Immunologic Mechanisms Of IBD Flashcards
What is IBD?
A term used to describe two disorders that involve chronic inflammation of the GI tract
Includes ulcerative colitis and Crohn’s disease
What is ulcerative colitis characterized by?
Chronic inflammation and ulcers in the innermost lining of the colon and/or rectum
What is Crohn’s disease characterized by?
Inflammation of the lining of the GI tract which often spreads deep into affected tissues and may occur in any part of the GI tract
Rectum is usually spared
IBD is associated with an increased permeability of what?
The epithelial barrier caused by impaired formation of tight junctions
IBD develops as a result of what?
A persistent inappropriate perturbation of highly regulated interaction between the immune ssytem and commensal bacteria of the normal micro biome resulting in dysbiosis and mucosal inflammation
The aberrant responses in IBD are to a large degree genetically determined and may include what?
Disruption of the barrier function (mainly in UC)
Dysfunction of microbe sensing (mainly in CD)
Changes in immunoregulation of innate and adaptive immune responses (both)
A low concordance rate in identical twins suggests what?
Imporatnace of environmental factors
50% for CD and 10% for UC
What are the functional roles of gut microbiota?
Protection of the host against invasion or colonization by pathogens
Facilitation of nutrient digestion and absorption in humans
Providing the immunological surveillance signals at the gut mucosa lumen interface
IBD develops in areas with high concentrations of what?
Bacteria (terminal ileum and the colon)
Surgical diversion of the fecal stream prevents what?
Intestinal inflammation
Reestablishment of the flow leads to recurrence of IBD
What has beneficial effects on IBD?
Use of abx and probiotics
Circulating Abs against what are detected in IBD?
Fecal bacterial antigens
What is the gut micro biome primarily comprised of?
The phyla bacteroidetes (largely bacteroides or Prevotella species) or Firmicutes (largely clostridium and Lactobacillus species)
Which factors have a major effect on gut microbiota?
Diet and other environmental factors + host genetics
What maintains gut homeostasis?
Symbiosis (a balanced microbial composition)
What does dysbiosis lead to?
Dysregulation of the immune system and to inflammation in a genetically susceptible host
May be caused by various environmental factors
True or false: no specific microbial organisms have been conclusively linked to the development of IBD
True
Which disease may play a role in the etiology of IBD?
Gastroenteritis (such as salmonella and campylobacter)
Individuals diagnosed with an acute gastroenteritis have been shown to have an increased risk of developing IBD
The prevalence of IBD is inversely associated with the prevalence of what?
Helminth colonization
Helminths are thought to play an important immunoregulatory role with the intestinal flora
Describe the prevalence of UC and CD in Asian and African populations
UC is 10 fold less common in Asian and African populations
CD seems very uncommon in Asia and Africa
If a first degree relative has IBD are the changes increased or decreased in an individual with that relative?
Increased
There is a greater concordance rate in which types of twins?
Monozygotic vs dizygotic twins
Describe the IBD1 gene
Found on chromosome 16
Contains CARD15/NOD2 genes
Describe CARD15?
Primarily expressed in macrophages and DCs
It’s an intracellular PPR
Recognizes MDP (a peptidoglycan constituent of both gram + and - bacteria)
Triggers activation of NF-kB
Individuals homozygous for susceptible variant (SNPs) of CARD15 have more than a 20 fold increased risk of developing what?
Crohn’s disease
What are the 3 possible mechanisms that CARD15/NOD2 mutations can lead to Corin’s disease?
Defective function of macrophages
Defective epithelial cell responses
Defective conditioning of APCs
Commensal bacteria ferment non-digestible polysaccharides ingested in the deity to produce what?
SCFAs which have anti inflammatory properties in macrophages, DCs, CD4 T cells, and intestinal epithelial cells
The microbiota induces host immune tolerance to commensal bacteria directly via what?
A microbe associated molecular pattern (MAMP)
Polysaccharide (PSA) signaling
Indirectly through the production of SCFAs
Potentially through expression of epithelial intestinal alkaline phosphatase (IAP) which detoxifies luminal LPS
What comprises the mucosal firewall of the GI tract?
The combination of the epithelial barrier, mucus layer, IgA, DCs and T cells
What is the function of the mucosal firewall?
Limits the passage and exposure of commensal pts to the GALT preventing untoward activation and pathology
Which pathway do commensal microbiota suppress?
NF-kB
Describe immune tolerance in the GI tract
The tolerance is related to DCs and macrophages which do not sense the presence of microflora and thus dont secrete pro-inflammatory cytokines
In IBD the tolerance is lost
What happens in the absence of commensal bacteroides?
Salmonella flagellin binds to TLR5 intestinal epithelial cells (IECs)
Activates IkB kinase (IKK) —> activation and nuclear translocation NF-kB
What happens in the presence of commensal bacteroides?
Proinflammatory response caused by S enteritidis is attenuated
Induction of peroxisome proliferation activated receptor (PPAR) which exports the activated NFkB from the nucleus
Crohn’s disease is characterized by the activation of which types of T cells?
Th1 and Th17 cell responses driven by IL-12, IL-6 and IL-12 produced by DCs and macrophages
Which cytokines do Th1 cells secrete?
IL-2, IFN-gamma, TNF
Which cytokines do Th17 cells secrete?
IL-17
Ulcerative colitis is characterized by an atypical activation of which cell?
Th2 cell and natural killer T cell (NKT) which produce IL-5 and IL-4 (Th2) and IL-13 (Th2 and NKT cells)
