immunopathogenic mechanisms of IBD Flashcards
ulcerative colitis is characterized by ulcers in _____ of the ______
innermost lining
colon or rectum
crohn ds is characterized by inflammation which often ____ into affected tissues and may occur in _____
spreads deep
in any part of the GI system
in IBD, the ____ bacterial of the cause inflammation, leading to ______ mucosal irritation. bacterial components cross _____to induce a __&___ immune response
commensal bacteria of the normal intestine
self sustained
mucosal barrier,
innate and adaptive
IBD develops as a result of ___ and ____
dysbiosis (inappropriate perturbation commensal bactera to immune system)
mucosal inflammation
aberrant immune responses in IBD include ____(both), ____ (UC), _____(Crohn)
changes in Treg immune regulation
disruption of barrier function
dysfunction of microbe sensing
a combination (+)___ and (-)__ test has the highest specificity
ASCA
pANCA
IBD is complex combination of
____intestinal inflammation, genetic susceptibility influenced by _____, ____ that act as adjuvants to stimulate other immune responses, and _____ triggers
chronic
luminal microbiota
microbial Ags
environmental triggers
what environmental factors can lead to IBD
NSAIDs, abx diet smoking stress epigenetics (microbes, enteric flora, permeability) appendectomy
what are the functional roles of gut microbiota in our beautiful symbiotic relationship
protection against invasion or colonization (outcompete)
facilitation of difestion and absorption
provide immunological surveillance signals
main players in normal gut microbiome
bacteriodetes (bacteriodes/provetella)
firmicutes (C. dif, lactobacillus)
describe the state of dysbiosis in ulcerative colitis
way more proteobacteria
E. Coli, desulfovibrio
describe the state of dysbiosis in crohn
way more firmicutes (C. dif, lactobacillus) and actinobacteria (bifidobacterium, collinsella)
what is the main predictor of diversity of infant microbiota
maternal IBD
–> lower diversity
what features control host microflora composition
host genetics maternal transfer abx/meds infection, inflammation stress, hygeine, age
while no specific organism has been proven to cause IBD, ___ (3) have shown to be related, as well as acute gastroenteritis caused by _____(2). prevalence of IBD is inversely associated with the prevalence of ___
M. paratuberculosis, persistent paramyxovirus (measles), listeria monocytogenes
salmonella, campylobacter
helminth colonization
genes related to IBD
a susceptibility locus ____ is found on chr __
___, primarily expressed in Mø/DCs and lost in Crohn, is an intracellular ___ that recognizes ___ and triggers acitvation of ___
IBD1, 16
CARD15, PPR, MDP, NF-kB
how does CARD15 mutation increase risk for IBD
mutation in CARD15 stops it from activating NFKB= no inflammation
–> defective Mø= persistent intracellular infection and chronic T cell stimulation
–> defective epithelial cell response –> LOF of barrier and increased exposure to mucosal microflora
–> inappropriate activation of APCs
speak to how gut microbiota maintains homeostasis
GALT development
maintain basal activation levels of Th17+Th1
increase barrier function by maintaining permeability
increase Treg and IL-10 formation,
suppress pathbionts
ferment non-digestible polysachs into SCFAs which have an ant-inflammatory properties in Mø, DCs, CD4 T cells, intestinal epithelial cells
describe the pathway of SCFA function
released by microbiota after fatty acid metabolites
GP43 receptor on Treg cells –> release IL-10 -> block inflammatory response
the ___ represents the primary barrier limiting contact between the microbiota and host tissue. epithelial cells can produce ____ to limit exposure, and any translocating commensal bacteria are rapidly eliminated by ____. capture of Ags by DC leads to differentiation of ___(3)
mucus
antimicrobial peptides
tissue resident macrophages
Treg cells, Th17 cells, and IgA producing B cells
__+ __ + __ + __ = mucosal firewall
epithelial barrier + IgA + DCs + T cells
commensal microbiota suppresses the ___ pathway, so in IBD ___ is lost
NF-kB
tolerance to commensal bacteria
when pathogenic bacteria reach colon, they activate ___ on epithelium which starts a chain that activates pro-inflammatory genes? but normal commensal bacteria will ___ that inflammation
TLR5
attenuate
dysbiosis results in hyper-activation of ___(2) and inhibition of ___(2)
Th1 and Th17
Treg and IL-10
Th1/Th17 paradigm in crohn
IL-6,
IL-12–> Th1 –> IL-2, IFN-y (–> Mø –>TNF)
IL-23 –> Th17 –> IL-17
UC characterized by activation of ___ (2) which produce (3)__ which will cause ____ of colonic epithelium
Th2, NKT
IL-5, IL-4, IL-13 –> increased permeability
salt and pepper nucleus = stippling of the nucleus = ?
carcinoid tumor
secretory products and sx of esophageal carcinoid tumor
unknown
dysphagia, weight loss, reflux
substance P released in carcinoid syndrome will cause ___ due to increased __
diarrhea
peristalsis
CCK causes
gallbladder release
secretory products, sx, disease associations of carcinoid tumors of the stomach
histamine, somatostatin, serotonin
gastritis, ulcer, asx
atrophic gastritis, MEN-1
secretory products, sx, disease associations of carcinoid tumors of the proximal duodenum
gastrin, somatostatin, cholecystokinin
sx=peptic ulcer, biliary obstruction, abd pain
ds= zollinger-ellison syndrome, NF-1, sporadic
secretory products, sx, of carcinoid tumors of the jejunum and ileum
serotonin, substance P, polypeptide YY
sx= asx, obstruction, metastatic ds
secretory products, sx, of carcinoid tumors of the appendix
serotonin, polypeptide YY
sx= asx
secretory products, sx, of carcinoid tumors of the colorectum
serotonin, peptide YY
abd pain, weight loss, incidental
Treg cells are activated by ___ presenting ___. They constituitively express __ and ___, and can directly act on either ___ or _____
APCs, autoAg
CTLA-4 and IL-2R
APCs or activated T cells
current trx for IBD
TNF blockers, for moderate to severe
risk for worsening HF, reactivation of infection and malignancy
