Katherine A. Fitzgerald, Ph.D.

University of Massachusetts Medical School, Amherst, MA

2015 Cell Signaling, Innate Immunity, Target Identification, Immune System Function

2015 Single Molecule May Slam the Brakes on Signals that Drive Autoimmunity

The study and what it means to patients

We are exploring if a specific molecule protects against lupus by jamming dangerous inflammatory signals, research that could lead to development of new anti-inflammatory treatments.

Summary

While we learn more each day about the signaling between the cells that contributes to autoimmunity, we are not always able to effectively stop these signals. One new approach to stopping these signals is to look at the underlying molecules that control their production.

Our discovery of a specific RNA, called long non-coding RNA-Eps, sheds new light on ways to interrupt damaging inflammatory signaling, with the potential to control autoantibodies and the destruction they cause to the body. We hypothesize that if we understand the regulation of this RNA, and the mechanisms by which this RNA prevents the inappropriate activation of the type I interferon inflammatory response that is common in lupus, we will be better equipped to control autoimmunity.

Scientific Abstract: The role of the long non-coding RNA lincRNA-Eps in Lupus

SLE is a debilitating systemic autoimmune disease characterized by the overproduction of pathogenic antibodies to nuclear and cytoplasmic antigens. Nucleic acid sensing endosomal TLRs (TLR7 and 9) detect RNA or DNA-associated macromolecular complexes respectively, leading to the activation of B cells, plasmacytoid dendritic cells (pDCs), neutrophils, as well as other cell types. Autoantigen-activated pDCs and APCs produce high levels of type I interferon (IFN) and pro-inflammatory cytokines, which further promote the development of autoantibodies and other pathogenic mechanisms.

The work proposed in this application will investigate the role of a long non-coding RNA called lincRNA-Eps, that we have identified, which restrains the transcription of type I IFNs and ISGs. We propose to understand the regulation of this lincRNA by TLRs, the mechanisms by which this lincRNA prevents the inappropriate activation of the type I IFN response and the impact of lincRNA-Eps-deficiency on spontaneous autoimmunity as well as TLR driven autoimmunity in vivo. Detailed mechanistic studies of how lncRNAs impact type I IFNs and ISGs and elucidation of their mode of action could provide critical insights that could potentially lead to the development of improved therapeutics for SLE and other autoimmune diseases.