Abstract
The transcription factor Blimp1 is not only an essential regulator of plasma cells, but also a risk factor for the development of autoimmune disease in humans. Here, we demonstrate in the mouse that the Prdm1 (Blimp1) gene was partially activated at the chromatin and transcription level in early B cell development, although mature Prdm1 mRNA did not accumulate due to posttranscriptional regulation. By analyzing a mouse model that facilitated ectopic Blimp1 protein expression throughout B lymphopoiesis, we could demonstrate that Blimp1 impaired B cell development by interfering with the B cell gene expression program, while leading to an increased abundance of plasma cells by promoting premature plasmablast differentiation of immature and mature B cells. With progressing age, these mice developed an autoimmune disease characterized by the presence of autoantibodies and glomerulonephritis. Hence, these data identified ectopic Blimp1 expression as a novel mechanism, through which Blimp1 can act as a risk factor in the development of autoimmune disease.
Highlights
Plasma cells serve an important role in the acute response to infection and in long-term protection of the host by providing humoral immunity through continuous secretion of antibodies.plasma cells often contribute to the pathogenesis of autoimmune disease by secreting self-reactive antibodies (Suurmond & Diamond, 2015; Tsokos et al, 2016)
The upstream regions A, B, and C were partially activated in pro-B cells, as shown by the presence of bivalent chromatin at region A and a subset of open chromatin sites in regions B and C compared to plasmablasts (Fig 1A)
The human PRDM1 (Blimp1) locus has been identified as a susceptibility gene for development of the autoimmune diseases systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA; Gateva et al, 2009; Raychaudhuri et al, 2009; Zhou et al, 2011)
Summary
Plasma cells often contribute to the pathogenesis of autoimmune disease by secreting self-reactive antibodies (Suurmond & Diamond, 2015; Tsokos et al, 2016). Within the B-lymphoid lineage, Blimp is predominantly expressed in antibody-secreting cells, where its highest expression is observed in quiescent long-lived plasma cells (Kallies et al, 2004). Consistent with this expression pattern, antibodysecreting cells are lost in mice with a B cell-specific deletion of the Prdm gene, demonstrating that Blimp is essential for the generation of plasmablasts and plasma cells (Shapiro-Shelef et al, 2003; Kallies et al, 2007). There are, no functional data available that would causally implicate PRDM1 in the pathogenesis of SLE or RA
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