The survival of long-lived plasma cells, which produce most serum immunoglobulin, is central to humoral immunity. We found here that the inhibitory Fc receptor FcgammaRIIb was expressed on plasma cells and controlled their persistence in the bone marrow. Crosslinking FcgammaRIIb induced apoptosis of plasma cells, which we propose contributes to the control of their homeostasis and suggests a method for therapeutic deletion. Plasma cells from mice prone to systemic lupus erythematosus did not express FcgammaRIIb and were protected from apoptosis. Human plasmablasts expressed FcgammaRIIb and were killed by crosslinking, as were FcgammaRIIb-expressing myeloma cells. Our results suggest that FcgammaRIIb controls bone marrow plasma cell persistence and that defects in it may contribute to autoantibody production.

There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive Multiple Sclerosis Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e. new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data is required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive Multiple Sclerosis Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1a,25 Dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) in regulating the growth and di erentiation of the normal prostate gland yet prostate cancer cells appear signi®cantly less sensitive to this action. Vitamin D 3 receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative e ects of 1a,25(OH) 2 D 3 and therefore it is unclear why prostate cancer cell lines are signi®cantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1a,25(OH) 2 D 3 are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 mM and 15 nM respectively), which alone were relatively inactive, synergized with 1a,25(OH) 2 D 3 in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D 3 hexa¯uoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclindependent kinase inhibitor, p21 (waf1/cip1) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1a,25(OH) 2 D 3 during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D 3 analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgendependent and independent prostate cancer. Oncogene (2001) 20, 1860 ± 1872.

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