| First Author | Ou P | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 9 | Pages | 109624 |
| PubMed ID | 34469734 | Mgi Jnum | J:312555 |
| Mgi Id | MGI:6765709 | Doi | 10.1016/j.celrep.2021.109624 |
| Citation | Ou P, et al. (2021) SMS2 deficiency impairs PKCdelta-regulated B cell tolerance in the germinal center. Cell Rep 36(9):109624 |
| abstractText | 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 delta (PKCdelta)'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. |
