Systemic lupus erythematosus (SLE) is characterized by deregulated activation of T and B cells, autoantibody production, and consequent formation of immune complexes. Liposomes with nonbilayer phospholipid arrangements (NPA), induced by chlorpromazine, procainamide, or manganese, provoke a disease resembling human lupus when administered to mice. These mice produce anti-NPA IgM and IgG antibodies and exhibit an increased number of TLR-expressing spleen cells and a modified gene expression associated with TICAM1-dependent TLR-4 signaling (including IFNA1 and IFNA2) and complement activation. Additionally, they showed a diminished gene expression related to apoptosis and NK cell activation. We hypothesized that such gene expression may be affected by miRNAs and so miRNA expression was studied. Twelve deregulated miRNAs were found. Six of them were common to the three lupus-like models. Their validation by qRT-PCR and TaqMan probes, including miR-342-3p, revealed that miR-155-5p and miR-200a-3p expression was statistically significant. Currently described functions for these miRNAs in autoimmune diseases such as SLE reveal their participation in inflammation, interferon production, germinal center responses, and antibody maturation. Taking into account these findings, we propose miR-155-5p and miR-200a-3p, together with the anti-NPA antibodies, as key players in the murine lupus-like models and possible biomarkers of the human SLE.
Liposomes are artificial models of cellular membranes that are used as delivery systems for genes, drugs and protein antigens. We have previously used them to study the antigenic properties of their phospholipids. Here, we used them to induce the production of IgG anti-non-bilayer phospholipid arrangements (NPAs) antibodies in mice; these antibodies cause cell lysis and trigger a lupus-like disease in mice. We studied the mechanisms that lead to the production of these antibodies, and provide evidence that NK1.1+, CD4+ T cells respond to NPA-bearing liposomes and deliver the help required for specific B cell activation and antibody class-switching to IgG. We found increased numbers of IL-4-producing NK1.1+, CD4+ T cells in the secondary lymphoid organs of mice administered with NPAs, and these cells also expressed CD40L, which is required for B cell activation. Additionally, we isolated and purified NK1.1+, CD4+ T cells from spleens and determined that they over-expressed 40 genes, which are key players in inflammatory processes and B cell stimulation and have TRAF6 and UNC39B1 as key nodes in their network. These results show that liposomes are membrane models that can be used to analyze the immunogenicity of lipids.
Deregulation of Th1 and Th17 immune responses is fundamental in the development of autoimmune diseases, like Systemic Lupus Erythematosus that is a chronic inflammatory autoimmune disease characterized by the production of autoantibodies that cause inflammation and damage to different organs. New therapeutic approaches for autoimmune diseases have been based on the fact that nematodes such as Trichinella spiralis decrease the inflammatory response by inducing the production of anti-inflammatory cytokines, which are potent modulators of T cell function. Recent studies have shown that the proteins secreted by T. spiralis, or the infection itself, induce a polarized Th2/Treg response and the production of regulatory cytokines, which are associated with the amelioration of autoimmune diseases such as colitis, respiratory tract inflammation, type 1 diabetes and experimental autoimmune encephalomyelitis. In this work, mice were infected and, after the life cycle was completed, a procedure to develop lupus was performed. The level of autoantibodies and antibodies anti-Trichinella were detected as well as the levels of Th1 and Th2 cytokines. Here, we show the relevance of studying the immune response in a murine model resembling the human lupus in the presence of T. spiralis muscular larvae, because it provides new information on the immunoregulation of lupus and reveals the effect on its progression.
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