Toll-like receptors in systemic autoimmune disease

Abstract

Autoreactive B cells can be activated effectively in vitro by endogenous DNA or RNA, as well as by DNA- or RNA-binding proteins, through a mechanism that depends on the B-cell receptor and Toll-like receptor 7 (TLR7) and/or TLR9. B-cell responses to RNA-associated autoantigens are markedly increased by type I interferons (IFNs). Similarly, it seems that TLR7 and TLR9 have important roles in the activation of plasmacytoid dendritic cells, through a mechanism that depends on the low-affinity receptor for IgG (FcγRIIa; also known as CD32), leading to the production of large amounts of type I IFNs. Mice that inherit the Y-chromosome-linked autoimmune accelerator (Yaa) mutation express twice the normal amount of TLR7 and are hyper-responsive to TLR7 ligands. The increased amount of TLR7 might account for the role of TLR7 in the acceleration of autoimmune disease in these mice. TLR9-deficient autoimmune-prone mice have a decreased capacity to produce antibodies specific for double-stranded DNA or nucleosomes, but they produce normal or increased amounts of antibodies specific for RNA-associated autoantigens. Nevertheless, TLR9 deficiency can lead to exacerbation of clinical disease in some animal models of systemic lupus erythematosus. TLR7-deficient autoimmune-prone mice have a decreased capacity to produce antibodies specific for RNA-associated autoantigens. In contrast to TLR9 deficiency, TLR7 deficiency does not lead to exacerbated clinical disease. In addition to DNA and RNA, other endogenous TLR ligands that are released from dead or dying cells or are released as a result of tissue injury have been found either to promote or to downregulate chronic inflammatory conditions.