Immunosenescence is a state of dysregulated immune function contributing to the increased susceptibility of the elderly to infection, and potentially to an increased susceptibility to autoimmune diseases, chronic inflammatory diseases, and cancer. The impact of immunosenescence of the mucosal immune system is highlighted by epidemiological studies that document a marked increase in mortality due to gastrointestinal infections in the elderly and an increased incidence of inappropriate mucosal immune responses as manifested by the 'second peak' of inflammatory bowel disease in individuals in their seventh decade of life. The mechanisms resulting in immunosenescence of the mucosal immune system are largely unexplored. Isolated lymphoid follicles (ILFs) are inducible organized intestinal lymphoid structures. In young animals these structures act as sites for the induction of 'homeostatic' mucosal immune responses including the production of antigen specific IgA. The hypothesis of this study is that as a consequence of age-related changes in the inflammatory response to luminal stimuli, ILF formation is augmented and aberrant resulting in impaired protective immunity and a predisposition toward inappropriate mucosal immune responses. ? Consequently we will examine the aberrant formation and function of ILFs with aging in this proposal.
In specific aim 1 we will use intestinal whole mounts stained with UEA-I lectin or anti-B220, immunohistochemistry, and flow cytometry to define the stage(s) of ILF formation that are augmented with aging.
In specific aim 2 we will examine the production/expression of lymphotoxin, chemokines, and chemokine receptors which have been identified to contribute to/drive ILF formation using quantitative PCR and flow cytometry and correlate these findings with the previously identified roles for these factors driving the specific stages of ILF formation found to be augmented in specific aim 1.
In specific aim 3 we will use immunhistochemistry, scanning and electron microscopy, flow cytometry, and in vitro cellular assays of cytokine production, and in vivo immunization to examine the function of ILFs in aging. The overall goal of this project is to understand how organ this specific dysfunction arises with aging, and to identify the factors/steps which are augmented with aging that act to drive this dysfunction. Future studies will attempt to manipulate specific steps in this process in a therapeutic manner. ? ? ?
| Ha, Christina Y; Newberry, Rodney D; Stone, Christian D et al. (2010) Patients with late-adult-onset ulcerative colitis have better outcomes than those with early onset disease. Clin Gastroenterol Hepatol 8:682-687.e1 |
| McDonald, Keely G; McDonough, Jacquelyn S; Dieckgraefe, Brian K et al. (2010) Dendritic cells produce CXCL13 and participate in the development of murine small intestine lymphoid tissues. Am J Pathol 176:2367-77 |
| Newberry, Rodney D (2008) Intestinal lymphoid tissues: is variety an asset or a liability? Curr Opin Gastroenterol 24:121-8 |
| McDonald, Keely G; Newberry, Rodney D (2007) Whole-mount techniques to evaluate subepithelial cellular populations in the adult mouse intestine. Biotechniques 43:50, 52, 54 passim |
