Through an ITIM-independent mechanism the FcγRIIB blocks B cell activation by disrupting the colocalized microclustering of the B cell receptor and CD19.
J Immunol
; 192(11): 5179-91, 2014 Jun 01.
Article
en En
| MEDLINE
| ID: mdl-24790152
B cell activation is regulated through the interplay of the BCR with the inhibitory coreceptor FcγRIIB and the activating coreceptor CD19. Recent studies suggest that Ag-driven BCR microclusters are efficiently converted to a signaling active state on colocalization with CD19 microclusters. Using total internal reflection fluorescence microscopy-based, high-resolution, high-speed live-cell and molecule imaging approaches, we show that when co-ligated to the BCR, the FcγRIIB can inhibit B cell activation by blocking the colocalization of BCR and CD19 microclusters within the B cell immunological synapse. Remarkably, this inhibitory function of FcγRIIB is dependent not on its well-characterized ITIM-containing cytoplasmic domain, but its transmembrane domain. Indeed, human primary B cells from systemic lupus erythematosus patients homozygous for gene encoding the loss-of-function transmembrane domain mutant FcγRIIB-I232T fail to block the synaptic colocalization of the BCR with CD19, leading to dysregulated recruitment of downstream signaling molecule p-PI3K to membrane proximal signalosome. This inhibitory function of FcγRIIB in impairing the spatial-temporal colocalization of BCR and CD19 microclusters in the B cell immunological synapse may help explain the hyper-reactive features of systemic lupus erythematosus patient B cells in reported studies. These observations may also provide new targets for therapies for systemic autoimmune disease.
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Banco de datos:
MEDLINE
Asunto principal:
Linfocitos B
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Activación de Linfocitos
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Receptores de Antígenos de Linfocitos B
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Receptores de IgG
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Antígenos CD19
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Lupus Eritematoso Sistémico
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Immunol
Año:
2014
Tipo del documento:
Article