The correlation between proteoglycan 2 and neuropsychiatric systemic lupus erythematosus.

The proposed pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) mainly includes ischemia and neuroinflammation mechanisms. Protein encoded by Proteoglycan 2 (PRG2) mRNA is involved in the immune process related to eosinophils, also being found in the placenta and peripheral blood of pregnant women. We evaluated the correlation between PRG2 and NPSLE for the first time and found that PRG2 protein was overexpressed in the serum of patients with NPSLE and correlated with the SLE disease activity index (SLEDAI) subset scores of psychosis. Moreover, we investigated the correlation between hippocampal PRG2 level and hippocampally dependent learning and memory ability in MRL/lpr mice, and discovered that the number of PRG2+GFAP+ astrocytes in the cortex and hypothalamus and the number of PRG2+IBA-1+ microglia in the hippocampus and cortex significantly increased in the MRL/lpr mice. These data provided a reference for the follow-up exploration of the role of PRG2 in SLE or other diseases.

Association of lipoproteins and thyroid hormones with cognitive dysfunction in patients with systemic lupus erythematosus.

BACKGROUND: Neuropsychiatric manifestations occur in up to 75% of adult systemic lupus erythematosus (SLE) patients and are one of the major causes of death in SLE patients. Cognitive dysfunction is a typical clinical feature of neuropsychiatric SLE (NPSLE), which seriously affects the quality of life of patients. Dyslipidaemia and thyroid symptoms, which are prevalent in SLE patients, have both been related to neuropsychiatric disturbances, including significant psychiatric and cognitive disturbances. This study aimed to investigate whether cognitive dysfunction in patients with SLE was related to the expression of serum thyroid hormone and lipoprotein levels. METHODS: A total of 121 patients with SLE and 65 healthy controls (HCs) at Nanjing Drum Tower Hospital completed a cognitive function test, and 81 SLE patients were divided into a high-cognition (n = 33) group and a low-cognition group (n = 48). The clinical and laboratory characteristics of the patients were compared; moreover, correlations between serum HDL-C, LDL-C, F-T3 and F-T4 levels and cognitive function were analysed. Serum levels of APOE, APOA1, IGF-1, and IGFBP7 in 81 patients were detected by ELISA, and the correlation between these four proteins and cognition was analysed separately. RESULTS: The patients with SLE with abnormal cognitive function were less educated than the HCs. For low-cognition patients, the levels of albumin, F-T3 (P <  0.05) and F-T4 decreased, while D-dimer, anti-dsDNA antibody, and IgM levels increased. Serum F-T3 and F-T4 levels positively correlated with cognition. Furthermore, serum protein levels of APOE and APOA1 showed no difference between the high- and low-cognition groups. However, the serum APOE levels were negatively correlated with line orientation scores, and APOA1 levels were positively correlated with coding scores. CONCLUSIONS: Serum F-T3 and F-T4 levels were both positively correlated with four indexes of cognition (language was the exception), while serum APOE levels were negatively correlated with line orientation scores, APOA1 levels were positively correlated with coding scores, and IGFBP7 levels were negatively correlated with figure copy scores. These results demonstrated that F-T3 and F-T4 might be clinical biomarkers of cognitive dysfunction in SLE.

MicroRNA-663 induces immune dysregulation by inhibiting TGF-ß1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus.

Mesenchymal stem cells (MSCs) are critical for immune regulation. Although several microRNAs (miRNAs) have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function, the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear. Here, we show that patients with systemic lupus erythematosus (SLE) display a unique miRNA signature in bone marrow-derived MSCs (BMSCs) compared with normal controls, among which miR-663 is closely associated with SLE disease activity. MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper (Tfh) cells and upregulation of regulatory T (Treg) cells by targeting transforming growth factor ß1 (TGF-ß1). MiR-663 overexpression weakens the therapeutic effect of BMSCs, while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice. Thus, miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

RKIP mediates autoimmune inflammation by positively regulating IL-17R signaling.

Th17 cells contribute to the development of autoimmune diseases by secreting interleukin-17 (IL-17), which activates its receptor (IL-17R) that is expressed on epithelial cells, macrophages, microglia, and resident neuroectodermal cells. However, the mechanisms through which IL-17R-mediated signaling contributes to the development of autoimmune disease have not been completely elucidated. Here, we demonstrate that Raf-1 kinase inhibitor protein (RKIP) deficiency in mice ameliorates the symptoms of experimental autoimmune encephalomyelitis (EAE). Adoptive T-cell-transfer experiments demonstrate that RKIP plays a predominant role in Th17-mediated, but not in Th1-mediated immune responses. RKIP deficiency has no effect on Th17-cell differentiation ex vivo, nor does it affect Th17-cell differentiation in EAE mice. However, RKIP significantly promotes IL-17R-induced proinflammatory cytokine and chemokine production. Mechanistically, RKIP directly interacts with IL-17RA and Act1 to promote the formation of an IL-17R-Act1 complex, resulting in enhanced MAPK- and P65-mediated NF-κB activation and downstream cytokine production. Together, these findings indicate that RKIP functions as an essential modulator of the IL-17R-Act1 axis in IL-17R signaling, which promotes IL-17-induced inflammation and autoimmune neuroinflammation.

A pilot study of the therapeutic efficacy and mechanism of artesunate in the MRL/lpr murine model of systemic lupus erythematosus.

Recent evidence indicates that artesunate has immunomodulatory properties that might be useful for treating autoimmune disease. In this study, we conducted a pilot study and explored the effect and mechanism of artesunate on the treatment of systemic lupus erythematosus using an MRL/lpr murine model. MRL/lpr mice were divided into control, cyclophosphamide (CTX) and artesunate treatment groups. Blood was collected to measure serum levels of creatinine, antinuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody. Twenty-four-hour urine was collected to measure levels of proteinuria. The concentration of monocyte chemotactic protein-1 (MCP-1) in serum and urine was measured. The expression of MCP-1 in kidney was detected by Western blot and immunohistochemistry assay, respectively. The expression of B cell activating factor (BAFF) in spleen was determined by real time-PCR and immunoblotting. We found that artesunate significantly increased the survival rate, body weight and blood leukocyte counts, and reduced the serum levels of ANA and anti-dsDNA antibody titer, 24 h urinary protein, and serum creatinine. Our results indicated that artesunate could decrease MCP-1, major pro-inflammation cytokine, in serum, urine and kidney. We also found that the level of BAFF, the major B cell activation factor, was decreased in artesunate treated MRL/lpr mice. Its efficacy was comparable with that of CTX in this study. Taken together, we have demonstrated that artesunate can inhibit the progression of disease and reverse the pathologic lesion of lupus nephritis.

Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice.

Recent evidence indicates that mesenchymal stem cells (MSC) possess immunosuppressive properties both in vitro and in vivo. We previously demonstrated the functional abnormality of bone marrow derived MSC in patients with systemic lupus erythematosus (SLE). In this study, we aimed to investigate whether transplantation of human bone marrow derived MSC affects the autoimmune pathogenesis in MRL/lpr mice. We found that human MSC from healthy donors reduced the proliferation of T lymphocytes from MRL/lpr mice in a dose-dependent fashion. Two weeks after in vivo transfer of MSC, we detected significantly reduced serum levels of anti ds-DNA antibodies and 24 hour proteinuria in MRL/lpr mice as compared with control groups without MSC transplantation. Moreover, flow cytometric analysis revealed markedly reduced number of CD4(+) T cells while increased Th1 subpopulation in MSC group and MSC + CTX group when compared with controls. Histopathological examination showed significantly reduced renal pathology in MSC-treated mice. Immunohistochemical studies further revealed reduced expression of TGF-beta, FN, VEGF and the deposition of complement C3 in renal tissue after MSC and MSC + CTX treatment. Taken together, we have demonstrated that transplantation of human MSC can significantly inhibit the autoimmune progression in MRL/lpr mice.