Chronic Frustrated Immune Response Flashcards
- Describe the factors that regulate the differentiation of Th0 cells in the Peyer’s Patches to Th1, Th2, or Th17 versus into Treg cells.
Th0 –> Treg via TGFB and (IL-10)
Th0 –> Th1/2/17 via TGFB + IL-6
- Discuss the relative influence of environment and genetics on the risk for inflammatory bowel disease.
Genetics: Gene assays can predict 23% of the risk in CD and 16% in UC, so there is a strong genetic component; however, concordance in MZ twins is only 30-35% for CD, and 10-15% for UC. Thus, environment & bad luck also play a role.
One model: in some IBD patients, an early (genetic?) event is an INCREASE in gut permeability so that certain secreted defensins, made by gut lining cells, are able to penetrate back into the tissues. There, acting as DAMPs, they stimulate macrophages to produce cytokines, including IL-6, thereby creating Th1, Th17, and Th2.
- Discuss the pathogenesis of celiac disease, and the relative role played by antibody and T cells. Discuss the importance of HLA alleles in this condition.
T cell immunity to gliadin peptides is responsible for the chronic inflammation
Ab role: TG2 is an enzyme in the gut lining that cross links glut amines. It might get stuck on gluten, go through illicit help mechanism, and therefore pt gets Abs to TG2
90% are HLA-DQ2, and most of the rest are HLA-DQ8; but most HLA-DQ2 or 8 people don’t get celiac disease, implicating other genetic and environmental factors
- Discuss the mechanism of chronic beryllium disease.
Inhaled Be becomes covalently linked to various peptides –> creates novel epitopes –> Th1 (Th17 also?) respond, and later a scarring Th2 responds too
Since the Be cannot be removed effectively by macs, the condition can become established and chronic even after a single inhalation exposure.
- Outline the Hygiene or Old Friends Hypothesis, and the observations that support it.
Hygiene: exposure to environmental dirt and infections HELPS IMMUNE SYSTEM MATURE normally, while lack of such exposure might leave a child in an infantile state
Evidence: Newborns start w/ Th2-dominated system which gradually balances out with Th1. Increase in Th2- (and the Th2-like Tfh that drive B cells to switch to IgE) mechanism diseases behind allergy
Old friends: certain harmless microorganisms have been in humans so long that we rely on their presence to instruct our immune systems not to overreact against commensals or low-grade pathogens. if you have adequate exposure to these old friends, you develop a balance between activation and regulation, driven by the right number of Treg.
Evidence: Lack of Tregs in afflicted individuals
- Discuss the idea that it may be possible to switch TH1/Th2/Th17 responses to Treg instead.
Introduction of certain Ag can elicit a Treg response that acts locally to down-regulated surrounding activated T cells.
