T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells.
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.
Herlands
Robin A
RA
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8035, USA.
Christensen
Sean R
SR
Sweet
Rebecca A
RA
Hershberg
Uri
U
Shlomchik
Mark J
MJ
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*
D001323:Autoantibodies; D002843:Chromatin; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9