Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease defined by immune dysregulation, antibody formation, followed by end-organ damage. MyD88 is a central immune adaptor protein that regulates disease pathogenesis in SLE that acts downstream of the Toll-like receptors, well known mediators of disease in SLE. Several components of the MyD88/TLR signaling pathway have been identified as risk alleles in SLE patients, including TLR7, TLR8, TLR9, IRAK1, IRAK4, OPN, and ACP1. Previously, we showed that global and B cell-specific MyD88-deficient mice exhibited ameliorated disease, including reduced organ damage and suppressed autoantibody formation. Whether MyD88 regulates only disease initiation or contributes to disease perpetuation after onset of symptoms is unclear. By defining the role of MyD88 in SLE pathogenesis, we will be able to determine if MyD88 is a potential therapeutic target for SLE patients.

Methods: Lupus prone (MRL.Fas^lpr) 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 lupus prone (MRL.Fas^lpr) mice in which B cell-specific depletion of MyD88 is induced by tamoxifen (hCD20-Tam Cre, Myd88^floxed) while both Cre negative littermates and hCD20-Tam Cre⁺ Myd88 sufficient mice were used as a comparator groups. For all groups, tamoxifen was orally administered biweekly starting after disease onset (12 weeks of age). Cell specific deletion was assessed using cell sorting and qPCR of genomic DNA. Mice were analyzed for disease pathology at 19 and 21 weeks of age for females and males respectively. Analysis included proteinuria, renal histology for both interstitial and histologic disease, dermatitis, autoantibody production, and immune cell activation. Survival analysis was performed on female mice.

Results: MRL.Fas^lpr mice with induced B cell-specific deletion of MyD88 (Tam,B-MyD88^fl/fl) exhibited a significant survival advantage over control mice (p< 0.05) with reduced kidney histologic disease, including both glomerulonephritis (p< 0.01) and interstitial inflammation (p< 0.01). Additionally, Tam,B-MyD88^fl/fl mice had reduced autoantibody formation as assessed by ANA immunofluorescence and ELISA. The B cell compartment was altered in these mice with no change in the percentage of total B cells, but vastly reduced ABC formation (defined as CD19⁺,CD11c⁺, CD11b⁺) (p< 0.005) and reduced total number of plasmablasts (CD19^int, CD138⁺, CD44⁺).

Conclusion: These experiments suggest that there is a continued role for MyD88 signaling in B cells throughout the course of disease in MRL.Fas^lpr 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-specific-myd88-regulates-pathology-after-disease-onset-in-murine-lupus/