title: Decreased Langerhans cell responses to IL-36γ: altered innate immunity in patients with recurrent respiratory papillomatosis.
abstract: Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36γ, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain TH1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of TH2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36γ protein, and that human keratinocytes transduced with HPV11 have reduced IL-36γ secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36γ by expressing inflammatory cytokines and chemokines. When stimulated with IL-36γ, iLCs from patients with RRP had lower expression levels of the TH2-like chemokine CCL-20 as compared with controls. Patients' iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of TH1- and a TH2-like chemokines by iLCs from patients could have consequences in the priming of IFN-γ expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36γ. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, TH1-like and/or Tc1-like adaptive response, thus resulting in the predominant TH2-like and/or Treg micromilieu present in papillomas.
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America Division of Allergy and Immunology, Department of Pediatrics, Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: DeVoti
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America Division of Allergy and Immunology, Department of Pediatrics, Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, United States of America.
authors.forename: Lynda
authors.initials: L
authors.lastname: Hatam
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America Department of Otolaryngology, Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lucs
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Afzal
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America Department of Otolaryngology, Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, United States of America.
authors.forename: Allan
authors.initials: A
authors.lastname: Abramson
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York, United States of America Department of Otolaryngology, Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, United States of America.
authors.forename: Bettie
authors.initials: B
authors.lastname: Steinberg
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America Elmezzi Graduate School of Molecular Medicine, Manhasset, New York, United States of America Division of Allergy and Immunology, Department of Pediatrics, Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bonagura
mesh_terms: D002478:Cells, Cultured; D054402:Chemokine CCL1 / Q000235:genetics / Q000276:immunology; D052140:Human papillomavirus 11; D006801:Humans; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology / Q000821:virology; D007801:Langerhans Cells / Q000276:immunology*; D007830:Larynx / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology*
chemical_list: C065971:CCL1 protein, human; D054402:Chemokine CCL1; C508589:IL36G protein, human; D007375:Interleukin-1; D053583:Interleukin-1beta