SMS2 deficiency impairs PKCδ-regulated B cell tolerance in the germinal center.
Cell Rep
; 36(9): 109624, 2021 08 31.
Article
en En
| MEDLINE
| ID: mdl-34469734
B cell tolerance prevents autoimmunity by deleting or deactivating autoreactive B cells that otherwise may cause autoantibody-driven disorders, including systemic lupus erythematosus (lupus). Lupus is characterized by immunoglobulin Gs carrying a double-stranded (ds)-DNA autospecificity derived mainly from somatic hypermutation in the germinal center (GC), pointing to a checkpoint breach of GC B cell tolerance that leads to lupus. However, tolerance mechanisms in the GC remain poorly understood. Here, we show that upregulated sphingomyelin synthase 2 (SMS2) in anti-dsDNA GC B cells induces apoptosis by directly activating protein kinase C δ (PKCδ)'s pro-apoptotic activity. This tolerance mechanism prevents lupus autoimmunity in C57/BL6 mice and can be stimulated pharmacologically to inhibit lupus pathogenesis in lupus-prone NZBWF1 mice. Patients with lupus consistently have substantially reduced SMS2 expression in B cells and to an even greater extent in autoimmune-prone, age-associated B cells, suggesting that patients with lupus have insufficient SMS2-regulated B cell tolerance.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos B
/
Autoinmunidad
/
Transferasas (Grupos de Otros Fosfatos Sustitutos)
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Centro Germinal
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Proteína Quinasa C-delta
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Tolerancia Inmunológica
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Lupus Eritematoso Sistémico
Límite:
Animals
Idioma:
En
Revista:
Cell Rep
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos