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SMS2 activates PKCĪ“ in germinal center B cells to eliminate lupus autoreactivity
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Huan, Chongmin
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Spring 2020
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2020-04-01
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Doctoral dissertation
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Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies against double stranded (ds)-DNA. Lupus remains a clinical challenge due to the lack of specific and effective treatments. Recent evidence indicates that the main source of lupus autoreactivity is the spontaneously generated autoreactive B cells that breach a tolerance checkpoint in the germinal center (GC). However, the information about the components and regulation of this GC tolerance checkpoint remains absent, which hampers the development of more effective and safer therapy for lupus patients.
Sphingomyelin synthase 2 (SMS2) is an enzyme that catalyzes the synthesis of sphingomyelin (SM) and diacylglycerol (DAG) on the plasma membrane. We found that SMS2 deficient mice had a lupus-like phenotype associated with impaired apoptosis of autoreactive GC B cells. Mechanistic studies showed that SMS2 was selectively upregulated in autoreactive GC B cells, and that SMS2 drove the apoptosis via activating protein kinase C Ī“ (PKCĪ“), a known lupus-associated regulator of B cell apoptosis. Consistent with this, mice with PKCĪ“ deficiency in GC B cells exhibited a similar lupus-like phenotype. Restoration of SMS2/PKCĪ“-regulated GC tolerance checkpoint by therapeutically stimulating SMS2 inhibited anti-dsDNA IgG production and alleviated lupus pathogenesis in NZBWF1 mice, a spontaneous lupus model commonly used in the preclinical studies. We therefore conclude that SMS2/PKCĪ“-regulated tolerance mechanism is an essential GC tolerance checkpoint that prevents lupus pathogenesis. Our study also provides a novel strategy for lupus treatment.
Citation
Ou, P. (2020) SMS2 activates PKCĪ“ in germinal center B cells to eliminate lupus autoreactivity. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/15793