title: Interruption of CXCL13-CXCR5 axis increases upper genital tract pathology and activation of NKT cells following chlamydial genital infection.
abstract: BACKGROUND
  Regulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection.
  
  
  RESULTS
  Disruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5-/- mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5-/- mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFNγ, CD4-IL-17, CD4-IL-10 & CD8-TNFα) in the oviducts. NKT cell depletion in vitro reduced IL-17α and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d-/- mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922).
  
  
  CONCLUSIONS
  These experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Janina
authors.initials: J
authors.lastname: Jiang
authors.forename: Ouafae
authors.initials: O
authors.lastname: Karimi
authors.forename: Sander
authors.initials: S
authors.lastname: Ouburg
authors.forename: Cheryl I
authors.initials: CI
authors.lastname: Champion
authors.forename: Archana
authors.initials: A
authors.lastname: Khurana
authors.forename: Guangchao
authors.initials: G
authors.lastname: Liu
authors.forename: Amanda
authors.initials: A
authors.lastname: Freed
authors.forename: Jolein
authors.initials: J
authors.lastname: Pleijster
authors.forename: Nora
authors.initials: N
authors.lastname: Rozengurt
authors.forename: Jolande A
authors.initials: JA
authors.lastname: Land
authors.forename: Helja-Marja
authors.initials: HM
authors.lastname: Surcel
authors.forename: Aila'
authors.initials: A
authors.lastname: Tiitinen
authors.forename: Jorma
authors.initials: J
authors.lastname: Paavonen
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Servaas A
authors.initials: SA
authors.lastname: Morré
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Kelly
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D054382:Chemokine CXCL13 / Q000378:metabolism / Q000502:physiology*; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D023502:Chlamydia muridarum / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060737:Reproductive Tract Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D012749:Sexually Transmitted Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044465:White People
chemical_list: D055610:Antigens, CD1d; D054382:Chemokine CXCL13; D016207:Cytokines; D054380:Receptors, CXCR5