Intricate interplay of cytokines determine the progression of SLE-like disease in BXSB.Yaa mice (BA12P.104)

Systemic lupus erythematosus (SLE) is a complex multi-organ disease that affects mostly females. It is caused by several environmental, genetic and stochastic factors. BXSB.Yaa is a recombinant inbred strain of mice with major manifestations that parallel those of human SLE, thereby making it a model system to investigate genetic and non-genetic determinants of disease initiation and progression. The Yaa mutation in male results due to translocation of a 4Mb chromosomal region, including Tlr7 gene, from X to the Y chromosome, making them susceptible to disease. The disease pathogenesis involves an intricate interplay of key cytokines such as IL-21, IL-6, Type I interferon (IFN) and IL-10. Enhanced expression of IL-21 by CD4-T (Tfh) cells expands autoreactive B cells that differentiate into plasmablasts and secrete autoantibodies. IL21 also promotes the development of CD8-T cells and NK cells which retard early disease development. Gene expression profiles of cells from young IL-21R deficient BXSB.Yaa mice revealed an “IFN signature” similar to human SLE females. Purified plasmacytoid dendritic cells (pDCs) from male mice produced higher levels of Type-I IFN than females. Type I IFN further stimulates IL6 producing B cells that drives differentiation of CD4 Tfh cells. IL6 also contributes to accelerated mortality in BXSB.Yaa mice. Moreover, BXSB.Yaa mice express IL10 and ablation of IL10 in these mice results in accelerated mortality.