title: Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation.
abstract: BACKGROUND
  Bruton tyrosine kinase (BTK) plays an essential role in various biologic functions of different cell types. Mutations in BTK lead to X-linked agammaglobulinemia (XLA) in humans. BTK was recently linked to the innate immune system, in particular, the Toll-like receptor (TLR) pathway; however, the TLR9 pathway has never been studied in dendritic cells (DCs) of patients with XLA.
  
  
  OBJECTIVE
  The aim of this study was to investigate the role of BTK in human DC activation upon TLR9 stimulation.
  
  
  METHODS
  DCs of patients with XLA and healthy donors were stimulated via TLR4/9 and evaluated for cell activation and cytokine production.
  
  
  RESULTS
  We showed that BTK plays an essential role in DC responses to unmethylated CpG oligodeoxynucleotide: although responses to lipopolysaccaride/TLR4 induce normal DC activation in terms of upregulation of specific markers (CD86, CD83, CD80, HLA-DR), the CpG/TLR9 pathway is completely impaired in patients with XLA. Furthermore, cytokine production upon TLR9 activation in patients with XLA is radically impaired in terms of IL-6, IL-12, TNF-α, and IL-10 production. Interestingly, BTK mediated STAT1/3 upregulation in a TLR9-dependent manner. The important role of BTK in human DC activation was confirmed after incubation of healthy DCs with ibrutinib, the specific BTK inhibitor, which resulted in impairment of TLR9 responses as seen in patients with XLA.
  
  
  CONCLUSIONS
  Analysis of these data suggests that BTK regulates human DC responses upon TLR9 engagement in terms of activation, cytokine production, and STAT1/3 upregulation. These findings may be of important significance for better understanding and managing different clinical conditions, such as agammaglobulinemia and lymphoid malignancies.
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy. Electronic address: vlougarisbs@yahoo.com.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Baronio
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Vitali
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Tampella
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cattalini
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tassone
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Soresina
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051217:Toll-Like Receptor 9; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: BTK; STAT1; STAT3; TLR9; dendritic cells