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Primary Development and Participation in a Foreign Antigen-Driven Immune Response of a Chromatin-Reactive B Cell Clonotype Are Not Influenced by TLR9 or Other MyD88-Dependent TLRs¹

Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107

Recent findings support a central role for TLRs in both foreign Ag-driven immune responses and systemic autoimmune diseases mediated by B lymphocytes. In vitro studies have shown that the Ag receptors (BCRs) on B cells specific for nuclear autoantigens can facilitate the delivery of these autoantigens to the endocytic compartment, resulting in activation of the nucleic acid-specific TLRs present in this subcellular locale. If this pathway is operative in vivo it might promote the development, survival, or activation of such autoreactive B cells. To test this idea, we evaluated the influence of a deficiency in the CpG DNA-specific TLR, TLR9, or all MyD88-dependent TLRs on the primary development and foreign Ag-driven immune response of B cells in a line of V_H knockin mice that contains a high frequency of "dual reactive" B cells specific for DNA-based autoantigens such as chromatin, as well as the hapten arsonate. We found that although development and activation of these B cells in vitro are clearly influenced by DNA-based autoantigens, TLR9 or MyD88 deficiencies had no apparent effect on the primary development and participation in the anti-arsonate response of these B cells in vivo. We discuss these results in the context of previous models for the role of TLR9 and other TLRs in the regulation of antinuclear Ag B cell development and activity.

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 a grant from the National Institutes of Health (AI038965) to T.M. F.C. received support from National Research Service Award Training Grants T32-AI07492 and T32-CA09683.

² Address correspondence and reprint requests to Tim Manser, BLSB Room 708, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107. E-mail address: manser{at}mail.jci.tju.edu

³ Abbreviations used in this paper: Ars, arsonate; AFC, Ab-forming cell; GC, germinal center; KLH, keyhole limpet hemocyanin; PABA, p-aminobenzoic acid; PNA, peanut lectin agglutinin; Tyr, tyrosine.