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¹ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115
² Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
³ Department of Immunology and Microbial Sciences, Scripps Research Institute, La Jolla, CA 92037
⁴ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
⁵ Feinstein Institute for Medical Research, Autoimmune and Musculoskeletal Disease Center, Manhasset, NY 11030
⁶ Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Cornell Medical Research Institute, White Plains, NY 10605

CORRESPONDENCE Laurie H. Glimcher: lglimche{at}hsph.harvard.edu

The unfolded protein response (UPR) is a stress response pathway that is driven by the increased load of unfolded proteins in the endoplasmic reticulum of highly secretory cells such as plasma cells (PCs). X box binding protein 1 (XBP1) is a transcription factor that mediates one branch of the UPR and is crucial for the development of antibody-secreting PCs. PCs represent only one class of terminally differentiated B cells, however, and little is known about the role for XBP1 in the other class: memory B cells. We have developed an XBP1^fl/fl CD19^+/cre conditional knockout (XBP1^CD19) mouse to build upon our current understanding of the function of XBP1 in PC differentiation as well as to explore the role of XBP1 in memory cell development. Using this model, we show that XBP1^CD19 mice are protected from disease in an autoantibody-mediated mouse lupus model. We also identify a novel developmental stage at which B cells express the traditional PC marker CD138 (syndecan-1) but have yet to undergo XBP1-dependent functional and morphological differentiation into antibody-secreting cells. Finally, we show that memory B cells develop normally in XBP1^CD19 mice, demonstrating that XBP1-mediated functions occur independently of any memory cell lineage commitment.

Abbreviations used: 7-AAD, 7-amino-actinomycin D; APC, allophycocyanin; BiP, Ig heavy chain binding protein; Blimp1, B lymphocyte-induced maturation protein 1; BODIPY, boron-dipyrromethane; cDNA, complementary DNA; cKO, conditional KO; dsDNA, double-stranded DNA; ERdj4, ER-localized Dnajb9; GC, germinal center; IHC, immunohistochemistry; IRE1, inositol-requiring transmembrane kinase/endonuclease 1; IRF4, IFN regulatory factor 4; mRNA, messenger RNA; NP, nitrophenol; Pax5, paired box gene 5; PC, plasma cell; PDI, protein disulfide isomerase; PI, propidium iodide; SLE, systemic lupus erythematosus; UPR, unfolded protein response; XBP1, X box binding protein 1.

© 2009 Todd et al.
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This article has been cited by other articles:

• Todd, D. J., McHeyzer-Williams, L. J., Kowal, C., Lee, A.-H., Volpe, B. T., Diamond, B., McHeyzer-Williams, M. G., Glimcher, L. H. (2009). XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. JCB 186: i13-i13 [Full Text]  

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