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

Abstract

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-g subcutaneous injection of mouse Y1 or mouse Y3 RNA, and the effects were observed.Results

Evidence of Autoimmune-Related Effects of Trichloroethylene Exposure from Studies in Mice and Humans

“…In the oral exposure studies, the duration of exposure period clearly influences the observed effects, with the acceleration (as measured by auto-antibody production, T-cell activation, and inflammatory cytokine secretion or serum levels) generally seen with shorter exposures (Blossom et al 2004; Griffin et al 2000a, 2000b), and clinical effects seen with longer exposure periods (Blossom et al 2007; Cai et al 2008; Gilkeson et al 2004; Griffin et al 2000b). The different effects seen with short compared with long exposure durations in the MRL +/+ mouse experiments may reflect the varying disease course and varying response in specific target tissues during different phases of pathogenesis (Greidinger et al 2007). It is interesting that the clinical effects seen in the MRL +/+ mouse chronic exposure studies (36–48 weeks) (Blossom et al 2007; Cai et al 2008; Griffin et al 2000b) differ somewhat from “normal” expression within these mice.…”

Diagnosis and risk stratification in patients with anti-RNP autoimmunity

“…Studies comparing MCTD and SLE patients have found increases in IgG, IL-10 and TNFa levels in the MCTD patients, with generally similar patterns of interferon gamma, IL-2, and IL-4 production [13–15]. We have suggested that differences in immune activation, such as preferential activation of TLR3 versus TLR7, could account for differences in disease expression between MCTD and RNP+ lupus [16]. …”

Endosomal Toll-like receptors in autoimmunity: mechanisms for clinical diversity

“…Mice with induced anti-RNP autoimmunity after stimulation with the TLR3 and TLR7 agonist U1-RNA were found to develop lung disease in TLR3-intact mice but renal disease in TLR3-null animals [4]. Likewise, mice treated with Y RNAs had different outcomes with regard to induction of renal disease and sialoadenitis based on the presence or absence of TLR3 expression of the test mice and on the endosomal TLR stimulatory patterns of the individual Y RNAs [21]. In a spontaneous lupus model, differing effects of TLR7 and TLR9 have been observed on tissue-specific disease manifestations: TLR7 knockouts had less severe nephritis than wild-type mice, while TLR9 knockouts had more severe nephritis and skin disease than wild-type mice (also supported by the finding of higher serum IFN-α levels and increased PDC activation) [22].…”

“…Each of the endosomal TLRs have also been observed in some circumstances to induce anti-inflammatory effects, such as prevention of renal disease with TLR3 and TLR9 [21,22] and prevention of sialadenitis with TLR7 [21]. Potentially anti-inflammatory pathways reported to be induced by these TLRs under some circumstances include induction of suppressor of cytokine signaling proteins [48,49] and enhancement of proteosome destruction of intracellular proinflammatory mediators [50].…”