Sandra Wolin, MD, PhD
Yale University, New Haven, CT
The role of Ro60-bound RNAs in SCLE
The Study and What it Means to Patients
“How does sunlight cause lupus skin flares? Many patients with lupus of the skin produce antibodies against a protein, Ro60, which normally binds RNA inside cells. We are testing whether sun exposure releases Ro60-RNA complexes that interact with the antibodies to cause skin rashes. Our findings could reveal a new pathway and novel drug targets for lupus of the skin.”
We know that patients with a form of lupus of the skin called subacute cutaneous lupus erythematosus (SCLE) make antibodies against an RNA-binding protein known as Ro60. We propose that in SCLE, sun exposure causes the release of Ro60 and its bound RNAs from skin cells, allowing them to form complexes with the antibodies. These complexes then activate receptors inside other cells, causing production of inflammatory molecules that result in skin rashes. To test this model we will use antibodies from SCLE patients to identify the Ro60-bound RNAs that are likely to activate these receptors. We will also determine if mice making antibodies against Ro60 develop SCLE-like disease.
Our study aims to test a new model for why lupus skin rashes occur after sun exposure that may also be applicable to systemic lupus.
Cutaneous lupus is associated with significant psychological stress and decreased quality of life. One form of cutaneous lupus, subacute cutaneous lupus erythematosus (SCLE), may provide a particularly tractable model for elucidating the contributions of autoantibodies and autoantigens to disease. SCLE patients possess anti-Ro antibodies and are strongly enriched for the HLA-DR3 haplotype. We propose that SCLE occurs when the antibodies form immune complexes (ICs) with Ro60 ribonucleoproteins released by sunlight-damaged keratinocytes. Upon uptake of the ICs by plasmacytoid dendritic cells (PDCs), the RNAs activate toll-like receptors (TLRs), resulting in type I interferon secretion. Our objectives are to identify those RNAs that are involved in SCLE pathogenesis and to develop a mouse model to allow testing of this hypothesis. First, we will use in vivo crosslinking and high-throughput sequencing to identify Ro60-bound RNAs that become extracellular in sunlight-exposed human keratinocytes. Second, we will determine which RNAs, as part of ICs, are the most potent activators of PDC TLRs. These experiments should serve as a paradigm for elucidating the contributions of RNA-containing autoantigens to lupus sequelae, thus facilitating development of therapeutics that target these RNAs.
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