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.
a. TGFβ favors Treg: Submucosal Peyer’s Patches have abundant TGFβ which favors the differentiation of Th0 cells into Treg cells. The dendritic cells in the Peyer’s Patch make IL-10, which lso favors Treg development. Thus, these sites are rite in Treg’s which makes sense since they have bacteria, and immunogens coming through the M cells of the gut epithelium. Also common are Tfh that drive B cells to make IgA so that mucus layer closest to the gut is almost sterile.
b. TGFβ + IL-6 favors Th1 and Th17: TGFβ and IL-6 has been shown to down regulate Treg and up regulate Th1 and Th17. IL-6 is produced by epithelial and other cells in response to stress or damage. Therefore, we have adapted by setting a “cut-off”, above a certain level of stress/damage (IL-6), we switch from Treg to defensive mode with Th1 and Th17 and Th2.
Discuss the relative influence of environment and genetics on the risk for inflammatory bowel disease.
a. Inflammatory bowel disease (IBD) includes Crohn’s Disease (affects the large and small intestine, especially terminal ileum, patchy) and ulcerative colitis (superficial in large intestine). Both diseases are thought to involve dysregulated immune responses, perhaps due to commensal bacteria, activated Th1, Th17 and Th2 against normal commensal organisms.
b. Genetically, there are 71 loci associated with risk of Crohn’s, 47 loci associated with risk of ulcerative colitis (identified through Genome Wide Association Studies). 28 of the loci are common between the two condition (NOD2 is one of the loci shared). The loci predict 23% of risk in Crohn’s and 16% in ulcerative colitis. Strong genetic component, but environment and bad luck also play a role. Concordance in monozygotic twin studies is 30-35% for Crohn’s and 10-15% for ulcerative colitis.
Discuss the pathogenesis of Celiac disease, and the relative role played by antibody and T cells.
Celiac disease, gluten-sensitive enteropathy, affects 1% of world population, is when the body decides gluten is dangerous and must be destroyed. Infants present with malabsorption, diarrhea and failure to thrive. In adults, non-specific (anemia, rash, and osteoporosis) symptoms secondary to malabsorption as the villi in the gut atrophy. Diagnostic hallmark: antibody, tissue transglutaminase 2, to gut endomysium (lining that supports smooth muscle layer). This enzyme makes protein crosslinks through glutamines and in some people it couples to and can’t release digestion-resistant glutamine-rich gliadin (wheat) peptides and turns itself into a B cell auto-antigen by the illicit help mechanism. It is T-cell immunity to gliadin peptides that causes chronic inflammation.
Discuss the importance of HLA alleles in Celiac Disease
90% of patients with celiac disease have HLA-DQ2 and the rest are HLA-DQ8 (these are the acidic and basic configuration of amino acids that allow gluten to be presented). But not everyone with these HLA’s gets celiac disease. Mix of genetics and environment. Treatable—just don’t eat gluten! Gut will revert back to normal!
Discuss the mechanism of chronic beryllium disease
This is a pulmonary inflammatory and fibrotic disease caused by exposure to inhaled beryllium dust. It is seen in miners (the largest mine is in Utah) and machinists, especially in the nuclear industry where Be alloys find many uses. Perhaps a million people have been exposed, and 15% of them are symptomatic. Inhaled Be can become covalently linked to various peptides and it is thought that this creates novel epitopes to which a Th1 (Th17 also?) response is made, and later a scarring Th2 response as well. Since the Be cannot be removed effectively by macrophages, the condition can become established and chronic even after a single inhalation exposure. It is strongly linked to HLA-DP alleles that have a glutamic acid at position 69 of the β chain (DPβE69). This creates a negatively charged pocket which could bind a Be+ coupled peptide
Outline the Hygiene or Old Friends Hypothesis, and the observations that support it.
The Hygiene or Old Friends Hypothesis was proposed in an attempt to explain the non-uniformities in the world-wide increase in allergies and asthma (less of an increase in poor vs rich countries, rural vs urban, equatorial vs. northern). It has been suggested that somehow living outside in the dirt and being exposed to predominate outdoor infections helps the immune system mature normally
What is the more recent “Old Friends Hypothesis”?
The more recent “Old Friends Hypothesis” posits a more complicated and evidence based theory saying that certain harmless microorgansims (namely non-TB mycobacteria, lactobacilli, and helminth worms) have been in humans for so long that they help to instruct our immune systems not to overreact to commensals or low-grade pathogens (ie. they help in the development of the correct number of Tregs). However, if during some critical stage in development (0-2 y/o?) a person does no interact with these harmless microorganisms, they may not develop the correct number of Tregs and be too ready activate a strong Th1, Th2 or Th17 response to an organism that poses a mere paltry threat or no threat at all
Discuss the idea that it may be possible to switch Th1/Th2/Th17 responses to Treg instead
Subsequent work has shown that the mechanism of the effect was not Th2 suppressing Th1, but rather an impressive increase in Treg in the gut, which can suppress Th1, Th17, and Th2 responses. It is fascinating to think that this could still take place in adults, and we are fortunate that although Treg are stimulated by recognizing their specific epitopes as are any other T cell, the effect of their suppression is not antigen-specific, so that many nearby activated T cells are down-regulated or do not differentiate into effectors
