Congenital B cell lymphocytosis linked to a novel germline CARD11 mutation (109.13)
| Autor: | Andrew Snow, Wenming Xiao, Benjamin Chaigne-Delalande, Stefania Pittaluga, Jeffrey Stinson, Helen Matthews, Wei Lu, Roland Schmitz, Sameer Jhavar, Huie Jing, Helen Su, Louis Staudt, Michael Lenardo |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 188:109.13-109.13 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.188.supp.109.13 |
| Popis: | Nuclear Factor-kappa B (NF-κB) governs the transcription of many genes for normal lymphocyte functions, but constitutive NF-κB activation is most often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we recently investigated a family with a unique, hereditary polyclonal B cell lymphocytosis. Here we report our discovery of a novel, germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a lymphocyte-specific scaffolding protein required for antigen receptor (AgR)-induced NF-κB activation in both B and T lymphocytes. Similar to somatic, gain-of-function CARD11 mutations described in diffuse large B cell lymphoma, E127G CARD11 spontaneously oligomerizes and activates NF-κB when upon ectopic expression in lymphoid cell lines. Primary lymphocytes from these patients also display evidence of CARD11 aggregation and constitutive NF-κB activity. In contrast to B cells, however, we observed that E127G CARD11 contributes to patient T cell hyporesponsiveness upon AgR stimulation, even though the proximal CARD11-associated signaling machinery is highly similar between B and T cells. Our findings suggest that an activating, germline CARD11 mutation can selectively induce B cell expansion and preferentially predispose to B cell malignancy without perturbing T cell homeostasis. |
| Databáze: | OpenAIRE |
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