Cunningham Research Lab

Systemic lupus erythematosus (SLE) is a disease that disproportionately affects females, and our group has a particular interest in autoimmunity, inflammation, and sex bias. We investigate the role of estrogen receptor alpha (ERα) in modulating the inflammatory response, and have focused our research effort on ERα variants. We use murine models of lupus and patient samples to study ERα modulation of Toll-like receptor (TLR)-signaling, with specific attention to dendritic cell dysfunction. In recent years, we discovered that lupus mice expressing an ERα short variant were protected from nephritis, despite similar serum autoantibody levels. Glomerular immune complex deposition was similar between WT and ERα short mutant mice, but renal inflammatory infiltrate and proteinuria were absent, suggesting that ERα mediates the cycle of local inflammation and progressive damage that leads to end stage renal disease.

Although the exact mechanism of its protective effect is currently unknown, we hypothesize that ERα short modulates the immune response due to a missing activation domain (AF-1). ERα short is structurally similar to an endogenous ERα variant (ERα46), expressed in both mice and humans, that also lacks the AF-1 domain. ERα46 differentially regulates gene transcription compared to ERα66, the classic isoform, and can also act at the plasma membrane to initiate rapid non-genomic signaling events. We believe ERα46 modulates ERα66 activity in a dose-dependent, tissue-specific manner, impacting the development and inflammatory actions of immune cells, and may protect against the development of lupus nephritis by down regulating TLR7-induced inflammation. We propose ERα46 as a novel therapeutic target in lupus and we have recently expanded our studies to look at cultured DCs from human peripheral blood mononuclear cells from SLE patients vs. healthy controls to further study the mechanism of ERα modulation of DCs in lupus.

As a rheumatologist and clinician-scientist specializing in the treatment of SLE, I am particularly eager to investigate new therapeutic targets for this disease, and the ERα46 variant and new anti-inflammatory SERMs appear to hold great promise. 

Publications

Pubmed Collection

Senior Author Publications

Senior Author PubMed Collection (senior author publications are most often associated with mentored projects)