Investigations of animal models of intestinal inflammation suggest that CD is a result of an aberrant immunologic response to commensal bacteria. In these models, disease development and progression hinge on the presence of T-cell reactivity to specific commensal bacteria. The flagellin, CBir1 has been identified as a dominant antigen with a role in both the innate and adaptive immune responses, which lead to colitis in murine models. 50% of patients with CD are anti-CBir1+, whereas patients with ulcerative colitis, other inflammatory Gl diseases or controls are anti-CBir. We have demonstrated selective loss of tolerance to specific bacterial antigens, and that multiple and high-level serum responses are associated with aggressive phenotypes while no response is associated with a benign disease course. Our preliminary data show that serum reactivity to CBir1 is independent of previously defined antigens, i.e. OmpC, 1-2, oligomannan, and that CBir1 expression is associated with ASCA- patients, and even those who are ASCA- in addition to being anti-OmpC- and anti-l2'. Data has shown that colitis-susceptible mice have a muted innate immune response to flagellin signaling of TLR5 and an exaggerated T-cell response to flagellin antigens. In colitis resistant strains, the opposite appears to be true. Our hypothesis Is that CD patients with high amplitude antibody response to flagellin have changes In dendritic cell and T-cell responses similar to those seen In mice and that these are based on genetic variations, all of which underline a clinical phenotype distinct from patients that lack such responses. We will test this hypothesis by 1. Defining the phenotype of CBir1-reactive CD patients by correlating the presence and the level of anti-CBir1 expression with anatomic location of disease and other inflammatory markers, determining when in the disease course the antibodies develop, determine the type of inflammation, i.e., whether it is Th1, and then determine whether anti-Cbirl expression can predict treatment outcomes with Th1 modifying agents or response to antibiotics. We will further determine whether specific epitope(s) of the CBir1 molecule are associated with pathologic subtypes. 2. Determining the genetic basis for the Th1 inflammation associated with anti-CBiM expression by testing 13 candidate genes involved in the innate and Th1 immune pathways to define allelic variations related to the magnitude of anti-CBir1 responses. 3. Defining the innate immune responses of monocytes and monocyte-derived dendritic cells to flagellin, CPG and LPS. 4. Determining whether T-cell responses to CBir1 are positively correlated with the magnitude of serum responses and negatively correlated with the magnitude of innate immune responses within the same patient.
Cao, Wei; Kayama, Hisako; Chen, Mei Lan et al. (2017) The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids. Immunity 47:1182-1196.e10 |
Zhao, Qing; Harbour, Stacey N; Kolde, Raivo et al. (2017) Selective Induction of Homeostatic Th17 Cells in the Murine Intestine by Cholera Toxin Interacting with the Microbiota. J Immunol 199:312-322 |
Tanner, Scott M; Daft, Joseph G; Hill, Stephanie A et al. (2016) Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer. J Histochem Cytochem 64:753-767 |
Pike, Brian L; Paden, Katie Ann; Alcala, Ashley N et al. (2015) Immunological Biomarkers in Postinfectious Irritable Bowel Syndrome. J Travel Med 22:242-50 |
Christmann, Benjamin S; Abrahamsson, Thomas R; Bernstein, Charles N et al. (2015) Human seroreactivity to gut microbiota antigens. J Allergy Clin Immunol 136:1378-86.e1-5 |
Singer, Jeffrey R; Weaver, Casey T (2015) Daughter's Tolerance of Mom Matters in Mate Choice. Cell 162:467-9 |
Tanner, Scott M; Berryhill, Taylor F; Ellenburg, James L et al. (2015) Pathogenesis of necrotizing enterocolitis: modeling the innate immune response. Am J Pathol 185:4-16 |
Daft, Joseph G; Lorenz, Robin G (2015) Role of the gastrointestinal ecosystem in the development of type 1 diabetes. Pediatr Diabetes 16:407-18 |
Harbour, Stacey N; Maynard, Craig L; Zindl, Carlene L et al. (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112:7061-6 |
Hepworth, Matthew R; Fung, Thomas C; Masur, Samuel H et al. (2015) Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4? T cells. Science 348:1031-5 |
Showing the most recent 10 out of 76 publications