Autoimmune rheumatologic diseases
Systemic lupus erythematosus (SLE) is a complex autoimmune disease defined by immune dysregulation. MyD88 is a central immune adaptor protein that regulates disease pathogenesis in SLE. Previously, we showed that global and B cell-specific MyD88-deficient mice exhibited ameliorated disease, including reduced organ damage and suppressed autoantibody formation. The role of MyD88 in B cells during disease initiation compared to disease perpetuation is still unclear.
Lupus prone (MRL.Faslpr) mice develop autoantibodies, proteinuria, dermatitis, and glomerulonephritis, with disease onset occurring between 9-11 weeks of age. In order to study the therapeutic potential of MyD88 suppression, we used hCD20-Tam Cre mice crossed to Myd88floxed mice in which B cell-specific depletion of MyD88 is induced by tamoxifen. Tamoxifen was orally administered biweekly starting after disease onset (12 weeks of age). Deletion of MyD88 was confirmed functionally and via qPCR.
Most notably, mice with induced B cell-specific deletion of MyD88 (Tam,B-MyD88fl/fl) exhibited a significant survival advantage over control mice (p< 0.05) and reduced kidney histologic disease, including both glomerulonephritis (p< 0.01) and interstitial inflammation (p< 0.01). Additionally, Tam,B-MyD88fl/fl mice had reduced autoantibody formation as assessed by ANA immunofluorescence and ELISA.
These experiments suggest that there is a continued role for MyD88 signaling in B cells throughout the course of disease in MRL.Faslpr lupus prone mice, rather than simply disease initiation. Numerous genetic deletions have resulted in suppressed disease onset in lupus models, but herein, we observed disease amelioration after disease onset. This portends that targeting MyD88 or its upstream activators may be a viable therapeutic option in SLE.