Differential tissue targeting of autoimmunity manifestations by Autoantigen‐Associated Y RNAs

OBJECTIVE: To assess the Y RNAs, a family of homologous RNAs that bind to the Ro autoantigen, for the ability to contribute to autoimmune disease by activating RNA-responsive Toll-like receptors (TLRs). METHODS: Using cell lines expressing or stably transfected with TLR-3, TLR-7, or TLR-8, we determined the patterns of RNA-specific TLR activation by in vitro transcripts of all of the known murine and human Y RNAs. Next, 8-10-week-old female mice were exposed to a single 50-microg subcutaneous injection of mouse Y1 or mouse Y3 RNA, and the effects were observed. RESULTS: Y RNA family members differed in their TLR reactivities. Both human and mouse Y3 RNAs, but not other human or mouse Y RNAs, prominently induced TLR-3 activation. Although most human and mouse Y RNAs activated TLR-7 efficiently, mouse Y3 RNA and human Y5 RNA did not. Single subcutaneous injections of mice with either mouse Y1 RNA or mouse Y3 RNA induced or inhibited lymphoid infiltrates in different target organs based on the Y RNA and TLR status of the mouse used. Mouse Y1 RNA induced kidney lesions in TLR-3-intact mice but not in TLR-3-knockout mice. In contrast, mouse Y3 RNA treatment was associated with nephritis in TLR-3-knockout mice but not in TLR-3-intact mice. Sialoadenitis developed in untreated TLR-3-/- mice and in TLR-3-/- mice treated with mouse Y3 RNA, but sialoadenitis was not present in TLR--/-) mice treated with mouse Y1 RNA. CONCLUSION: Y RNAs can induce innate immune responses and influence clinical manifestations of autoimmunity, suggesting that they are relevant to syndromes of anti-Ro autoimmunity. Distinct patterns of tissue targeting can be seen after exposure to different Y RNAs, in a pattern that correlates with the innate immune signals they induce. Thus, the balance of innate immune signals induced by exposure to endogenous Y RNAs may help determine the nature of the clinical syndrome in anti-Ro autoimmunity.