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Modulatory Effects of 1,25-Dihydroxyvitamin D₃ on Human B Cell Differentiation

Sheng Chen^*,, Gary P. Sims^1,*, Xiao Xiang Chen, Yue Ying Gu, Shunle Chen and Peter E. Lipsky^2,*

^* Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and Shanghai Clinical Center for Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) can modulate immune responses, but whether it directly affects B cell function is unknown. Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1,25(OH)₂D₃ levels, suggesting that vitamin D might play a role in regulating autoantibody production. To address this, we examined the effects of 1,25(OH)₂D₃ on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded. The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1,25(OH)₂D₃, although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1,25(OH)₂D₃ and/or activation. Importantly, 1,25(OH)₂D₃ up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation. These results indicate that 1,25(OH)₂D₃ may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Medimmune, One Medimmune Way, Gaithersburg, MD 20878.

² Address correspondence and reprint requests to Dr. Peter E. Lipsky, Intramural Research Program Autoimmunity Branch Chief, National Institute of Arthritis and Musculoskeletal and Skin Diseases, 9000 Rockville Pike, Building 10, Room 6D47C, Bethesda, MD 20892. E-mail address: lipskyp{at}mail.nih.gov

³ Abbreviations used in this paper: 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; AID, activation-induced cytidine deaminase; ANA, antinuclear Ab; ₂M, ₂-microglobulin; BCL6, B cell lymphoma 6; BLIMP1, B lymphocyte-induced maturation protein 1; DC, dendritic cell; ERN1, endoplasmic reticulum to nucleus signaling; IRF4, IFN regulatory factor 4; PI, propidium iodide; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; VDR, vitamin D₃ receptor; XBP1, X box-binding protein.

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