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U1 snRNPs bind to TLR7 and drive cytokine production by human dendritic cells.

According to a study on page 1575, cellular debris might help trigger the autoimmune disease systemic lupus erythematosus (SLE). Vollmer and colleagues show that endogenous complexes of RNA and protein, often released from dying cells, engage activating receptors in dendritic cells (DCs). The activated DCs then launch an inappropriate immune response against these self-complexes, thus triggering autoimmune disease.

In patients with SLE, the clearance of apoptotic cells is often delayed, in part because of unexplained defects in macrophage phagocytosis. As a result, cellular debris accumulates and is thought to be a source of autoantigens. But a simple piling up of undisposed waste does not explain the specificity of the autoantibody response in patients with SLE—a response selectively targeted against nucleic acid–containing molecules, including chromatin and small nuclear ribonucleoproteins (snRNPs).Vollmer and colleagues now show that snRNPs, such as U1, can be taken up by human DCs when complexed with antibodies from SLE serum. Once inside, the RNA component of the snRNPs engages the intracellular receptors Toll-like receptor (TLR)-7 and TLR8—which are normally triggered by microbial RNAs—thus activating the immune response. The ability to engage TLR7 depended on uridine-rich sequences in the U1 RNA. These sequences were also found in other autoantigens targeted in SLE, suggesting that the ability to engage intracellular TLRs might be a key to autoantibody specificity in SLE.

How the process of autoantibody formation is initiated is still unclear. Recent studies have shown evidence for tolerance defects in patients with SLE that allow autoreactive antibody-producing B cells to escape deletion. Others have shown that RNA-associated autoantigens can trigger TLR7 signaling in B cells, suggesting the possibility that autoreactive B cell escapees and immune-stimulating DCs conspire to trigger an immune response against RNA-associated antigens.

hvanepps{at}rockefeller.edu

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Jörg Vollmer, Sibylle Tluk, Claudia Schmitz, Svetlana Hamm, Marion Jurk, Alexandra Forsbach, Shizuo Akira, Kindra M. Kelly, Westley H. Reeves, Stefan Bauer, and Arthur M. Krieg
J. Exp. Med. 2005 202: 1575-1585. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 654K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Van Epps, H. L. Search for Related Content PubMed Articles by Van Epps, H. L. Related Collections Related Article Social Bookmarking                            What's this?