Elucidation of Retroelement-induced autoimmune responses in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is linked to abnormally high levels of type I interferons, signaling molecules that cause inflammation. While the cause of this increased interferon activity in SLE is not yet fully understood, recent findings from Dr. Iwasaki’s lab point to retroelements as a culprit. Retroelements are highly repetitive DNA sequences integrated into our genome, or genetic material. Endogenous retroviruses (ERVs) are a member of the retroelement family of viruses that infected our ancestors millions of years ago, leaving remnants that make up approximately 8% of our genome. Recent studies have also shown that these ERVs are involved in regulating T cells, which typically identify and combat foreign pathogens. In SLE, some T cells become autoreactive, meaning that they mistakenly recognize the body’s own antigens as foreign invaders, leading to an immune attack on healthy tissues. Autoreactive T cells can also activate B cells, another immune cell type, to produce autoantibodies, which also mistakenly target the body’s own cells. Dr. Iwasaki previously identified autoantibodies in people with SLE that specifically target ERVs, leading her to test whether these individuals also have ERV-targeted T cells. Dr. Iwasaki will identify and characterize ERV-specific T cells in samples from individuals with cutaneous lupus, when lupus affects the skin, to better understand the immune response to an increased level of ERVs.

The expression, or activity, of ERVs is controlled by a process called methylation, which can be likened to turning off a light switch. Methylation causes a gene to be turned off, or silenced, preventing it from producing proteins. Dr. Iwasaki will disrupt a specific methylation pathway in the skin of mice to test whether increased ERV activation leads to systemic inflammation and autoimmunity. Dr. Iwasaki will then evaluate the immune response to the increased skin ERV activation in this mouse model by measuring their interferon levels, autoantibodies, T cells and other factors. Dr. Iwasaki aims to provide evidence connecting ERVs to the development of autoreactive T cells in SLE, shedding light on retroelements as potential drivers of autoimmunity in this disease and pointing the way to a potential new treatment approach.

What this study means for people with lupus:

Standard therapies for SLE, including corticosteroids and broad immunosuppressive agents, often produce adverse side effects. Newer treatments recently approved for SLE show promising results but do not work on all patients. The development of targeted treatments has been limited by the incomplete understanding of SLE. Dr. Iwasaki’s findings can potentially enable the development of new therapies that specifically target retroelement-induced immune responses in SLE.

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. Though several drugs have recently been approved for SLE, the backbone of therapy for many patients remains corticosteroids and immunosuppressive agents with broad, often unfavorable side effects rather than more targeted therapies with limited adverse effects. The development of new therapies has been limited by the incomplete understanding of SLE pathogenesis. 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. One emerging hypothesis for these elevated interferon signatures includes deregulated expression of retroelements including endogenous retroviruses (ERVs). ERVs are a part of a larger family of repetitive DNA sequences termed retroelements that include endogenous retroviruses (viral remnants of retroviruses that have been integrated in our genomes over millennia, approximately 8% of our genome) as well as Long Interspersed Nuclear Elements (LINEs, approximately 19% of our genome).

Prior work from the Iwasaki laboratory discovered antibodies targeting ERVs in patients with SLE which correlated with interferon gene expression signatures. We hypothesize that deregulated expression of retroelements induces an inflammatory antiviral expression program and likewise generates a reservoir of autoantigens that trigger adaptive immune responses in SLE patients, initiating and propagating autoimmunity. To address this hypothesis, our proposal will (1) delineate the gene and retroelement expression patterns as well as inflammatory cytokine levels in the peripheral blood and skin of SLE patients and (2) identify and phenotype retroelement-specific autoreactive CD4+ T cells. In addition, we will (3) mechanistically evaluate immune responses targeting retroelements using genetic mouse models. Through the 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 future therapeutic potential.