Chronic "frustrated immune response" Flashcards
Toruses
Our insides are really outside.
In the Gut…
There is NORMALLY a lot of cytokine TGFbeta in the submucosal peyers Patches, and that FAVORS the differentiation of ThO cells into Treg. The resident dentritic cells here make IL-10 and that also favors Treg development (immunosuppressant cells). These sites are rich in Treg cells, which is desirable considering the constant exposure to with bacteria- and food-derived, non-pathogenic, potential immunogens coming through the M cells of the gut epithelium
Also common in peyers 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.
the combination of TGFbeta and IL-6 has shown
to downregulate Treg and upregulate Th1, Th2, and Th17. This indicates damage is happening.
IL-6 is produced
by epithelial and other cells in response to stress or damage. For example when salmonella comes in. This is an innate response.
Model of the gut has a lot of disparate observations
immune response to them, taking place in an environment dominated by TGF, 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 switches from Treg production to defensive Th1, Th17, or Th2.
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.”
Chronic frustrated immune responses
Any time the immune system is trying to get rid of foreign antigen that it can’t eliminate or encapsulate, it will remain chronically active and the ttissues in which it takes place will become a metaphric battlefield.
Inflammatory bowel disease
Term includes Crohn Disease and Ulcerative Colitis (UC). Crohns 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, perhaps to commensal bacteria.
Some causal thoughts for IBD
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 componentbut the environment and ‘bad luck’ also play important roles, since concordance in monozygotic twins is only 30-35% for CD, and 10-15% for UC3. SO GENETICS, ENVIRONEMENT, and BAD LUCK are the cause.
In some human studies suggests that 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. LEAKY in early signs of these diseases.
Whatever the proximate causes in IBD is, 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 inflammation 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.
Celiac Disease
AKA gluten-sensitive enteropathy, effects 1% of the worlds population. Make immune response against peptides in wheat.
In infants it presents as malabsorption, diarrhea, and failre to thrice.
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.
Hallmark diagnostic of Celiac
Small intestinal biopsy. Also useful in diagnosis is antibody to the guy endomysium, the lining that supports the smooth muscle layer the specific antigen is tissue transglutaminase 2 (TG2). CELIAC IS NOT AN AUTOIMMUNE SINCE it is an outcome, not the cause of the disease.
Transglutaminase 2 (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. This is because it is bound to foreign protein (gluten) and the B cell can put gluten on surface. So now making antibody to TG2. So gut making antibody to enzyme that is part of your body. This is part of your enzomezium.
Celiac disease reaction however
it is T cell immunity to gliadin peptides that is responsible for the chronic inflammation. Ninety percent of people with this condition 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. AVOID GLUTEN AND THE SYMPTOMS WILL FADE AND THE GUT CAN REVERT TO NORMAL.
Celiac disease poorly controlled
Some patients with poorly-controlled celiac disease will develop a skin condition called dermatitis herpetiformis (dermatitis that looks like herpes). Biopsy shows that there is autoantibody in the skin to skin-specific transglutaminase 3 (TG3). There is evidence that this antibody actually causes the SKIN lesions. Perhaps not surprisingly, the antibody is IgA, which probably arose from the anti-TG2 of celiac by epitope spreading.
Chronic beryllium disease
This is a pulmonary inflammatory and fibrotic disease caused by exposure to inhaled beryllium dust. t 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.
Beryllium continued
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.
Psoriasis
There is some evidence that this chronic inflammatory condition of skin also involves an inappropriate, unregulated T cell response to normal skin organisms. It is associated with the allele HLA-Cw*06:02 (a class I gene, which in this case may be in linkage disequilibrium with a pathogenic Class II allele.) Interestingly, this allele is high in African Americans, who are in most studies at greater risk for psoriasis than Caucasians—but in sub- Saharan Africa the allele is high among Black people but prevalence of psoriasis is low, clearly suggesting environmental factors play a role
Periodontal Disease
This chronic inflammatory condition is the major cause of tooth loss; prevalence in the US is about 8% in the young, 16% in the elderly. It is strongly associated with several bacterial species, but the association is complex and not well understood. The gingival crevice between the gum and the tooth root is not easily cleared by saliva, and yet cell- mediated immunity cannot reach there because it’s outside the body; so it’s a great place for bacteria to live, if it’s not kept scrupulously clean
Periodontal disease characteristics
It has many of the characteristics of inflammatory bowel disease, including a shift from a TGFβ milieu to one with IL-6 and TGFβ. There is an association with rheumatoid arthritis (antibodies to citrullinated peptides are seen in both conditions, and they are linked to smoking and environmental pollution.)
Periodontal disease treatment
Immunosuppressive therapy improves periodontitis, though it’s rarely prescribed for it. Tocilizumab, a blocking monoclonal antibody to the IL-6 receptor, has been reported to be effective in severe periodontal disease, but the side effects were worrisome.
