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Human IgA-Inducing Protein from Dendritic Cells Induces IgA Production by Naive IgD⁺ B Cells¹

Mark A. Endsley^*, Leo M. Njongmeta, Elisabeth Shell, Matthew W. Ryan^,¶, Alexander J. Indrikovs, Seckin Ulualp^¶, Randall M. Goldblum, Waithaka Mwangi and D. Mark Estes^2,*,

^* Department of Microbiology and Immunology, Department of Pathology, Blood Bank Division, and Department of Pediatrics, Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555; Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843; and ^¶ Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX 75390

Over the last several years, there has been a great deal of progress in characterizing the role of dendritic cells (DCs) in the activation and modulation of B cells. DC-secreted chemokines can induce B cell trafficking to the lymph nodes. DC-produced survival factors such as B cell-activating factor of the TNF family and a proliferation-inducing ligand have been shown to be essential for B cell maturation, but have also been implicated in class-switch recombination and B cell lymphoma survival. Recently added to this list of DC-derived factors effecting B cells is IgA-inducing protein (IGIP). In this study, we characterize production of IGIP by human DCs, and examine its capacity to induce IgA class switching and differentiation of naive B cells in vitro. Monocyte-derived DCs were cultured in vitro with TLR agonists (TLR3, 4, 5, and 9) and other factors, including CD40 ligand, GM-CSF, and IL-4 as well as the neuropeptide vasoactive intestinal peptide. Under in vitro stimulation with vasoactive intestinal peptide and CD40L, IGIP mRNA expression could be up-regulated as much as 35-fold above nonstimulated samples within 12–48 h. Naive B cells cultured with exogenous recombinant human IGIP produced IgA in greater quantities than nonstimulated controls. Finally, we demonstrate that IGIP stimulation drives the production of µ- switch circles from IgM⁺IgD⁺ naive human B cells, indicating its role as an IgA switch factor.

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 This work was supported by National Institutes of Health Grant 1R21AI060728. M.A.E. was supported by a predoctoral fellowship from the McLaughlin Memorial Endowment Fellowship Fund.

² Address correspondence and reprint requests to Dr. D. Mark Estes, Department of Pediatrics, Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555. E-mail address: dmestes{at}utmb.edu

³ Abbreviations used in this paper: VIP, vasoactive intestinal peptide; BAFF, B cell-activating factor of the INF family; APRIL, a proliferation-inducing ligand; DC, dendritic cell; mDC, monocyte-derived DC; CD40L, CD40 ligand; PACAP, pituitary adenylate cyclase-activating polypeptide; IGIP, IgA-inducing protein; RA, retinoic acid; rh, recombinant human; Fwd, forward; Rev, reverse; IDV, integrated density value; RE, relative expression; CSR, class switch recombination; SIgA, secretory IgA; Pam₃CSK₄, tripalmitoylated lipopeptide 3CysSerLys4; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor.