title: Brugia malayi microfilariae induce a regulatory monocyte/macrophage phenotype that suppresses innate and adaptive immune responses.
abstract: BACKGROUND
  Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive.
  
  
  OBJECTIVE
  To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses.
  
  
  RESULTS
  Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner.
  
  
  CONCLUSIONS
  Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients.
authors.affiliation: Freie Universität Berlin, Center for Infection Medicine, Institute of Immunology, Berlin, Germany.
authors.forename: Noëlle Louise
authors.initials: NL
authors.lastname: O'Regan
authors.affiliation: Freie Universität Berlin, Center for Infection Medicine, Institute of Immunology, Berlin, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Steinfelder
authors.affiliation: Freie Universität Berlin, Center for Infection Medicine, Institute of Immunology, Berlin, Germany.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Venugopal
authors.affiliation: Blue Peter Public Health and Research Centre-LEPRA Society, Hyderabad, Andhra Pradesh, India.
authors.forename: Gopala B
authors.initials: GB
authors.lastname: Rao
authors.affiliation: Humboldt Universität Berlin, Department of Biology, Molecular Parasitology, Berlin, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.affiliation: Blue Peter Public Health and Research Centre-LEPRA Society, Hyderabad, Andhra Pradesh, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Srikantam
authors.affiliation: Freie Universität Berlin, Center for Infection Medicine, Institute of Immunology, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hartmann
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis; D000818:Animals; D017178:Brugia malayi / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004605:Elephantiasis, Filarial / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D018793:Interleukin-13 / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D008297:Male; D008842:Microfilariae / Q000276:immunology*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D010641:Phenotype; D014958:Wuchereria bancrofti / Q000276:immunology*; D055815:Young Adult
chemical_list: C508609:IL10 protein, human; D018793:Interleukin-13; D016753:Interleukin-10