Mechanisms of retroelement-mediated autoimmunity in lupus erythematosus

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded Yale University $170,964 on May 15, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846), a Project Grant supporting a five-year career development award (K08AR086982) in dermatology and physician-scientist training.

The award funds research into retroelement-mediated mechanisms of systemic lupus erythematosus, a highly morbid autoimmune disease affecting over 200,000 patients in the United States. The investigator will delineate gene and retroelement expression patterns and inflammatory cytokine levels in peripheral blood and skin of SLE patients; identify and phenotype retroelement-specific autoreactive CD4+ T cells; and mechanistically evaluate immune responses targeting retroelements in the skin using genetic mouse models. Prior laboratory work identified antibodies targeting retroelements in SLE patients that correlated with interferon gene expression signatures. The research hypothesizes that retroelements contribute to SLE through type I interferon induction and by serving as autoantigens triggering adaptive immunity.

Performance extends through March 31, 2031, at Yale University in New Haven, Connecticut.

Abstract

This is a career development award application for a dermatologist and physician-scientist studying the role of retroelements in systemic lupus erythematosus (SLE). SLE is a highly morbid autoimmune disease with major manifestations that include disfiguring skin rashes as well as joint and kidney pathology. In the united states, IT is estimated that over 200,000 patients have SLE. The pathogenesis of SLE remains incompletely understood. Of the implicated pathways, elevated antiviral type i interferon signaling as well as autoreactive t cells have been identified as possible mediators of disease, though the etiology of these antiviral signals as well as the antigenic targets of t cells are not well established. Prior work from our laboratory discovered antibodies targeting retroelements in patients with SLE which correlated with interferon gene expression signatures. We hypothesize that retroelements contribute to SLE through two distinct mechanisms: by inducing type i interferon responses and by serving as a source of autoantigens that trigger adaptive immunity. This proposal will (1) delineate gene and retroelement expression patterns and inflammatory cytokine levels in the peripheral blood and skin of SLE patients, (2) identify and phenotype retroelement-specific autoreactive CD4+ t cells, and (3) mechanistically evaluate immune responses targeting retroelements in the skin using genetic mouse models. Through characterization of these autoreactive t cell populations and correlation with gene, retroelement, and inflammatory protein levels, these studies will evaluate a previously undescribed pathway to autoimmunity with therapeutic potential. This proposal describes a rigorous five-year career development training program supporting my transition to an independent investigator. After completing my MD and PHD in biochemistry and molecular biology, i continued my clinical and research training at yale in the investigative dermatology program which combines clinical dermatology residency training with protected research time. I have now embarked on an intensive immunology training program under the mentorship of DR. Akiko iwasaki, a pioneer and world leader in deciphering the complex interplay among viruses, innate immune recognition, and adaptive immunity. In addition to the intellectual development and practical laboratory-based training that i will continue to receive in DR. Iwasaki's lab, i have developed a training program built on didactic coursework in immunology and computational biology. This plan is supported by the expertise of dedicated and experienced mentors with extensive domain knowledge in relevant disciplines. Yale school of medicine, along with the departments of dermatology and immunobiology, will provide the resources, support, and infrastructure to assist me in achieving the aims described in this proposal and my long-term goal of developing into an independent physician-scientist studying autoimmune skin disease.