Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with many different permutations of symptom presentation. A large subset of SLE patients have been shown to present with elevated interferon stimulated gene (ISG) expression, and Type I IFNs (IFNαβ) have been shown to drive disease in murine models through global IFNα Receptor (IFNAR) knockouts. However, the disease contribution of distinct immune cell subsets in response to constitutively increased levels of IFNαβ is not fully understood. We utilized a B-cell specific IFNAR knockout (BΔIFNAR) on the B6.Nba2 spontaneous-lupus background to determine the contribution of IFNαβ stimulated B cells in disease. We found that IFNαβ signaling in B cells is driving increased splenomegaly, increased populations of activated B cells, and increased populations of germinal center (GC) B cells, memory B cells, and plasma blasts/cells, but did not affect the development of glomerulonephritis and immune-complex deposition. IFNAR expression by B cells also drove production of anti-chromatin IgG, and anti-dsDNA and -nRNP IgG and IgG2C auto-antibody levels, as well as increased Bcl2 expression, affecting GC B cell survival in B6.Nba2 mice.
Systemic lupus erythematosus (SLE) is an autoimmune disorder disproportionally affecting women. A similar sex difference exists in the murine New Zealand Black/White hybrid model (NZBWF1) of SLE with all females, but only 30-40% of males, developing disease within the first year of life. Myeloid-derived suppressor cells (MDSCs) are prominent in NZBWF1 males and while depletion of these cells in males, but not females, promotes disease development, the mechanism of suppression remains unknown. S100a9, expressed by neutrophils and MDSCs, has previously been shown to exert immunosuppressive functions in cancer and inflammation. Here we investigated if S100a9 exerts immunosuppressive functions in NZBWF1 male and female mice. S100a9+/+, S100a9+/- and S100a9-/- NZBWF1 mice were followed for disease development for up to 8 months of age. Serum autoantibody levels, splenomegaly, lymphocyte activation, glomerulonephritis and proteinuria were measured longitudinally or at the time of harvest. In accordance with an immunosuppressive function of MDSCs in male mice, S100a9-deficient male NZBWF1 mice developed accelerated autoimmunity as indicated by increased numbers of differentiated effector B and T cells, elevated serum autoantibody levels, increased immune-complex deposition and renal inflammation, and accelerated development of proteinuria. In contrast, female mice showed either no response to S100a9-deficiency or even a slight reduction in disease symptoms. Furthermore, male, but not female, S100a9-/- NZBWF1 mice displayed an elevated type I interferon-induced gene signature, suggesting that S100a9 may dampen a pathogenic type I interferon signal in male mice. Taken together, S100a9 exerts an immunosuppressive function in male NZBWF1 mice effectively moderating lupus-like disease development via inhibition of type I interferon production, lymphocyte activation, autoantibody production and the development of renal disease.
BackgroundSystemic Lupus Erythematous (SLE) is an autoimmune disease of unknown etiology affecting 5 million people worldwide. It is known that 50%–70% of lupus patients present with an interferon-alpha (IFN-) gene signature, and it has been shown in multiple mouse models that lupus-like disease can be abolished by IFN- receptor (IFNAR) gene deficiency. Furthermore, disease can be halted by ablating the main producers of IFN-, the plasmacytoid dendritic cells. Thus, IFN- likely has a causative role in lupus-like disease. Multiple immune cells express IFNAR, but it is not known what the effect of IFN- stimulation is on each cell type and how that stimulation affects symptom presentation. We hypothesize that BIFNAR mice would be specifically protected from splenomegaly, B cell activation, and ANA production, due to IFN-s known ability to enhance the antibody response.MethodsTo examine the role of B cell responses to IFN- stimulation in mouse lupus-like disease, we studied B cell specific IFNAR-deficiency (BIFNAR) in the B6.Nba2 spontaneous lupus-like disease model, using flow cytometry, ELISA, qRT-PCR and Immunostainings. We also immunized the mice with NP-CGG or NP-Ficoll in complete Freunds adjuvant to determine the effect of IFNAR-expression by B cells during antibody responses to exogenous antigen.ResultsAt four months of age, BIFNAR mice displayed slightly reduced spleen sizes, although this decrease was not significant until nine months of age. Furthermore, starting at 4 months of age, BIFNAR mice displayed reduced levels of chromatin specific ANAs along with reduced populations of plasmablasts, plasma cells and activated B cells. All other measures of disease showed no difference including total IgG and IgM production, immune complex deposition and C3 complement fixation in the kidney glomeruli, and glomerular size. Somewhat surprising, antibody responses to T-dependent and T-independent immunizations were also not affected.ConclusionsIFN- stimulation on B cells contributed to splenomegaly, increased B cell activation and differentiation, and subsequent production of chromatin specific ANAs, but had no specific role in the response to exogenous antigen. Thus, IFN- remains a valid therapeutic target for SLE; especially in patients presenting with high ANAs.Funding Source(s):R01AI118774
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.