TLR9 restricts survival of anergic anti-DNA B cells in systemic lupus erythematosus yet is also required for their activation (BA4P.219)

Abstract

Abstract Anti-DNA autoantibodies are a clinical hallmark of systemic lupus erythematosus. Nucleic acid reactive B cells arise in the bone marrow even in healthy individuals, but are tolerized by mechanisms including receptor editing, functional anergy, and/or deletion. TLR9, a sensor of endosomal dsDNA, both promotes and regulates systemic autoimmunity in vivo, but the mechanisms of its apparently contradictory roles in autoimmunity remained unclear. Here, using the 3H9 anti-DNA B cell receptor (BCR) transgene in the autoimmune-prone MRL.Fas-lpr mouse model of lupus, we identify the stages at which TLR9 contributes to establishing and breaking B cell tolerance. Although TLR9 is dispensable for editing and establishment of anergy, TLR9 limits anti-DNA B cell lifespan in the periphery and is thus tolerogenic. In the absence of TLR9, anti-DNA B cells have much longer lifespans and accumulate in the follicle, neither activated nor deleted. These cells retain some characteristics of anergic cells, in that they have elevated basal BCR signaling but impaired induced responses and downregulate their cell surface BCR expression. Nonetheless, in older autoimmune-prone animals, TLR9 is required for spontaneous peripheral activation of anti-DNA B cells and their differentiation into AFCs via an extrafollicular pathway. Thus, TLR9 has paradoxical roles in regulating anti-DNA B cells: it helps purge the peripheral repertoire of autoreactive cells yet is also required for their activation.