While much work has explored the role of Immunoregulation in IBD, the genetics for this role In human is limited, their antigenic specificities of regulatory T cells are poorly understood, and strategies for their therapeutic manipulation are lacking. During the previous award period, studies in Project 3 uncovered a new immunoregulatory T cell population, termed invariant HLA-E T cells (Qa-1 in mice), with antigenic specificity for a prevalent antigenic complex (HLA-E/Hsp60.4 peptide) characteristic of target cells undergoing the molecular stress response. This Invariant T cell population Is dependent on commensal microbial composition, and cytolytically targets activated immune cell types yielding In vivo protection In animal IBD models. New collaborative work suggests that HLA-E alleles affect UC disease severity, and that certain inhibitory NK receptors/HLA binding partners (K1R2DL2/3 and HLA-C1) both modify CD risk, and affect invariant HLA-E T cell levels. This project tests two hypotheses: (a) patients with gene variants for loci controlling inhibitory NK receptor/HLA pairs, or for microbial serologies, will have reduced mucosal invariant T cells; and (b) patients with combinations of those gene variants will have more severe inflammation, and more severe clinical course. These hypotheses will be tested by determining (1) the tissue distribution and function of invariant HLA-E T cells; (2) the genetic effect of inhibitory NK receptor/MHCI and Qa-1 (the murine HLA-E homologue) on the efficiency and mechanism of Invariant Qa-1 T cell immunoregulation in mice; and (3) the genetic interaction of HLA-C1, K1R2DL2/3, HLA-E, NKG2A, and anti-microbial antibodies (levels and associated genetic loci) on Invariant HLA-E T cells and disease severity. If successful, these studies will reveal how genetic loci for two classes of receptors, and host traits in commensal microbial interaction, modulate a new class of regulatory T cells and their role In severity of disease in CD and UC. Such genetic traits to stratify patients for this mode of immunoregulation deficiency and its potential therapeutic Intervention.
KIR2DL2/HLA-C1, and anti-microbial antibody-associated loci, are among the first common genetic variants that may link disease severity with levels of a class of immunoregulatory T cells. If successful, these genetic variants will permit better prediction of disease course in individual patients, and a subset of patients with a mode of Immunoregulation deficiency potential suitable for therapeutic intervention.
|Brant, Steven R; Okou, David T; Simpson, Claire L et al. (2017) Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology 152:206-217.e2|
|Volkmann, Elizabeth R; Hoffmann-Vold, Anna-Maria; Chang, Yu-Ling et al. (2017) Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts. BMJ Open Gastroenterol 4:e000134|
|Gonsky, Rivkah; Fleshner, Phillip; Deem, Richard L et al. (2017) Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn's Disease. Gastroenterology 153:219-232|
|Schwerd, T; Bryant, R V; Pandey, S et al. (2017) NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease. Mucosal Immunol :|
|Zhang, Hong; Zheng, Libo; McGovern, Dermot P B et al. (2017) Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis. J Immunol 198:2133-2146|
|Xu, Chunlan; Ghali, Sally; Wang, Jiani et al. (2017) CSA13 inhibits colitis-associated intestinal fibrosis via a formyl peptide receptor like-1 mediated HMG-CoA reductase pathway. Sci Rep 7:16351|
|Zhang, Hong; Zheng, Libo; Chen, Jeremy et al. (2017) The protection role of Atg16l1 in CD11c+dendritic cells in murine colitis. Immunobiology 222:831-841|
|Rivas, Manuel A; Graham, Daniel; Sulem, Patrick et al. (2016) A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun 7:12342|
|Hoang-Yen Tran, D; Hoang-Ngoc Tran, D; Mattai, S A et al. (2016) Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor. Int J Obes (Lond) 40:1424-34|
|van der Gracht, Esmé; Zahner, Sonja; Kronenberg, Mitchell (2016) When Insult Is Added to Injury: Cross Talk between ILCs and Intestinal Epithelium in IBD. Mediators Inflamm 2016:9765238|
Showing the most recent 10 out of 254 publications