On the lupus-prone MRL-lpr/lpr (MRL-lpr) background, AM14 rheumatoid factor (RF) B cells are activated, differentiate into plasmablasts, and undergo somatic hypermutation outside of follicles. Using multiple strategies to impair T cells, we found that such AM14 B cell activation did not require T cells but could be modulated by them. In vitro, the signaling adaptor MyD88 is required for IgG anti-chromatin to stimulate AM14 B cell proliferation when T cells are absent. However, the roles of Toll-like receptors (TLRs) in AM14 B cell activation in vivo have not been investigated. We found that activation, expansion, and differentiation of AM14 B cells depended on MyD88; however, mice lacking either TLR7 or TLR9 displayed partial defects, indicating complex roles for these receptors. T cell-independent activation of certain autoreactive B cells, which gain stimuli via endogenous TLR ligands instead of T cells, may be the initial step in the generation of canonical autoantibodies.
Bibliographical noteFunding Information:
We thank J. Craft and Z. Yin for generously providing the Tcrb −/− mice and UC-7 Ab. We thank M. Horniak, T. Hunt, M. Baez, and D. Kent for outstanding animal husbandry. We thank the members of the Shlomchik lab autoimmunity group for many useful discussions and A. Rothstein and J. Craft for critical comments on the manuscript. The research was supported by NIH grants P01-AI36529 and P01-AR050256.
ASJC Scopus subject areas
- Infectious Diseases
- Immunology and Allergy