Immuno - IBD Flashcards
compare rectal involvement b/w UC and CD
UC: universal rectal involvement
CD: in 40% of patients the rectum is spared
compare aberrant responses b/w UC and CD
UC: disruption of barrier function
CD: dysfunction of microbe sensing
describe the mucosal barrier dysfunction and exaggerated mucosal immunity in IBD
IBD has increased permeability of epithelial barrier –> commensal bacteria of normal microbiota cause inflammatory reactions leading to self-sustained mucosal inflammation –> bacterial components cross mucosal barrier –> contact immune cells –> induced innate and adaptive responses in immune system
IBD develops as a result of _______
a persistent and inappropriate perturbation of highly regulated interaction b/w immune system and commensal bacteria of normal microbiome resulting in dysbiosis and mucosal inflammation
how do ASCA and pANCA tests help diagnose CD
positive ASCA and negative pANCA have a specificity of 97% for CD
how do we know that environmental factors have an impact on IBD
50% chance in monozygotic twins for CD and 10% for UC
what genetic defect is associated with IBD1
crohn dz
describe the IBD1 locus
found on chromosome 16
- contains CARD15/NOD2 genes
- defects in CARD15/NOD2 found in 17-27% cases of CD
describe the CARD15 gene
found in the IBD1 locus
- intracellular pathogen recognition receptor (PPR)
- recognizes molecules containing specific structure called muramyl dipeptide and activates NF-KB
what cells express CARD15
monocytes/macrophages
how do mutations in CARD15 affect expression of NF-KB
mutations in CARD15 reduces activation of NF-KB
how do CARD15 mutations on NF-KB affect inflammation
initial abnormality in NF-KB causes:
1) increased susceptibility to chronic intracelluar infections
2) disrupts mucosal homeostasis
what is the role of commensal bacteria in gut homeostasis
1) they directly suppress pathogens through induction of Treg cells and stimulation of IL-10
2) ferment nondigestible polysaccharides to produce SCFAs which have anti-inflammatory properties
how does bacteroids fragilis specifically help in GI tract homeostasis
1) induction of Treg cell populations in lamina propria
2) plays a role in maintenance of basal level of TH17 cells which are important for the integrity of the epithelial barrier
describe the mucosal firewall
1) epithelial cells produce antimicrobial peptides that limit exposure to commensal microbiota
2) tissue resident macrophages rapidly eliminate translocating commensals
3) commensal antigens can be captured by dendritic cells leading to Treg, Th17, and IgA producing B cells
how do aerobic and anaerobic bacteria trigger UC and CD
aerobic: triggers UC
anaerobic: triggers CD
describe the path from a naive CD4 T cell to the response in CD
naive CD4 T cell –> activated T cell –> IL-12 –> TH1 cell –> IFN-y –> Ag presentation and cellular immunity
naive CD4 T cell –> activated T cell –> IL-6, IL-23, TGF-B –> TH17 cell –> IL-17 –> tissue inflammation
describe the path from a naive CD4 T cell to the response in UC
naive CD4 T cell –> activated T cell –> IL-4 –> TH2 cell –> IL-4, IL-5, IL-13 –> humoral immunity and allergy
how do Treg cells suppress immune responses in the GI tract
they create tolerance to resident commensal bacteria and dietary antigens
–> IBD is a breakdown of this tolerance
why does the gut have so many Treg cells
limited expression of pro-inflammatory cytokines by APCs and excess of TGF-B results in differentiation of naive T cells into Treg cells which suppress TH1, TH2, and TH17 responses
how to Tregs suppress APCs
they do so directly through cell-to-cell interactions or indirectly via cytokines or chemokines
two immuno-therapeutic approaches in treatment of IBD
TNF blockers
leukocyte (integrin) adhesion inhibitors
when do you give leukocyte (integrin) adhesion inhibitors
when patients have failed previous therapy including TNF blockers
leukocyte (integrin) adhesion inhibitors increase pts risk for what
progressive multifocal leukoencephalopathy (PML)
