The immunological potential of galectin-1 and -3.

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The immunological potential of galectin-1 and 3

A family of \u3b2-galactosides-binding proteins, called galectins, have recently emerged as novel molecules with immunoregulatory functions. These proteins are expressed in both inflammatory and non-inflammatory cells including monocytes, macrophages, dendritic cells, mast cells, and B and T cells, giving a broad spectrum of involvement in the immune response. Galectins are uniquely capable of acting both intracellularly and extracellularly, affecting such processes as cell adhesion, signaling, proliferation, differentiation, and apoptosis. Different members of this family have been shown to modulate several pathological processes such as allergic reactions, autoimmunity, and tumor invasion. Therefore, understanding the role of galectins in achieving appropriate proliferative and effector responses to antigens will yield important insights to autoimmune diseases and delineate novel strategies for disease intervention

Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19(-/-), IL-17A(-/-) and IL-22(-/-) mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology

High levels of soluble CTLA-4 are present in anti-mitochondrial antibody positive, but not in antibody negative patients with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease frequently characterized by anti-mitochondrial autoantibodies (AMA). A minority of patients are AMA-negative. Cytotoxic-T-Lymphocyte-Antigen-4 (CTLA-4) is a surface molecule expressed on activated T-cells delivering a critical negative immunoregulatory signal. A soluble form of CTLA-4 (sCTLA-4) has been detected at high concentrations in several autoimmune diseases, and its possible functional meaning has been suggested. We aimed to evaluate sCTLA-4 concentration in sera of patients with PBC and to correlate it to immunological abnormalities associated with the disease. Blood samples were collected from 82 PBC-patients diagnosed according to international criteria (44 AMA-positive/MIT3-positive and 38 AMA-negative-MIT3-negative), and 65 controls. sCTLA-4 levels were evaluated by ELISA and Western blot. Increased sCTLA-4 concentrations were found in all AMA-positive PBC-patients, but in none of the AMA-negative ones, nor in normal controls or in controls with unrelated liver diseases. sCTLA-4 presence was associated with autoantibodies against MIT3, but not with nuclear autoantibodies (sp100, gp210). This is the first study to demonstrate that levels of sCTLA-4 are elevated in sera of PBC patients. However, they are clearly restricted to patients with AMA positivity, suggesting an immunological difference with respect to AMA-negative ones

T cell costimulation blockade blunts pressure overload-induced heart failure

18nonenoneKallikourdis, Marinos; Martini, Elisa; Carullo, Pierluigi; Sardi, Claudia; Roselli, Giuliana; Greco, Carolina M.; Vignali, Debora; Riva, Federica; Ormbostad Berre, Anne Marie; Stølen, Tomas O.; Fumero, Andrea; Faggian, Giuseppe; Di Pasquale, Elisa; Elia, Leonardo; Rumio, Cristiano; Catalucci, Daniele; Papait, Roberto; Condorelli, GianluigiKallikourdis, Marinos; Martini, Elisa; Carullo, Pierluigi; Sardi, Claudia; Roselli, Giuliana; Greco, Carolina M.; Vignali, Debora; Riva, Federica; Ormbostad Berre, Anne Marie; Stølen, Tomas O.; Fumero, Andrea; Faggian, Giuseppe; Di Pasquale, Elisa; Elia, Leonardo; Rumio, Cristiano; Catalucci, Daniele; Papait, Roberto; Condorelli, Gianluig

Galectin-3:A Modifiable Risk Factor in Heart Failure

Myocardial galectin-3 is upregulated upon cardiac stressors such as angiotensin II and pressure overload leading to cardiac remodeling and heart failure. The expression level of galectin-3 mirrors the progression and severity of heart failure and therefore, galectin-3 is being used as a biomarker for heart failure. However, as galectin-3 is causally involved in pathological myocardial fibrosis it has been suggested that galectin-3 also actively contributes to heart failure development. In this review we discuss how galectin-3 could be a target for therapy in heart failure. Currently, attempts are being made to target or inhibit galectin-3 using natural or pharmaceutical inhibitors with the aim to ameliorate heart failure. Available experimental evidence suggests that galectin-3 inhibition indeed may represent a novel tool to treat heart failure. A strong interaction with aldosterone, another strong pro-fibrotic factor, has been described. Clinical studies are needed to prove if galectin-3 may be used to install specific treatment regimens