Inhibition of human B-cell development into plasmablasts by histone deacetylase inhibitor valproic acid Anne-Kathrin Kienzler, MSc, Marta Rizzi, MD,

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Inhibition of human B-cell development into plasmablasts by histone deacetylase inhibitor valproic acid Anne-Kathrin Kienzler, MSc, Marta Rizzi, MD, PhD, Maike Reith, MSc, Stephen L. Nutt, PhD, Hermann Eibel, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 6, Pages 1695-1699.e9 (June 2013) DOI: 10.1016/j.jaci.2013.01.018 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 B-cell phenotype and immunoglobulin secretion. Cells were stimulated as indicated. A, Naive B cells. Percentage of CD27highCD38high cells within live CD19+ cells is indicated. Absolute counts of CD27highCD38high cells of activated naive (B) and memory (C) B cells 9 days after activation. IgM (D), IgG (E and G), and IgA (F and H) concentrations in culture supernatant fluids of naive (D-F) and memory (G and H) B cells 9 days after stimulation. Each symbol represents one independent experiment; ns, Not significant. **P < .01. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 B-cell viability and proliferation. Naive B cells were stimulated as indicated for 6 days. A, Percentages of live (AnnexinV−PI−), dead (AnnexinV+PI+) and apoptotic (AnnexinV+PI−) cells determined. B and C, B cell proliferation was analyzed by CFSE labeling. CD27 (D) and CD38 (E) expression within CFSE-labeled CD19+ cells. A, Each symbol represents one independent experiment; B, D, and E are representative for 6 independent experiments; C is representative for 3 independent experiments; BAFF, B-cell activating factor; ns, not significant. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Memory B-cell differentiation into plasmablasts is not influenced by VPA treatment, whereas naive B-cell differentiation is affected in a dose-dependent manner. A, Representative flow cytometric analysis of human memory B cells stimulated with CD40L and IL-21 in the presence or absence of VPA as indicated. Percentage of CD27highCD38high cells within live CD19+ cells is shown. B, Percentage of CD27high CD38high cells from 3 different donors activated and analyzed as shown in A. C, Naive B cells were stimulated as indicated. Absolute count of CD27highCD38high cells 6 days after activation is plotted on the y axis. Each symbol represents one independent experiment; ns, Not significant; *P < .05. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 VPA inhibits blast formation and early expression of CD69, induces MHC class II expression, but does not influence CD86 expression and calcium influx on BCR stimulation. Naive B cells were stimulated as indicated. A and B, Blast formation was determined by analyzing cell size by forward scatter in flow cytometry. Expression of the early activation markers CD69 (C and D), HLA-DR (E and F), and CD86 (G and H) analyzed by flow cytometry. A, C, E, and G are representative FACS plots; (B, D, F, and H) depict the median fluorescence intensity over time. Each symbol represents one independent experiment. I, Calcium influx on BCR stimulation of VPA-treated compared with untreated cells. Shown is 1 representative of 2 independent experiments. BCR, B-cell receptor; FSC, forward scatter; HLA-DR, human leukocyte antigen DR; FACS, fluorescence-activated cell sorting; MFI, median fluorescence intensity; ns, not significant. *P < .05. **P < .01. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 No variation in expression of B-cell fate–determining genes in the presence of VPA. Naive B cells were activated as indicated. mRNA levels of AICDA (A), PRDM1 (B), XBP1 (C), IRF4 (D), BCL6 (E), and PAX5 (F) were determined by quantitative PCR at indicated time points. Each symbol represents one independent experiment. AICDA, Activation-induced cytidine deaminase; PRDM1, PR domain containing 1, with ZNF domain; XBP1, X-box binding protein 1; IRF4, interferon regulatory factor 4; BCL6, B-cell CLL/lymphoma 6; PAX5, paired box 5. *P < .05. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 VPA at a dose of 0.25 mmol/L does not induce apoptosis, but inhibits B- and T-cell proliferation. (A-E, H, and I) Naive B cells or PBMCs (F and G) were stimulated as indicated for 6 days. A, Percentages of live (AnnexinV−PI−) and dead (AnnexinV+PI+) cells, including apoptotic (AnnexinV+PI−) cells. B-G, Lymphocyte proliferation was analyzed by CFSE labeling. B, B-cell proliferation in the presence of escalating doses of VPA. C and F, Representative FACS plot showing the gating strategy for statistical analysis of proliferation. D, E, and G, Percentage of cells that have undergone indicated numbers of divisions. Statistics was performed for cells that have undergone 3 or more divisions. Percentage of CFSElow and CD27high (H) or CD38high (I) cells gated on CD19+ cells for 8 independent experiments. In A, D, E, and G-I each symbol represents 1 independent experiment; in B each symbol represents the mean of 2 independent experiments. PI, Propidium iodide; α-, anti-; BAFF, B-cell activating factor; lo, low expression; hi, high expression; ns, not significant. *P < .05. **P < .01. ***P < .001. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 CD40 and IL-21R expression and JAK-STAT signaling in B cells are not modulated by VPA. (A-K, Naive B cells were stimulated as indicated.) A and B, Cell surface expression of CD40. A, Representative FACS plot. B, MFI of CD40 in 3 independent experiments. C-E, IL-21R expression. C, Variation of relative IL-21R mRNA expression over time in culture. D, Representative FACS plot. E, MFI of IL-21R in 4 independent experiments. Relative mRNA levels of JAK3 (F), STAT3 (G), STAT5A (H), and STAT5B (I) over time in culture. Each symbol represents one independent experiment. J, Cells were lysed after 6 days in culture either directly, or after 15 minutes (K) of pulse stimulation with IL-21. Lysates were analyzed by Western blot analysis with the use of antibodies specific for JAK3 and STAT5 or their phosphorylated forms, and for β-actin. L, MEC1 cells were cultured as indicated. Cells were lysed after 4 days either directly (lane 1) or after 15 minutes of pulse stimulation with IL-21 (lanes 2-3). Lysates were analyzed by Western blot analysis with the use of an antibody specific for STAT3 or its phosphorylated form. (p)JAK3, (phospho) Janus kinase 3; (p)STAT3, 5A, 5B, (phospho) signal transducer and activator of transcription 3, 5 isoform A and B; t=0, before activation; d3, 3 days after activation; FACS, fluorescence-activated cell sorting; MFI, median fluorescence intensity; ns, not significant. Journal of Allergy and Clinical Immunology 2013 131, 1695-1699.e9DOI: (10.1016/j.jaci.2013.01.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions