Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormal autoreactivity in B cells. Lymphocytes and their soluble mediators contribute to the disease pathogenesis. We recently demonstrated that infecting lupus mice with malaria confers protection against lupus nephritis by attenuating oxidative stress in both liver and kidney tissues. In the current study, we further investigated B cell autoreactivity in female BWF1 lupus mice after infection with either live or gamma-irradiated malaria, using ELISA, flow cytometry and Western blot analysis. The lupus mice exhibited a significant elevation in plasma levels of IL-4, IL-6, IL-7, IL-12, IL-17, IFN-α, IFN-γ, TGF-β, BAFF and APRIL and a marked elevation of IgG2a, IgG3 and ant-dsDNA autoantibodies compared with normal healthy mice. Infecting lupus mice with live but not gamma-irradiated malaria parasite partially and significantly restored the levels of the soluble mediators that contribute to the progression of lupus. Furthermore, the B cells of lupus mice exhibited an increased proliferative capacity; aberrant overexpression of the chemokine receptor CXCR4; and a marked elevation in responsiveness to their cognate ligand (CXCL12) via aberrant activation of the PI3K/AKT, NFκB and ERK signaling pathways. Interestingly, infecting lupus mice with live but not gamma-irradiated malaria parasite restored a normal proliferative capacity, surface expression of CXCR4 and B cell response to CXCL-12. Taken together, our data present interesting findings that clarify, for the first time, the molecular mechanisms of how infection of lupus mice with malaria parasite controls B cell autoreactivity and thus confers protection against lupus severity.
Highlights
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that is characterized by abnormal B cell activation and differentiation [1], a loss of tolerance to nucleic acids and their associated proteins and the production of autoantibodies that cause tissue damage [2]
We observed that lupus mice had aberrant and significantly elevated levels of IL-4, IL-6, IL-7, IL-12, IL-17, IFN-α, IFN-γ, TGF-β, BAFF and APRIL compared with the control non-lupus healthy mice (Ã P < 0.05)
In SLE, several cytokines are involved in general immune dysregulation and abnormalities in the signaling pathways of B lymphocytes, which contribute to the development of SLE pathogenesis and autoimmune disease [35]
Summary
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that is characterized by abnormal B cell activation and differentiation [1], a loss of tolerance to nucleic acids and their associated proteins and the production of autoantibodies that cause tissue damage [2]. Two members of the tumor necrosis factor (TNF) family, BAFF (B cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand), are already known for their crucial roles in normal B cell survival, differentiation and apoptosis and have recently been shown to be expressed by B-CLL cells [10] In this context, systemic activation of the immune system induces aberrant BAFF and APRIL expression in B cells in patients with SLE [11]. Previous studies have revealed that murine SLE is characterized by high levels of the IgG2a and IgG3 autoantibodies, which cause glomerulonephritis [14, 15] Chemokines and their receptors are crucial for chemotaxis, lymphocyte homing to secondary lymphoid organs and, subsequently, Ag recognition [16, 17]. In the current study, we investigated the possible effects of infection with P. chabaudi on the plasma cytokine profile and on B cell biology in term of autoreactivity, chemotaxis, proliferation and signaling pathways in a murine model of SLE
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