Immuno-Pathogenic Mechanisms of Inflammatory Bowel Disease (IBD) (part 2 of 2) Flashcards
the prevalence of IBD varies among different populations; UC is less common in what populations?
UC is 10-fold less common in Asian and African populations
the prevalence of IBD varies among different populations; CD seems very uncommon in what populations?
Asia and africa
the genetic risk of getting IBD is increased when?
among first-degree relatives
when is there a greater concordance rate for IBD?
in monozygotic twins vs. dizygotic twins
what is associated with a predisposition for developing IBD?
there have been over 200 single nucleotide polymorphisms (SNPs) that are associated with a predisposition for developing IBD; NOT MUTATIONS, but SNPs!
what are SNPs?
they are defined as loci variants with alleles that differ at a single base
what is the susceptibility locus for IBD found on chromosome 16?
IBD-1
what does the IBD-1 locus contain?
CARD15/ NOD2 genes
where is CARD15 primarily expressed?
in macrophages/ dendritic cells
defects in what have been found in 17-27% of cases of CD?
defects in CARD15/NOD2
what is CARD15?
an intracellular PPR (pattern recognition receptor)
what does CARD15 recognize?
MDP (muramyl dipeptide- a peptidoglycan constituent of both gram positive and gram negative bacteria)
CARD15 triggers activation of what?
NF-kB
What are 3 broad mechanisms of Crohn’s disease caused by NOD2 mutations?
1) defective function of macrophages; 2) defective epithelial-cell responses; 3) defective “conditioning” of APCs
what does defective function of macrophages lead to?
persistent intracellular infection of macrophages and chronic stimulation of T cells by macrophage-infecting organisms
what does defective epithelial-cell responses lead to?
loss of barrier function and increased exposure to the mucosal microflora
what does defective “conditioning” of APCs lead to?
inappropriate activation of APCs and disruption of the homeostatic balance of effector and regulatory cells
what does colonization of the GI with beneficial bacteria induce?
the development of GALT
during homeostasis, the gut microbiota has important roles in what?
permeability of the GI tract and intestinal immunity
the microbiota maintains the basal level of what?
Th17 and Th1 cell activity in the lamina propria
beneficial subsets of commensal bacteria tend to have what?
anti-inflammatory activities
what do beneficial commensal bacteria suppress? and how?
pathobionts; partly through the induction of Treg cells and stimulation of IL-10 production by immune cells
what do commensal bacteria ferment?
nondigestible polysaccharides ingested in the diet (eg cellulose) to produce SCFAs
what are the qualities of SCFAs?
they have anti-inflammatory properties in macrophages, dendritic cells, CD4+ T cells and intestinal epithelial cells
what is the receptor for SCFAs?
GPR43
a colonization of intestinal cells with segmented filamentous bacteria (SFB), bacteroides fragilis, clostridium spp. results in what?
induction of Treg cells in the lamina propria
besides Treg cell induction, what is the other role of SFBs?
maintenance of the basal activation level of Th17 cells, which are important for the integrity of the epithelial barrier
what represents the primary barrier limiting contact between the microbiota and host tissue preventing microbial translocation?
mucus
what do epithelial cells produce that also play a significant role in limiting exposure to the commensal microbiota?
antimicrobial peptides
what are translocating commensals rapidly eliminated by?
tissue-resident macrophages
presentation of commensal Ags by the DCs leads to what?
the differentiation of commensal-specific Treg cells, Th17 cells, and IgA-producing B cells
commensal-specific lymphocytes traffic to what?
the lamina propria and Payer’s patches
in peyer’s patches, Tregs can further promote what?
class switching and IgA generation against commensals
what comprises the mucosal firewall?
the combination of the epithelial barrier, mucus layer, IgA, and DCs and T cells
what is the purpose of the mucosal firewall?
it limits the passage and exposure of commensals to the gut-associated lymphoid tissue, preventing untoward activation and pathology
what does the commensal microbiota suppress?
the NF-kB pathway
what is the immune tolerance of the microbiota related to?
to DCs and macrophages which do not sense the presence of microflora and thus do not secrete pro-inflammatory cytokines; IN IBD THE TOLERANCE IS LOST
what occurs in IBD in association with immune tolerance and the microbiota?
tolerance is lost; consequently, a chronic immuno-inflammatory response is triggered in the mucosa
dysbiosis results in what?
a loss of protective bacteria and/or in the accumulation of colitogenic pathobionts, which leads to chronic inflammation
chronic inflammation involves what?
hyperactivation of Th1 and Th17 cells and inhibition of Treg cells producing IL-10
what is the tipping point associated with IBD?
if an acute inflammation cannot be resolved by anti-inflammatory mechanisms, it leads to chronic intestinal inflammation
chronic inflammation may cause complications of IBD such as what?
fibrosis, stenosis, abscess, fistula, cancer, etc.
the process of T cell activation and differentiation is modulated by what?
co-stimulatory signals (cytokines and ligands) between APCs and naive (or memory) T cells
crohn’s disease is characterized by the activation of what?
Th1 and Th17 cell response
what are the th1 and th17 cell responses driven by?
IL-12, IL-6, and IL-23 produced by DCs and macrophages
what do Th1 cells secrete?
IL-2, IFN-gamma, and TNF
what do Th17 cells secrete?
IL-17
ulcerative colitis is characterized by an atypical activation of what?
Th2 cell and natural killer T cells (NKT)
what do Th2 cells produce?
IL-5 and IL-4 and IL-13
what do NKT cells produce?
IL-13
what cytokine causes an activated T cell to become a Th1 cell?
IL-12
what product of Th1 cell leads to crohn’s disease?
IFN-gamma
what cytokine causes an activated T cell to become a Th2 cell?
IL-4
what products of Th2 cells lead to ulcerative colitis?
IL-4, IL-5, IL-13
what cytokines cause an activated T cell to become a Th17 cell?
IL-6, IL-23, TGF-beta
what products of Th17 cells lead to crohn’s disease?
IL-17
what is IL-23 produced by?
activated APCs (macrophages and DCs)
what is IL-23 closely related to?
IL-12
what cytokines are needed for inhibition of IBD and maintenance of tolerance?
IL-10 and TGF-beta
what would happen if you lost function of the SNPs for IL-10 and TGF beta?
you would be predisposed to IBD
what would happen if you gain function of the SNPs for IL-10 and TGF-beta?
you would be protected from IBD
what cytokines are important for the cell-mediated inflammation and CD in IBD?
TNF-alpha, IFN gamma, IL-1, IL-6, IL-2, IL-17, and IL-22
what happens if you lose the function of the SNPs for the cell mediated inflammation and CD?
you would be protected from CD
what happens if you gain function of the SNPs for the cell mediated inflammation and CD?
you would be predisposed for CD
what are the cytokines important for antibody-mediated inflammation and UC?
IL-4, IL-5, and IL-13
what happens if you lose the function of the SNPs for antibody mediated inflammation and UC?
you would be protected from UC
what happens if you gain the function of SNPs for antibody mediated inflammation and UC?
you would be predisposed to UC
immune responses in the intestinal lumen GI are tightly regulated; how??
there is tolerance to resident commensal bacteria and dietary antigens present; there is also a rapid immune response against pathogenic microbes; there is active suppression by Treg cells
IBD is believed to be the result of a breakdown of what?
tolerance to resident enteric bacteria (microbiota)
what do Treg cells secrete?
Il-10 and TGF-beta
limited expression of pro-inflammatory cytokines by APCs and excess of TGF-beta results in what?
differentiation of naive T cells into T reg cells
where can Treg cells act?
locally in various tissues and draining lymph nodes
Treg cells become activated by what?
APC presenting auto-Ag
what do Treg cells constitutively express?
CTLA-4 and an alpha-subunit of IL-2 receptor (CD25) which render IL-2R a high affinity binding
how do Treg cells suppress APCs?
directly through cell-to-cell interactions or indirectly by inhibitory cytokines
Treg cells might act directly on activated T cells via what?
CTLA-4 and by IL-2 deprivation
what are the current treatment options for IBD?
TNF blockers
what are TNF blockers?
they are humanized monoclonal Ab that bind TNF
besides TNF blockers, what is on the horizon for treatment for IBD?
fecal microbiota transplantation
