title: Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis.
abstract: BACKGROUND
  Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood.
  
  
  OBJECTIVE
  To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens.
  
  
  METHODS
  DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans- and P brasiliensis-pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (T(H)) 17 cells, and production of IFN-γ, TGF-β, IL-4, IL-5, and IL-17.
  
  
  RESULTS
  Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed T(H)2 pattern response.
  
  
  CONCLUSIONS
  Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Otavio
authors.initials: O
authors.lastname: Cabral-Marques
authors.forename: Christina
authors.initials: C
authors.lastname: Arslanian
authors.forename: Rodrigo Nalio
authors.initials: RN
authors.lastname: Ramos
authors.forename: Mariana
authors.initials: M
authors.lastname: Morato
authors.forename: Lenafriederike
authors.initials: L
authors.lastname: Schimke
authors.forename: Paulo Vitor
authors.initials: PV
authors.lastname: Soeiro Pereira
authors.forename: Sonia
authors.initials: S
authors.lastname: Jancar
authors.forename: Janaíra Fernandes
authors.initials: JF
authors.lastname: Ferreira
authors.forename: Cristina Worm
authors.initials: CW
authors.lastname: Weber
authors.forename: Gisele
authors.initials: G
authors.lastname: Kuntze
authors.forename: Nelson Augusto
authors.initials: NA
authors.lastname: Rosario-Filho
authors.forename: Beatriz Tavares
authors.initials: BT
authors.lastname: Costa Carvalho
authors.forename: Patricia Cruz
authors.initials: PC
authors.lastname: Bergami-Santos
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Hackett
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Jose Alexandre Marzagão
authors.initials: JA
authors.lastname: Barbuto
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
mesh_terms: D000293:Adolescent; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology* / Q000472:pathogenicity; D002177:Candidiasis / Q000150:complications / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000150:complications / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010228:Paracoccidioides / Q000276:immunology* / Q000472:pathogenicity; D010229:Paracoccidioidomycosis / Q000150:complications / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D023201:CD40 Ligand