title: Altered α-defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour-permissive microenvironment.
abstract: Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical HPV infections into (pre)neoplastic lesions suggests that viral antigens are not adequately recognized by innate immunity or presented to the adaptive immune system. Members of the defensin family have recently been found to inhibit viral and bacterial pathogens, to stimulate the migration of immune cells and to play a role in anticancer responses. In the present study, we focused on the poorly characterized human α-defensin 5 (HD-5) and its possible role in these processes. We showed that HD-5 was able to prevent HPV virion entry into cervical keratinocytes and to influence adaptive immunity. Indeed, this peptide specifically induced the chemoattraction and proliferation of both activated T lymphocytes and immature dendritic cells in a CCR2/CCR6-dependent manner and stimulated the infiltration of these professional antigen-presenting cells in a (pre)neoplastic epithelium transplanted in vivo in immunodeficient mice. No chemotactic effect was observed with plasmacytoid dendritic cells, macrophages or natural killer cells. Proliferative and angiogenic effects of HD-5 were also assessed in vitro and in vivo. However there was a striking regional disparity in expression of HD-5, being prominent in ectocervical, vaginal and vulvar neoplasia, while absent, or nearly so, in the cervical SC junction. Taken together, these results suggest one possible explanation for why the SC junction is uniquely vulnerable to both high-risk HPV infection (via reduced HD-5 expression and viral entry) and progression of neoplasia (via altered cell-mediated immune responses and altered microenvironment).
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hubert
authors.forename: Ludivine
authors.initials: L
authors.lastname: Herman
authors.forename: Patrick
authors.initials: P
authors.lastname: Roncarati
authors.forename: Catherine
authors.initials: C
authors.lastname: Maillard
authors.forename: Virginie
authors.initials: V
authors.lastname: Renoux
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Demoulin
authors.forename: Charlotte
authors.initials: C
authors.lastname: Erpicum
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Jacques
authors.initials: J
authors.lastname: Boniver
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D030361:Papillomavirus Infections / Q000276:immunology*; D011230:Precancerous Conditions / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D014594:Uterine Neoplasms / Q000276:immunology / Q000821:virology*; D023084:alpha-Defensins / Q000096:biosynthesis*; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000821:virology
chemical_list: C500225:DEFA5 protein, human; D023084:alpha-Defensins
keywords: HPV; cervix; defensin