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Exogenous and Endogenous TLR Ligands Activate Anti-Chromatin and Polyreactive B Cells¹

Michele L. Fields^*, Michele H. Metzgar^*, Brian D. Hondowicz^*, Sun-Ah Kang, Shawn T. Alexander^*, Kristin D. Hazard^*, Alice C. Hsu^*, Yang-Zhu Du, Eline Luning Prak, Marc Monestier and Jan Erikson^2,*

^* The Wistar Institute, Philadelphia, PA 19104; Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19122; and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Autoreactive B cells may become activated in a T-independent manner via synergistic engagement of the BCR and TLRs. Using the V_H3H9 Ig H chain transgene to track anti-chromatin B cells, we demonstrate that V_H3H9/V1 anti-chromatin B cells proliferate in response to stimulatory oligodeoxynucleotides containing CpG motifs, suggesting that these autoreactive B cells are responsive to TLR9 signaling. Strikingly, some V_H3H9 B cells, but not the well-characterized V_H3H9/V1 B cells, proliferate spontaneously in culture medium. This proliferation is blocked by inhibitory CpG oligodeoxynucleotides, implicating the TLR9 (or possibly TLR7) pathway. Most hybridomas generated from the proliferating cells are polyreactive, and one exhibits binding to nuclear Ags but not to the other Ags tested. Thus, B cells carrying autoreactive and/or polyreactive specificities may be susceptible to T cell-independent activation via dual engagement of the BCR and TLRs.

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