title: Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.
abstract: Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain-containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Torres
authors.forename: Rubén
authors.initials: R
authors.lastname: Martinez-Barricarte
authors.forename: Sonia
authors.initials: S
authors.lastname: García-Gómez
authors.forename: Marina S
authors.initials: MS
authors.lastname: Mazariegos
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.forename: Rita
authors.initials: R
authors.lastname: Rholvarez
authors.forename: Anaïs
authors.initials: A
authors.lastname: Jiménez-Reinoso
authors.forename: Lucia
authors.initials: L
authors.lastname: del Pino
authors.forename: Rebeca
authors.initials: R
authors.lastname: Rodríguez-Pena
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferreira
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández-Jiménez
authors.forename: Victor
authors.initials: V
authors.lastname: Toledano
authors.forename: Carolina
authors.initials: C
authors.lastname: Cubillos-Zapata
authors.forename: Mariana
authors.initials: M
authors.lastname: Díaz-Almirón
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
authors.forename: José L
authors.initials: JL
authors.lastname: Unzueta-Roch
authors.forename: Silvia
authors.initials: S
authors.lastname: Sánchez-Ramón
authors.forename: Jose R
authors.initials: JR
authors.lastname: Regueiro
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Granados
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Rebeca
authors.initials: R
authors.lastname: Pérez de Diego
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002675:Child, Preschool; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; C488088:Bcl10 protein, mouse; D016328:NF-kappa B