobulin G; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2