Immuno of IBD Flashcards
chronic inflammation and ulcers in the innermost (superficial) lining of the colon and/or rectum
ulcerative colitis
inflammation of the lining of the GI which often spreads deep into affected tissues and may occur in any part of the GI
Crohn’s disease
What is spared in 40% of patients with CD?
the rectum
- in contrast to universal rectal involvement in UC
what causes increased permeability of the epithelial barrier?
impaired formation of tight junctions
is disruption of barrier function a response seen mainly in UC or CD?
UC
immune system sensing foreign/aberrant microbes, seen more in UC or CD?
CD
- main factor is TLR’s in Chron’s, failure of Treg cells in both
ASCA-positive more likely in UC or CD?
CD
- combination of positive ASCA and negative pANCA has a positive predictive value of 96% and specificity of 97% for CD
pANCA-positive more likely in UC or CD?
UC
what are the two most important environmental factors leading to IBD?
- microbes/enteric flora (CD)
- membrane permeability (UC)
where does IBD develop?
the terminal ileum and colon (areas of high bacterial concentration)
circulating Abs against what, are detected in IBD?
fecal bacterial antigens
what show reactivity against fecal antigens?
lymphocytes
where do the majority of our gut flora reside?
the colon and cecum 10^9-10^12 (compared to 10^3-10^7 in the small intestine)
the gut microbiome is composed primarily of which phyla?
90% belong to Bacteroidetes (largest percentage) and Firmicutes phyla
which disease is more likely if there is an increase in Proteobacteria in the gut flora?
UC
which disease is more likely if there if a significant increase in Firmicutes and Actinobacteria (with a decrease in the amount of Bacteroidetes)
CD
what is the main predictor of diversity of infant microbiota?
maternal IBD
- infant stool of mothers with IBD showed significantly altered adaptive immune system response of the intestines
dysbiosis leads to what, of the immune system?
dysregulation and inflammation (in a genetically susceptible host)
what effect does a high fiber diet have on gut flora?
increases bacteroidetes, firmicutes, and actinobacteria
- decreases proteobacteria
what effect does high protein (or high carb) diet have on gut flora?
increases bacteroidetes, firmicutes, and proteobacteria
what effect does a high fat diet have on gut flora?
decreases bacteroidetes, firmicutes, and proteobacteria
individuals diagnosed with what, have been shown to subsequently have an increased risk of developing IBD?
gastroenteritis
the prevalence of what, is inversely associated with the prevalence of IBD?
- *HELMINTH COLONIZATION**
- thought to play important immunoregulatory role with intestinal flora
where is UC 10-fold less common, and CD very uncommon?
Asia and Africa
what LOF mutations are associated with CD?
CARD15/NOD2 (IBD-1 locus on xsome 16)
- defects found in 17-27% of CD cases
NOTE: homozygous individuals of CARD15 variant have 20-fold risk of developing CD
what interleukens are associated with CD?
IL3, IL4, IL5, IL13, and TNF
what is CARD15?
intracellular pathogen recognition receptor (PPR)
- recognizes molecules containing specific structure called muramyl dipeptide (MDP) -> triggers activation of NF-kb -> adaptive immune response
where is CARD15 primarily expressed?
monocytes/macrophages
what does a mutation in CARD15 lead to?
reduces activation of NF-kb -> inhibiting adaptive immune response
- increases susceptibility to chronic intracellular infection
- disrupts CARD15-mediated effects on APC, leading to less effector and Treg cell activation
colonizaton of the GI with beneficial bacteria induces what?
- development of GALT
- increased Treg cells
- increased IL10
microbiota maintains the basal level of what types of T cells?
Th17 and Th1 (important for membrane integrity)
what are directly suppressed by beneficial commensal bacteria via induction of Treg cells and stimulation of IL10 production?
pathobionts
short chain fatty acids tend to have what?
anti-inflammatory properties
SCFAs -> FA metabolites -> GPR43 -> what?
Treg cells -> IL10 –> BLOCKING inflammatory response
segmented filamentous bactera (SFB) colonization results in what?
induction of Treg cell populations in the lamina propria
- also plays a role in Th17 levels (important for epithelial integrity)
microbiota participate in the formation of active what?
secondary forms of bile acids
what makes up the mucosal firewall?
epithelial barrier, mucus layer IgA, DC’s, and T cells
Where does IgA class switching occur?
in Peyer’s patches
which pathway does commensal mirobiota suppress?
NF-kb pathway
what triggers UC?
- *epithelial antigens and altered AEROBIC bacteria**
- Salmonella enteritidis -> binds TLR5 -> activates NF-kb -> PRO-inflammatory genes
what triggers CD?
- *ANAEROBIC bacteria**
- bacteroides thetaiotaomicron -> stimulates transcription factor PPAR -> exports activated NF-kb from nucleus
chronic inflammation leads to hyperactivation of what?
- and inhibition of what?
hyperactivation of Th1 and Th17
- inhibition of Treg cells and IL10
which disease is characterized as a Th1 and Th17-type disease?
(Th1 and Th17 cooperation!)
CD
- Th1 secretes IL2, IFNy, TNF
- Th17 secretes IL17, IL22
which disease is characterizes as a Th2-type disease?
- *UC**
- Th2 cells secrete IL5
- NK cells secrete IL13
leads to B cell and WBC recruitment (humoral response)
what activates Th17 cells?
IL6, IL23, TGFb
what activates Th1 cells?
IL12
what activates Th2 cells?
IL4
what produces IL6 and IL23?
APC’s
IL23 is closely related to what, and regulates Th1 cell responses?
IL12
NOTE: IL23 also regulates macrophage and DC resposes
what is the most important inducer or macrophages and DC’s?
IFN-y
what is the most powerful inducer of Th17?
IL23
GOF SNP’s of:
- TNFa, IFNy, IL1, IL6, IL2, IL17, IL22
predispose you to what?
cell-mediated inflammation and CD
GOF SNP’s of:
- IL4, IL5, IL13
predispose you to what?
Ab-mediated inflammation and UC
IBD is believed to be the result of a breakdown of tolerance to what?
resident enteric bacteria
Treg cells suppress APC’s directly through what
- and indirectly via what?
- directly: cell-cell interaction
- indirectly: cytokines or chemokines
inadequate suppression of effector T cells leads to what?
inflammation and IBD
- normally, Treg cells suppress activation of effector T cells and prevent IBD
what are the current treatment options for IBD?
- TNF blockers (administered IV, for moderate-severe UC or CD, risk for worsening HF, infection and malignancy)
- leukocyte adhesion inhibitors (recommended in pts who failed previous TNF therapy, risk of life-treatening progressive multifocal leukoencephalopathy)
what is on the horizon for IBD treatment?
fecal microbiota transplantation (FMT)
