Chronic Frustrated 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.
What cytokine do you usuallly find in large numbers in the submucosal Peyer’s patches? It differentiated what into what?
What IL is made by resident dendritic cells that also favor Treg development?
There is normally a lot of the cytokine TGFβ in the submucosal Peyer’s Patches, and that favors the differentiation of Th0 cells into Treg.
The resident dendritic cells here make IL-10, and that also favors Treg development.
Thus these sites are rich in Treg cells, which is desirable considering the constant exposure to bacteria- and food- derived, non-pathogenic, potential immunogens coming through the M cells of the gut epithelium.
- Describe the factors that regulate the differentiation of Th0 cells in the Peyer’s Patches to Th1, Th2, or Th17 versus into Treg cells.
In the Peyer’s patches you can also find____ that drive B cells towards making IgA.
The combination of what two cytokines downregulates Treg and UP regulates Th1, Th2, and Th17?
IL-6 is produced by ______ cells in response to stress and damage.
If a peptide comes in unaccompanied by damage or inflammation, you probably don’t want to make an immune response to it, so it’s good to make T regs.
Also very common in Peyer’s Patches are Tfh that specifically drive B cells towards making IgA, so that the mucus layer nearest the epithelial cells that line the gut is, surprisingly, almost sterile. More than one immunologist has suggested the Tregs can differentiate easily into such Tfh, and vice versa; a nice touch, as they’d both prevent harmful responses and help protective ones.
► However, the combination of TGFβ and IL-6 has been shown to downregulate Treg and up regulate Th1, Th2, and Th17 (the CD4+ Th that makes IL-17 and is expanded by IL-23; both these cytokines are also common in areas of inflammation.)
IL -6 is produced by epithelial and other cells ► in response to stress or damage. This model links a lot of disparate observations. Normal commensal gut organisms have evolved to live in the lumen and not try to invade; the immune response to them, taking place in an environment dominated by TGFB, is mostly by Treg at a steady level.
When the innate response indicates a threat, it makes stress cytokines like IL -6 and the response switch es from Treg production to defensive Th1, Th17, or Th2.
What does NOD2 recognize?
What does it activate?
The recognition of normal vs. abnormal organisms is doubtless mostly carried out by innate immunity via PRR that bind various PAMPs.
These include the TLRs we discussed early on, and several other PRR systems, including one called NOD2.
NOD2 detects muramyl dipeptide, a component of bacterial cell walls, and triggers cytokine production by activating NF- κB. There are also complex PAMP- recognizing assemblies called “inflammasomes.”
- Discuss the relative influence of environment and genetics on the risk for inflammatory bowel disease.
What areas of the large and small intestine does Crohn Disease affects?
What about UC?
In IBD patients an increase in gut permeability leads to secretion of ______, by gut lining cells, which are able to penetrate back into the tissues. What are the consequences of this?
This term includes Crohn Disease (CD) and ulcerative colitis (UC).
-CD affects the large and small intestine, especially the terminal ileum. There are microabcesses in the wall of the intestine, generalized inflammation throughout the wall (so that fistulas can develop between the lumen and the peritoneum), and the disease process is ‘patchy’ with affected areas interspersed with healthy ones. The abscesses eventually become granulomas.
UC is usually more superficial in the large intestine, and can erode the surface leading to bleeding.
► Both are thought to involve dysregulated immune responses, probably to commensal bacteria. Genome-wide association studies (GWAS) have identified 163 loci associated with significant risk in IBD. 30 are specific for CD, and 23 for UC. A hundred and ten loci are in common between the two conditions. So there is a strong genetic component ; but the environment and ‘bad luck’ also play important roles, since concordance in monozygotic twins is only 30-35% for CD, and 10-15% for UC.
One interesting model with support from human studies suggests that in so me IBD patients, an early (genetic? post-infectious? ) event is an increase in gut permeability so that certain secreted defensins, made by gut lining cells, are able to penetrate back int o the tissues.
There, acting as DAMPs, they stimulate macrophages to produce inflammatory cytokines, including IL-6. Whatever the proximate causes, the outcome is that the patient has activated Th1, Th17, and Th2 against normal commensal organisms as if trying to rid the gut of these creatures; but they never can, so the inflammati on goes on and on.
–>This will eventually change the populations of microorganisms in the intestines (the microbiome) and that may further exacerbate the condition. Some workers have gone so far as suggesting ‘fecal transplants’ to replace the microbiome in IBD patients with one derived from healthy donors.
- 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.
- Discuss immunological aspects of celiac disease that are non-autoimmune and autoimmune, and describe the mechanism whereby to tTG2 is made.
What happens to the villi of the gut?
How do you diagnose it?
What is the specific antigen in tissue called?
What cells are responsible for chronic inflammation?
What HLAs are involved? Do people with them do they show the disease (always)?
Also called gluten-sensitive enteropathy, this condition affects almost 1% of the world’s population.
In infants it presents as malabsorption, diarrhea, and failure to thrive; in adults it can be so nonspecific as to defy clinical diagnosis, with a variety of symptoms (osteoporosis, anemia, rash) secondary to malabsorption as the villi in the gut atrophy.
The diagnostic gold standard is a small intestinal biopsy. Also useful in diagnosis is antibody to the gut endomysium, the lining that supports the smooth muscle layer; the specific antigen is tissue transglutaminase2 (TG2). This enzyme makes protein crosslinks through glutamines, and in some people may, if it couples to but can’t release digestion -resistant, glutamine-rich gliadin (wheat) peptides, inadvertently turn itself into a B -cell autoantigen by the ‘foreign + self hybrid antigen’ help mechanism (review that in the Type II Unit).
Note, though, that ► it is T cell immunity to gliadin peptides that is responsible for the chronic inflammation. Ninety percent of people with this condition are HLA-DQ 2, 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.
This is another example of a frustrated immune response: the body has decided that gluten is dangerous and must be destroyed, so the gut becomes the battleground on which this endless struggle is waged. However, unlike IBD, there is a fix a vailable: if the patient avoids gluten (wheat, rye , and barley) the symptoms will fade and the gut can revert to normal.
- Discuss the mechanism of chronic beryllium disease
Be can bind to various peptides and it is thought that it creates novel epitopes to ______ T cells.
How many times does it take for the conditions to be developed?
Linked to HLA_____.
This is a pulmonary inflammatory and fibrotic disease caused by exposure to inhaled beryllium dust. It is seen in miners (the la rgest mine is in Utah) and machinists, especially in the nuclear industry where Be alloy s find many uses. Perhaps a million people have be en 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 b y macrophages, the condition can become established and chronic even after a single inhalation exposure.
It i s 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, something non - DPβE69 alleles can’t do.
- Outline the Hygiene or Old Friends Hypothesis, and the observations that support it.
Newborns start out with a ______ dominated immunse system, which gradually balances out with ____.
First proposed by D. P. Strachen in 1989, this was an attempt to explain certain non-uniformities in the world-wide increase in allergy and asthma.
Broadly, there has been less of an increase in: poor countries as compared to rich ones; equatorial versus northern countries; rural populations as opposed to urban; slums as opposed to rich neighborhoods; children of large families as opposed to only children. All of this suggested that exposure to environmental dirt and infections helped the immune s ystem mature normally, while lack of such exposure mi ght leave a child in an infantile state.
There is good evidence that newborns start out with a Th2 -dominated system which gradually balances out with Th1. So Strachen suggested that this might explain the increase in Th2- (and the Th2-like Tfh that drive B cells to switch to IgE) mechanism diseases. It’s an appealing idea , but it ran into some trouble because the same clean rich people who should, by this explanation, be Th 2-dominated are also at increased risk of Th1 diseases like ulcerative colitis and Crohn disease, multiple sclerosis and juvenile diabetes.
How can the same group be Th 2- and Th1-dominated at the same time? The model was too simple , not surprisingly since Treg had barely made it onto the scene at that time.
- Outline the Hygiene or Old Friends Hypothesis, and the observations that support it.
Old Friend Hypothesis:
It says that certain harmless microorganisms — notably non-tuberculosis Mycobacteria, lactobacilli, and helminth worms — 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.
Specifically , ► if you have adequate exposure to these old friends, you develop a balance between activcation and regulation, driven by the right number of Treg.
► But i f you have been old-friendless most of your life, you may have too few Treg and be too ready to make a strong Th1 or Th2 or even Th17 response to some organism that really isn’t much of a threat (gut flora) or is no threat at all (pollen), especially if you already have allelic va riants of genes that predispose y ou to do so.
- Discuss the idea that it may be possible to switch Th1/Th2/Th17 responses to Treg instead.
A group of Iowa gastroenterologists decided that in Crohn Disease (CD) and Ulcerative Colitis (UC), Th1 are bad and Th2 might, by opposing Th1, be good.
In 2005 it was still thought that the important event was Th1 -Th2 “sibling rivalry.” (Th1 do, to an extent, suppress Th2 development, and vice versa, as they perhaps compete for limiting growth factors.)
How to effect a switch? Well, they reasoned, parasite responses are strongly Th2-dominated. So they recruited a group of quite ill CD patients and fed them some drinks of fresh pig whipworm ova. This was safe because the worms will only live a few days in the human gut. In a short, open-label study, the improvement in their patients’ s_ymptom scores was remarkable._
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.
