Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. McClain M, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA. Nature Medicine 11, 85-89 (2004).
First published online in Nature Medicine last December, this paper by Judith James of the Oklahoma University Health Sciences Center et. al. investigates the origins of autoimmunity in systemic lupus erthematosus (SLE) by attempting to identify the environmental agents that could potentially incite autoimmunity. Using peptide arrays, the authors identified the initial autoantigenic epitope for some lupus patients positive for antibodies to 60 kDa Ro. This initial epitope directly cross-reacts with a peptide from the latent viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1).
Immunizing animals with either the first epitope of 60 kDa Ro or the cross-reactive EBNA-1 epitope resulted in the animals progressively developing autoantibodies binding multiple epitopes of Ro and spliceosomal autoantigens, the authors write. Eventually, the animals acquire clinical symptoms of lupus such as leukopenia, thrombocytopenia and renal dysfunction. As a result, the authors conclude that some humoral autoimmunity in human lupus arises through molecular mimicry between EBNA-1 and lupus autoantigens, and they suspect that Epstein-Barr virus plays an etiologic role in SLE.
PJ Utz
Assistant Professor of Medicine
Division of Rheumatology and Immunology
Stanford University School of Medicine
RNA interference: A mammalian SID-1 homologue enhances siRNA uptake and gene silencing efficacy in human cells. Duxbury MS, Ashley SW, Whang EE. Biochem Biophys Res Commun 331, 459-463 (2005).
SID-1 is a transmembrane protein that mediates systemic RNA interference in Caenorhabditis elegans. Whang et al. show that the mammalian SID-1 homologue FLJ20174 localizes to the cell membrane of human cells and enhances their uptake of small interfering RNA (siRNA), resulting in increased siRNA-mediated gene silencing efficacy. This is the first demonstration to show that overexpression of a membrane protein enhances siRNA internalization in mammalian cells, the authors write, raising the possibility of enhancing the efficacy of RNA interference.
According to recommender Cabon, RNA interference in C. elegans can be triggered by soaking the worm in a double-stranded RNA solution, and the entry of dsRNA requires a specific transporter, SID-1. Duxbury et al. demonstrate here that the expression of a mammalian homologue of SID-1 allows the entry of siRNA in cell culture, she says. The expression of this siRNA transporter in vivo has yet to be determined but would help understanding how siRNA injected in vivo in the absence of any transfection agent can penetrate into tissues and inhibit their target gene, Cabon says.
Florence Cabon
Team Leader
French National Center for Scientific Research (CNRS)
Systematic discovery of regulatory motifs in human promoters and 3’UTRs by comparison of several mammals. Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES, Kellis M. Nature 434: 338-45 (2005).
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Lewis BP, Burge CB, Bartel DP Cell 120: 15-20 (2005).
In a search for genome-wide sequence conservation in regulatory regions, Xie et al. predict that as many as 20 percent of human genes are potential targets of microRNAs. By comparison, in a search directed at microRNA binding sites in target mRNAs, Lewis et al. predict that as many as 30 percent of human genes are targets of microRNAs. Sequences in a gene’s 3’UTR demonstrate less conservation than is seen in translated regions. However, these authors identified short, conserved sequences in the 3’UTR of multiple genomes that correspond to microRNA binding sites.
These observations suggest that microRNA-gene regulatory networks are much more extensive than previously thought, says Novina. If microRNAs and their seed regions in the mRNA targets are evolutionarily conserved, then it is possible that the microRNA-gene regulatory networks are also conserved, he adds. We are only beginning to understand microRNA function and these results invite further exploration into microRNAs and their participation in gene regulatory networks, says Novina.
Carl Novina
Assistant Professor
Dana-Farber Cancer Institute & Harvard Medical School