title: Chronic lymphocytic leukemia: a paradigm of innate immune cross-tolerance.
abstract: Infections are a significant cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections is multifactorial and includes hypogammaglobulinemia, conventional therapy with alkylating drugs, and recently, purine analogs and mAb-associated T cells. Patients without these risk factors also suffer from infections, although the mechanism remains unknown. In a cohort of 70 patients with CLL, we demonstrated that their monocytes were locked into a refractory state and were unable to mount a classic inflammatory response to pathogens. In addition, they exhibited the primary features of endotoxin tolerance, including low cytokine production, high phagocytic activity, and impaired Ag presentation. The involvement of miR-146a in this phenomenon was suspected. We found miR-146a target genes, such as IRAK1 and TRAF6, were manifestly downregulated. Our study provides a new explanation for infections in patients with CLL and describes a cross-tolerance between endotoxins and tumors.
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain;
authors.forename: Teresa
authors.initials: T
authors.lastname: Jurado-Camino
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain; Hematology Department, University Hospital Infanta Sofía, San Sebastian de los Reyes, Madrid 28702, Spain;
authors.forename: Raúl
authors.initials: R
authors.lastname: Córdoba
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain;
authors.forename: Laura
authors.initials: L
authors.lastname: Esteban-Burgos
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain;
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández-Jiménez
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain;
authors.forename: Victor
authors.initials: V
authors.lastname: Toledano
authors.affiliation: Hematology Department, University Hospital Infanta Leonor, Madrid 28031, Spain;
authors.forename: Jose-Angel
authors.initials: JA
authors.lastname: Hernandez-Rivas
authors.affiliation: Hematology Department, Hospital del Tajo, Aranjuez, Madrid 28300, Spain;
authors.forename: Elena
authors.initials: E
authors.lastname: Ruiz-Sainz
authors.affiliation: Hematology Department, Hospital del Sureste, Arganda del Rey, Madrid 28500, Spain;
authors.forename: Teresa
authors.initials: T
authors.lastname: Cobo
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain;
authors.forename: María
authors.initials: M
authors.lastname: Siliceo
authors.affiliation: Innate Immunity Group, IdiPAZ, La Paz Hospital, 28046 Madrid, Spain; Laboratory of Immunogenetics, IdiPAZ, La Paz Hospital, 28046 Madrid, Spain; and.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Perez de Diego
authors.affiliation: HM Hospitales and National School of Health, Madrid, Spain.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Belda
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain; elopezc@salud.madrid.org carolina.cubillos@idipaz.es.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cubillos-Zapata
authors.affiliation: Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Madrid 28046, Spain; Innate Immunity Group, IdiPAZ, La Paz Hospital, 28046 Madrid, Spain; elopezc@salud.madrid.org carolina.cubillos@idipaz.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004731:Endotoxins / Q000276:immunology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology
chemical_list: D016207:Cytokines; D004731:Endotoxins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D048029:TNF Receptor-Associated Factor 6; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases