DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma.
Blood
; 126(16): 1911-20, 2015 Oct 15.
Article
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| MEDLINE
| ID: mdl-26272216
ABSTRACT
Follicular lymphoma (FL) results from the accumulation of malignant germinal center (GC) B cells leading to the development of an indolent and largely incurable disease. FL cells remain highly dependent on B-cell receptor (BCR) signaling and on a specific cell microenvironment, including T cells, macrophages, and stromal cells. Importantly, FL BCR is characterized by a selective pressure to retain surface immunoglobulin M (IgM) BCR despite an active class-switch recombination process, and by the introduction, in BCR variable regions, of N-glycosylation acceptor sites harboring unusual high-mannose oligosaccharides. However, the relevance of these 2 FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM(+) FL B cells activated a stronger BCR signaling network than IgG(+) FL B cells and normal GC B cells. BCR expression level and phosphatase activity could both contribute to such heterogeneity. Moreover, we underlined that a subset of IgM(+) FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), which could in turn trigger delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within the FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN-dependent adhesion of highly mannosylated IgM(+) FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacologic BCR inhibitors abolished such crosstalk between macrophages and FL B cells. Altogether, our data support an important role for DC-SIGN-expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets.
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Banco de datos:
MEDLINE
Asunto principal:
Inmunoglobulina M
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Receptores de Antígenos de Linfocitos B
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Transducción de Señal
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Moléculas de Adhesión Celular
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Regulación de la Expresión Génica
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Linfoma Folicular
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Receptores de Superficie Celular
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Lectinas Tipo C
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Macrófagos
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2015
Tipo del documento:
Article