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Clinical immunology : the official journal of the Clinical Immunology Society v.183, 2017년, pp.132 - 141   SCI SCIE SCOPUS
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Complete knockout of estrogen receptor alpha is not directly protective in murine lupus

Scott, Jennifer L. (Medical University of South Carolina, Division of Rheumatology and Immunology, Charleston, SC 29425, USA ) ; Wirth, Jena R. (Medical University of South Carolina, Division of Rheumatology and Immunology, Charleston, SC 29425, USA ) ; Eudaly, Jackie (Medical University of South Carolina, Division of Rheumatology and Immunology, Charleston, SC 29425, USA ) ; Ruiz, Phil (University of Miami, School of Medicine, Department of Pathology, 1611 N.W. 12th Ave., Holtz Center, East Tower, Room 2101, Miami, FL 33136, USA ) ; Cunningham, Melissa A. (Medical University of South Carolina, Division of Rheumatology and Immunology, Charleston, SC 29425, USA ) ;
  • 초록  

    Abstract Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease that disproportionately affects women. Despite a known role for hormonal factors impacting autoimmunity and disease pathogenesis, the specific mechanisms of action remain poorly understood. Our laboratory previously backcrossed “estrogen receptor alpha knockout (ERαKO)” mice onto the NZM2410 lupus prone background to generate NZM/ERαKO mice. This original ERαKO mouse, developed in the mid-1990s and utilized in hundreds of published studies, is not in fact ERα null. They express an N-terminally truncated ERα, and are considered a functional KO. They have physiologic deficiencies including infertility due to disruption of a critical activation domain (AF-1) at the N terminus of ERα, required for most classic estrogen (E2) actions. We demonstrated that female NZM/ERαKO mice had significantly less renal disease and significantly prolonged survival compared to WT littermates despite similar serum levels of autoantibodies and glomerular immune complex deposition. Herein, we present results of experiments using a lupus prone true ERα−/− mice (deletional KO mice on the NZM2410 background), surprisingly finding that these animals were not protected if they were ovariectomized, suggesting that another hormonal component confers protection, possibly testosterone, rather than the absence of the full-length ERα. Highlights NZM2410 ERα−/− mice are not protected from lupus disease expression if ovariectomized. ERα disruption increases, not decreases, autoantibody production in the NZM2410 model. E2 can exacerbate lupus disease expression via a mechanism that is independent of ERα. DCs & their subsets (cDC1, cDC2) are not altered by E2 or ERα on the NZM background.


  • 주제어

    Lupus .   Estrogen receptor alpha .   Testosterone .   Estrogen .   Autoantibody.  

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