Systemic lupus erythematosus (SLE) is a chronic and multisystemic autoimmune disease characterized by deregulated innate and adaptive immune responses, which lead to the polyclonal activation of B cells and to a massive production of auto-antibodies that form immune complexes and cause tissue damage. SLE aetiology is not completely understood,
The mouse model of a lupus-like disease developed by our research group is unique, because it’s obtained by the stabilization of lipidic structures called non-bilayer phospholipid arrangements (NPAs), which induce the production of anti-NPA antibodies that trigger the disease in mice, which are in turn detected in patients with systemic lupus erythematosus. NPAs are produced when a lipid bilayer composed of conic and cylindric phospholipids, is modified by certain drugs (procainamide, chlorpromazine) or the manganese cation. Usually, drugs/substances are chosen to be tested as NPA inducers when they are known to trigger a lupus-like disease in humans. However, here we selected a group of molecules only by their structural similarity with the known inducers and the known destabilizer (chloroquine) and experimentally tested their effect on the formation or destabilization of NPAs in liposomes by flow cytometry. Firstly, we identified promethazine and procaine, similar to chlorpromazine and chloroquine, respectively. Promethazine acted as an inducer, with a broader range of concentrations of action in comparison with chlorpromazine, but it was more sensitive to the destabilizer. Procaine was found to be a weaker destabilizer than chloroquine, as it has an effect only at higher concentrations. This strategy showed that molecular characteristics could also be good predictors of their action on lipid bilayers and NPAs formation.
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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