The role of toll-like receptors in systemic autoimmune disease

The AM14 B cell receptor, derived from an autoimmune Fas-deficient mouse, is a rheumatoid factor specific for IgG2a. B cells expressing the AM14 receptor have been effectively activated by immune complexes (ICs) consisting of IgG2a associated with endogenous TLR ligands that essentially serve as autoadjuvants. One source of endogenous ligand is DNAse-sensitive material, presumably chromatin, released from dead/dying mammalian cells. The chromatin response was blocked by endosome acidification inhibitors, eliminated in MyD88-deficient cells and markedly reduced, in TLR9-deficient cells; residual activity appeared to depend on a TLR(s) other than TLR9. Sources of TLR9-reactive mammalian DNA have been explored. AM14 B cells also responded to ICs consisting of IgG2a bound to RNA-associated autoantigens. These responses were eliminated in MyD88-deficient cells but unaffected by TLR9 deficiency. Thus, activation depends on BCR-directed delivery of the ICs to vesicular compartments that contain an appropriate TLR. Intriguingly, such BCR/TLR co-engagement leads to the expression of gene products not elicited by independent activation of the BCR (anti-IgM F(ab′)2) or TLR9 (CpG s-ODN) alone. The effects of nucleic acid-associated ICs on both B cells and antigen presenting cells indicate that the TLR9 subfamily may be a key target for therapeutic intervention in patients with systemic autoimmune diseases.