Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing Systemic Lupus Erythematosus (SLE). SLE is caused, in part, by the survival of self-reactive B cells which produce autoantibodies that can deposit in tissues such as the kidney leading to tissue injury and significant morbidity.
In murine lupus models, IRF5-deficiency has been shown to reduce disease severity, in part, by ameliorating immune complex-mediated kidney disease. IRF5 is highly expressed in B cells where it is involved in isotype switching to IgG2a and TLR-mediated activation. However, whether IRF5 contributes to lupus pathogenesis by promoting B cell differentiation or plasma cell survival is not fully understood. We hypothesized that IRF5 may contribute to disease in the MRL/lpr lupus mouse model by promoting B cell survival through regulation of B lymphocyte stimulator (BLyS).
We evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model by measuring splenomegaly, lymphadenophathy, severity of kidney disease, as well as total serum IgG and anti-Sm/RNP and anti-nuclear autoantibodies. In addition we analyzed the splenic and bone marrow lymphocyte populations and measured serum BLyS levels over the course of disease.
We found that IRF5-deficient (IRF5-/-) MRL/lpr mice developed much less severe disease compared to their IRF5-sufficient (IRF5+/+) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4+ T cell numbers, IRF5-/- MRL/lpr mice had similar numbers of all splenic B cell subsets compared to IRF5+/+ MRL/lpr mice, suggesting that IRF5 is not involved in B cell development to the mature B cell stage. However, IRF5-/- MRL/lpr mice had greatly reduced numbers of splenic plasmablasts and bone marrow plasma cells. Despite the marked reduction in serum IgG and plasmablast numbers in IRF5-/- MRL/lpr mice, serum BLyS levels remained highly elevated with no difference observed between groups.
Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation and independently of BLyS production. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-regulatory-factor-5-promotes-disease-in-the-mrllpr-mouse-model-of-lupus/