Cross-regulation between TLR7, TLR8, and TLR9 in autoreactive B cells. (167.22) | doi.page

Cross-regulation between TLR7, TLR8, and TLR9 in autoreactive B cells. (167.22)

The Journal of Immunology2011Vol. 186(1_Supplement), pp. 167.22–167.22

Nathaniel Green, Michelle Debatis, Ann Marshak‐Rothstein

Abstract

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against intracellular targets, frequently nucleic acid associated proteins. Toll-like receptors (TLR) 7 and TLR9 (which recognize single stranded RNA and DNA respectively) have been shown by our lab to be critical in the activation of autoreactive B cells. Genetic deletion of TLR7 significantly reduces disease, whereas genetic removal of TLR9 leads to exacerbated disease. To understand the basis for this difference, we examine the in vitro responses elicited by DNA- and RNA-containing immune complexes (ICs). TLR9-/- autoreactive B cells respond more strongly than TLR9+/+ B cells to RNA ICs, however TLR7-/- and TLR7+/+ autoreactive B cells respond comparably to DNA ICs. Since it has been shown that TLR7 mediated responses can significantly increase with a two-fold change in expression, we examined whether the absence of TLR9 changed the expression levels of TLR7, or vice versa. While TLR7 and TLR9 expression were unaffected by the absence of the other TLR, TLR7 knockout B cells expressed greatly enhanced levels of TLR8, which is thought to be suppressive. In fact, TLR7-/- B cells show a repressed response to DNA ICs in the presence of TLR8 ligands. This inhibitory effect of TLR8 on TLR9 mediated responses in TLR7 knockouts could partially explain the dramatically decreased disease seen in TLR7 deficient autoimmune prone mouse models.

Abstract

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