Organ-specific autoimmune diseases like Type 1 Diabetes and Multiple Sclerosis result from the interplay between environmental and genetic factors. Recent studies indicate that activation of self-reactive T cells and alterations of immune regulatory pathways may occur at the intestinal level and maybe modulated by environmental factors that modify the gut environment such as diet and microbiota composition. Our goal is to determine whether the intestinal environment plays a role in the pathogenesis of autoimmune diseases such as T1D and MS and to promote immune tolerance in the gut through diet and microbiota modifications for preventions/ treatment of those extraintestinal autoimmune disorders.
Type 1 Diabetes (T1D) and Multiple Sclerosis (MS) are autoimmune diseases mediated by self-reactive T cells that destroy insulin-producing b cells and the myelin sheaths. Both genetic and environmental factors are involved in the pathogenesis of T1D and MS but the mechanisms governing the activation of autoimmune T cells are still largely unknown. Growing evidence supports the notion that the gut environment influences the pathogenesis of extra-intestinal autoimmune diseases such as T1D and MS. Specifically, an inflammatory intestinal environment induced by diet and/or commensal microbiota composition can promote activation of autoimmune T cells including islet-specific and myelin-specific self-reactive T lymphocytes within the gut mucosa and/or systemically, thereby triggering T1D or MS pathogenesis. Recently, our group found that humans affected by T1D and MS have alterations of gut mucosal immunity with inflammatory immunological profiles. Moreover, we demonstrated in pre-clinical models of T1D that an inflammatory gut environment promotes activation of self (islet)-reactive T cells by inducing loss of gut barrier continuity and abnormal interaction between immune cells and commensal gut microbiota leading to activation of self(islet)-reactive T cells and autoimmune diabetes.
We are currently investigating in humans and animal models of T1D and MS how gut inflammation, modification of the microbiota composition and intestinal and mucus barrier integrity affect the autoimmune pathogenesis of T1D and MS. Furthermore, we are exploiting the capacity of probiotic and prebiotic therapeutic approaches to modulate T1D pathogenesis in designed clinical trials.
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Sorini C, Cosorich I, Falcone M. New therapeutic perspective in Type 1 Diabetes: dietary interventions prevent β cell-autoimmunity by modifying the gut metabolic environment. Cell Mol Immunol. 2017 Dec; 14 (12):951-953.
Cosorich I, Dalla-Costa G, Sorini S, Ferrarese R, Messina MJ, Dolpady J, Radice E, Mariani A, Testoni PA, Canducci F, Comi G, Martinelli V and Falcone M. High frequency of intestinal Th17 cells correlated with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017 Jul 12; Vol.3, no.7, e1700492
Betto E, Usuelli V, Mandelli A, Badami E, Sorini C, Capolla S, Danelli L, Frossi B, Guarnotta C, Ingrao S, Tripodo C, Pucillo C, Gri G, Falcone M. Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype. Clin Immunol. 2017 May; 178:29-38.
Di Pietro C, De Giorgi L, Cosorich I, Sorini C, Fedeli M and Falcone M. miRNA-133b regulation of Th-POK expression and dendritic cell signals affect NKT17 cell differentiation in the thymus. J Immunol. 2016 Oct 15;197(8):3271-3280.
Dolpady J, Sorini C, Di Pietro C, Cosorich I, R Ferrarese, D Saita, M Clementi, F Canducci, Falcone M. Oral probiotic VSL#3 prevents T1D by modulating microbiota and promoting indoleamine 2,3-dioxygenase (IDO)-enriched tolerogenic intestinal environment. J Diab Res. 2016; 2016:7569431.
Betto E, Usuelli V, Mandelli A, Sorini C, Badami E, Capolla S, Danelli L, Frossi B, Guarnotta C, Ingrao S, Tripodo C, Pucillo C, Gri G, Falcone M. Mast cells promote autoimmune diabetes by favoring effector Th17 cell differentiation. Clinical Immunology 2015. S1521-6616(15)30082-6.
Badami E, Sorini C, Coccia M, Molteni L, Bolla AM, Scavini M, Mariani A, Bosi E, Falcone M. Defective differentiation of regulatory FoxP3+ T cells by small intestinal dendritic cells in Type 1 Diabetic patients. Diabetes 2011 Aug;60(8):2120-4.
McGuire HM, Vogelzang A, Ma CS, Hughes WE, Silveira PA, Tangye SG, Christ D, Fulcher D, Falcone M, King C. Subset of interleukin-21(+) chemokine receptor CCR9(+) T helper cells target accessory organs of the digestive system in autoimmunity. Immunity 2011. 34(4):602-15.