Gender disparity has been recently reported for the severity of inflammatory bowel disease (IBD), with female patients with Crohn's disease (CD), one of the idiopathic IBDs, likely to experience more severe disease manifestations compared to males, and with symptom activity associated with hormonal surges during puberty, pregnancy and the post-partum period. Although the precise etiology is currently unknown, it is well accepted that IBD results from a dysregulated immune response to environmental factors (e.g., gut microflora) in genetically-predisposed individuals. However, the mechanism(s) underlying sex differences in IBD is an understudied area of investigation and little is known regarding how the orchestration of genetics, host immunity, as well as the gut microenvironment leads to gender disparity, specifically in Crohn's patients. Based on our extensive preliminary data, the central hypothesis of the present proposal is that gut microbial ligands signaling through TLR9 promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in experimental CD, such as that observed in SAMP mice, a spontaneous model of CD-like ileitis, and in patients with CD. This hypothesis will be tested by performing two specific aims: 1) Determine the impact of the gut microbiota on sex differences in the phenotypic and functional properties of the mucosal Treg population/subpopulations, and 2) Determine the mechanism(s) as to how TLR9 activation specifically results in sex-associated gut inflammation. The proposed studies are designed to elucidate potential mechanism(s) underlying sex differences in spontaneous, experimental Crohn's-like ileitis, and identify potential, early diseas pathways that can lead to the development of novel, gender-targeted strategies to improve treatment of patients suffering from this devastating disease.
Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases (IBD)s, is characterized by a chronic, relapsing inflammation of the GI tract that is generally thought to result from uncontrolled immune responses to environmental factors in genetically predisposed individuals. Recent evidence shows that clear gender disparity in CD exists, with females displaying more severe disease manifestations than males that is associated with hormonal surges during puberty, pregnancy and the post-partum period;however, sex differences in mucosal immunity, in general, and IBD, in particular, is an understudied area of investigation. The present proposal will investigate one potential mechanism that gut microbial ligands promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in the pathogenesis of chronic intestinal inflammation, such as that observed in IBD.
|De Salvo, Carlo; Wang, Xiao-Ming; Pastorelli, Luca et al. (2016) IL-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis. Am J Pathol 186:885-98|
|Buela, Kristine-Ann G; Omenetti, Sara; Pizarro, Theresa T (2015) Cross-talk between type 3 innate lymphoid cells and the gut microbiota in inflammatory bowel disease. Curr Opin Gastroenterol 31:449-55|
|Omenetti, Sara; Brogi, Marco; Goodman, Wendy A et al. (2015) Dysregulated intrahepatic CD4(+) T-cell activation drives liver inflammation in ileitis-prone SAMP1/YitFc mice. Cell Mol Gastroenterol Hepatol 1:406-419|
|De Salvo, Carlo; Ray, Shuvra; Pizarro, Theresa T (2014) Mechanisms and models for intestinal fibrosis in IBD. Dig Dis 32 Suppl 1:26-34|
|Goodman, W A; Garg, R R; Reuter, B K et al. (2014) Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol 7:1255-65|
|Ray, Shuvra; De Salvo, Carlo; Pizarro, Theresa T (2014) Central role of IL-17/Th17 immune responses and the gut microbiota in the pathogenesis of intestinal fibrosis. Curr Opin Gastroenterol 30:531-8|
|Pastorelli, Luca; De Salvo, Carlo; Mercado, Joseph R et al. (2013) Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol 4:280|
|Ishikawa, D; Okazawa, A; Corridoni, D et al. (2013) Tregs are dysfunctional in vivo in a spontaneous murine model of Crohn's disease. Mucosal Immunol 6:267-75|
|Pastorelli, Luca; De Salvo, Carlo; Vecchi, Maurizio et al. (2013) The role of IL-33 in gut mucosal inflammation. Mediators Inflamm 2013:608187|
|Goodman, Wendy A; Pizarro, Theresa T (2013) Regulatory cell populations in the intestinal mucosa. Curr Opin Gastroenterol 29:614-20|