Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity
Juan Manuel Torres, … , Jean-Laurent Casanova, Rebeca Pérez de Diego
Juan Manuel Torres, … , Jean-Laurent Casanova, Rebeca Pérez de Diego
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5239-5248. https://doi.org/10.1172/JCI77493.
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Research Article

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

Juan Manuel Torres, Rubén Martinez-Barricarte, Sonia García-Gómez, Marina S. Mazariegos, Yuval Itan, Bertrand Boisson, Rita Álvarez, Anaïs Jiménez-Reinoso, Lucia del Pino, Rebeca Rodríguez-Pena, Antonio Ferreira, Enrique Hernández-Jiménez, Victor Toledano, Carolina Cubillos-Zapata, Mariana Díaz-Almirón, Eduardo López-Collazo, José L. Unzueta-Roch, Silvia Sánchez-Ramón, Jose R. Regueiro, Eduardo López-Granados, Jean-Laurent Casanova, Rebeca Pérez de Diego

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Figure 4

Effect of human BCL10 deficiency on fibroblast immunity.

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Effect of human BCL10 deficiency on fibroblast immunity. Complementation...
Complementation studies in fibroblasts. (A) Production of IL-6 and IL-8, as assessed by CBA, in primary fibroblasts after stimulation with LPS, zymosan, curdlan, and poly(I:C). C1–C3 are positive controls. The values shown (mean ± SEM) were calculated from 3 independent experiments. (B) NF-κB ELISA of nuclear extracts from fibroblasts from C1, C2, and P1 after stimulation with LPS, zymosan, and poly(I:C) for 60 minutes. The values shown (mean ± SEM) were calculated from 3 independent experiments. (C) Immunoblot analysis of BCL10 in primary fibroblasts from a control, primary fibroblasts from P1, cells from P1 transfected with mock vector (P1-Mock), and cells from P1 transfected with the WT BCL10 plasmid (P1-WT). GAPDH was used as a loading control. The control shown is representative of the 3 controls analyzed. Shown are results from a single representative experiment of 3 performed. (D) Production of IL-6 (note logarithmic scale) and IL-8, as assessed by CBA, in primary fibroblasts after stimulation with LPS, zymosan, curdlan, and poly(I:C). P1 denotes cells from the patient subjected to the same transfection treatment, but without the plasmid, acting as a control for the state of the cells. The values shown (mean ± SEM) were calculated from 3 independent experiments.