Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.
Systemic lupus erythematosus (SLE) is a chronic multifactorial autoimmune disease; its pathology is mainly attributed to auto-antibodies that cause inflammation and tissue damage. Our group proposed that lipids associated in non-bilayer phospholipid arrangements (NPA) are involved in the development of SLE. BALB/c mice developed a disease very similar to human SLE when they received Mn2+ or drugs chlorpromazine, procainamide (which stabilize NPA in the plasma membrane), or liposomes bearing NPA induced by these drugs or by Mn2+. Recently, we found that the gene expression profile of mice with lupus was different to that found in healthy mice and was similar to patients with SLE: in mice with lupus genes involved in presentation of exogenous antigens, antibody production and TLR4 and NOD2 signaling and some genes encoded for complement proteins were over-expressed, while genes for NK cell recognition and apoptosis were under-expressed. In the present study, we used the mouse immunopathology miScriptTM miRNA PCR Array in order to compare mature microRNA profile between mice with lupus and healthy mice. The results indicated 9 microRNAs deregulated, 4 microRNAs were underexpressed (miR-155, miR-146b, miR-23, miR-let-7d) which can regulate positively transcription of RNAs associated with IL-6, IL-1 and 5 microRNAs were overexpressed (miR-205, miR-200a, miR-18a, miR-207 and miR-574) which can regulate negatively transcription of RNAs associated with apoptosis and T cell response. This results were validated used TaqMan microRNA Assays and were similar to those found in human LES. Then this study highlight the importance of microRNAs in regulate immune process that has implications in the pathogenesis of LES an inflammatory disease.
Anti-lipid IgG antibodies are produced in some mycobacterial infections and autoimmune diseases (lupus, anti-phospholipid syndrome). However, few studies have addressed the mechanisms that lead to the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a mouse model of lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membrane of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which are involved in the development of the disease. We used this model of lupus to investigate the in vivo mechanisms that lead to the production of anti-lipid IgG antibodies. B cells are activated, in response to most protein antigens, via germinal centers or extrafollicular reactions. In germinal centers, a T cell-dependent response leads to isotype switch, somatic hypermutation, affinity maturation and memory generation, whereas these events do not usually occur in extrafollicular reactions. In this mouse model of lupus induced by chlorpromazine-stabilized NPA, we found plasma cells producing NPA-specific IgGs in the inguinal lymph nodes, the spleen, and bone marrow of mice. We also found a significant number of germinal center B cells specific for NPA in the inguinal lymph nodes and the spleen, and we demonstrated the presence of NPA in these same germinal centers. In contrast, we found very few extrafollicular reaction B cells specific for NPA. Altogether, our data suggest that, in this murine model of lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.