title: CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Little is known about what drives the appearance of lymphoid follicles (LFs), which may function as lymphoid organs in chronic obstructive pulmonary disease (COPD). In animal infection models, pulmonary LF formation requires expression of homeostatic chemokines by stromal cells and dendritic cells, partly via lymphotoxin.
  
  
  OBJECTIVE
  To study the role of homeostatic chemokines in LF formation in COPD and to identify mechanism(s) responsible for their production.
  
  
  METHODS
  Peripheral lung homeostatic chemokine and lymphotoxin expression were visualized by immunostainings and quantified by ELISA/quantitative reverse transcriptase-polymerase chain reaction in patients with COPD with and without LFs. Expression of lymphotoxin and homeostatic chemokine receptors was investigated by flow cytometry. Primary lung cell cultures, followed by ELISA/quantitative reverse transcriptase-polymerase chain reaction/flow cytometry, were performed to identify mechanisms of chemokine expression. Polycarbonate membrane filters were used to assess primary lung cell migration toward lung homogenates.
  
  
  RESULTS
  LFs expressed the homeostatic chemokine CXCL13. Total CXCL13 levels correlated with LF density. Lung B cells of patients with COPD were important sources of CXCL13 and lymphotoxin and also expressed their receptors. Cigarette smoke extract, H2O2, and LPS exposure up-regulated B cell-derived CXCL13. The LPS-induced increase in CXCL13 was partly mediated via lymphotoxin. Notably, CXCL13 was required for efficient lung B-cell migration toward COPD lung homogenates and induced lung B cells to up-regulate lymphotoxin, which further promoted CXCL13 production, establishing a positive feedback loop.
  
  
  CONCLUSIONS
  LF formation in COPD may be driven by lung B cells via a CXCL13-dependent mechanism that involves toll-like receptor and lymphotoxin receptor signaling.
authors.affiliation: Department of Critical Care Medicine and Pulmonary Services, Evaggelismos General Hospital, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Litsiou
authors.forename: Maria
authors.initials: M
authors.lastname: Semitekolou
authors.forename: Ioanna E
authors.initials: IE
authors.lastname: Galani
authors.forename: Ioannis
authors.initials: I
authors.lastname: Morianos
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Tsoutsa
authors.forename: Panagiota
authors.initials: P
authors.lastname: Kara
authors.forename: Dimitra
authors.initials: D
authors.lastname: Rontogianni
authors.forename: Ion
authors.initials: I
authors.lastname: Bellenis
authors.forename: Maria
authors.initials: M
authors.lastname: Konstantinou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Potaris
authors.forename: Evangelos
authors.initials: E
authors.lastname: Andreakos
authors.forename: Paschalis
authors.initials: P
authors.lastname: Sideras
authors.forename: Spyros
authors.initials: S
authors.lastname: Zakynthinos
authors.forename: Maria
authors.initials: M
authors.lastname: Tsoumakidou
mesh_terms: D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013183:Sputum / Q000737:chemistry / Q000166:cytology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D008233:Lymphotoxin-alpha; D051193:Toll-Like Receptors