The Effects Of SM934, A Water-soluble Artemisinin Derivative, On The Treatment Of Systemic Lupus Erythematosus

Systemic lupus erythematosus(SLE) is a systemic autoimmune disease characterized by the overactivation of B cells and the production of numerous autoantibodies. It follows a relapsing and remitting course and involves multiple organs, which could even worse progress to chronic renal failure and/or death. According to WHO, about one million Chinese, and millions more worldwide, have lupus. However, SLE therapy is now mainly based on nonspecific immunosuppression and symptom control since the pathological mechanism of SLE is still unclear. Therefore, it has become an important issue to explore the pathogenesis of SLE and develop new drugs with high efficacy and low toxicity.Female MRL/lpr mice, as a classic animal model of SLE, develop spontaneously autoimmune syndromes due to the deficiency of fas gene including lupus nephritis, hematological changes, massive lymphadenopathy, splenomegaly and autoantibody formation. This study aims to further illustrate the pathological mechanism of SLE by examining the disease process, pathological characteristics, and immune function changes of MRL/lpr mice. The results showed that, female MRL/lpr mice initiated the early onset of disease from the age of 8-12 week; skin lesion and lymphadenopathy could be observed at the age of 14 week; at 16 week, the mice showed obviously proteinuria; when at 20 week, the mice processed to severe lupus; and the mortality rate got to 50% at the age of 24 week. In addition, about 10% of the mice developed joint inflammation similar to human rheumatoid arthritis. Notably, the serum levels of anti-nuclear antibodies(ANA) in MRL/lpr mice increased with age.Further investigations revealed that the percentage of CD4+ T cells and CD8+ T cells in the spleen of MRL/lpr mice decreased with age, while the percentage of abnormal double negative(DN) T cells increased. Additionally, B cell dropped from 47.9%(4 week-old) to 6.98%(24 week-old), confirming the B lymphocytopenia symptom in the spleen of MRL/lpr mice. Consistent with literature reports, germinal center(GC) B cell was typically effaced as these lupus-prone mice age. As expected, activated CD69+ B cells and antibody-secreting plasma cells(PCs) largely accumulated in aged MRL/lpr mice. Contrary to the results in spleen, the number of CD4+ T cells and CD8+ T cells infiltrated in kidney increased and the number of DN T cells decreased with the disease progress. Furthermore, the imbalance of T cell subsets gradually emerged with the age increase: the number of Th1 and Th17 cells escalated, and Treg cells declined. Taken together, this part of work illustrated the disease process, pathological characteristics, and immune function changes of MRL/lpr mice, providing a guidance for further clarification of lupus pathogenesis and related drug evaluation.We previously reported that SM934, a water-soluble artemisinin derivative, could treat murine lupus models. In the current study, we further investigated the therapeutic effects of SM934 at modified dosage regimen on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in SLE. Given orally at a twice-daily regimen, SM934(5mg/kg, 2.5mg/kg, 1.25mg/kg) significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms, decreased the serum ANA, as well as the pathogenic cytokine IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the compartment of B cells in the spleen of MRL/lpr mice by increasing quiescent B cells, maintaining germinal center B cells, decreasing activated B cells and reducing PCs. Ex vivo, SM934 suppressed TLR-triggered activation and proliferation of B cells and antibody secretion. Moreover, this study indicated that SM934 interfered B cell intrinsic pathway by downregulating TLR7/9 m RNA expression, My D88 protein expression and phosphorylation of NF-κB. In human PBMCs, consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B cell activation and PC differentiation. In conclusion, twice a day dosing regimen highlighted the therapeutic effects of SM934 on lupus-prone MRL/lpr mice by suppressing B cell activation and formation of plasma cells.In summary, we comprehensively studied the disease process, pathological characteristics, and immune function changes of lupus-prone MRL/lpr mice. Then, we investigated the therapeutic effects of SM934 on MRL/lpr mice and explored its effects on B cell responses. This work is valuable for further illustration of the pathogenesis of SLE and exploration of novel treatment targets. At the same time, it provides new evidence and clues for research about artemisinin compounds in the field of autoimmune diseases.