Immunology of IBD Flashcards
What is the hygiene hypothesis?
theory that not getting exposure to germs early causes incr risk of allergic and autoimmune dz –> increased incidence of IBD
*note: not due to genetic drift, all environmental caused
What can be altered in the epithelial barrier in IBD?
impaired formation of tight jxns –> increased permiability of barrier
bacteria can cross mucosal barrier –> induce innate and adaptive responses
What type of bacteria does the GI react to in IBD?
normal intestinal microbiota –> self sustained mucosal inflammation
Microbiome
combined genomes of all organisms that constitue the mcirobiota
mycobiota
subset of microbiota that includes fungi alone
Virome
collection of all viruses, including viruses integrated into the human genome, found in or on humans
dysbiosis
condition in which there is disequilibrium of the microbial communities that constitute the microbiota at a given body site
gnotobiotic
“known life”
describes animals in which the full complement of colonizing microbes is known
Which component of the pathogenesis of IBD (barrier or microbe sensing) is more prominent in UC and CD respectively?
UC = mainly disruption of barrier function
CD = dysfunction of microbe sensing more prominent
Which ANCA/ASCAs are positive in UC and crohns dz respectively?
CD: + ASCA
UC: + pANCA
microbial Ags act as ______ that stimulate immune responses
adjuvants
Where does IBD develop?
in areas of high bacterial concentration
(terminal ileum and colon)
What is the colonization environment of the colon and cecum like?
low pH
SCFAs abundant
most microbes
Where are lactobacilli found?
duodenum and jejunum
Where in the GI tract are ther more anti-microbial peptides (AMPs)?
farther up - duodenum
What type of bacteria grow in the ileum and colon?
What of note do they produce?
obligate anaerobes
produce SCFAs, actate, propionate, and butyrate
What are firmicutes?
normal gut microbiome
clostridium and lactobacillus most impt
What are bacteroidetes?
normal gut flora
bacteroides, prevotella xylanibacte
What does a healthy microbiota look like?
UC?
CD?
healthy: high bacteroidetes > firmicutes > others
UC: more proteobacteria, less normal ones
CD: more actinobacteria and firmicutes, wayy less bacteriodetes
When does spontaneous IBD develop in the lab?
not in germ-free environment
develops rapidly when these mice are colonized by commensals
get exacerbated disease if GFM colonized w/ microbiotas from IBD donors
What happens to babies born of IBD women?
babies have diff microbiota and altered adaptive immune system
High fiber diet effect on microbiota
increased bacteriodetes, firmicutes, and actinobacteria
less proteo
High protein diet effect of microbiota
increased bacteroidetes, firmicutes, and proteos
High fat diet effect on microbiota
decreased bacteroidetes, firmicutes, and proteo
High carb diet effect on microbiota
increased bacteroidetes, firmicutes, and actinobacteria
What infection has an inverse relationship to incidence of IBd?
helminth colonization
What microbe infections might be implicated in dev of IBD?
M paratuberculosis
persistent measles
listeria
salmonella and campylobacter
What is the role of genetic factors in IBD?
a bunch of different loci that encode for immuno-inflammatory components
certain SNPs associated more w/ IBD
(more CD genes than UC)
What is the role of IBD-1 in Crohns?
IBD-1 on chr 16 –> encodes CARD15/NOD2
MDP from bacteria (peptidoglycan) –> CARD15 on macrophages/DCs recognize –> triggers NF-KB activation
defects in CARD15 found in 17-27% of CD
homozygous for susceptible variant –> 20x more likely to develop CD
What are the possible mechanisms of CD caused by NOD2 mutations
defective function of macrophages –> chronic T cell response bc persistent intracelular infection
defective phages –> defective epithelial barrier
inappropriate activation of APCs and loss of balance
How do microbiota affect the intestinal mucosal barrier?
colonization –> GALT
microbiota maintain basal level of Th17 and th1 cells
beneficial bacteria increase Tregs and IL-10
good bacteria, Tregs and IL-10 inhibit bad bacteria
How are SCFAs produced and why are they good?
commensal bacterial ferment nondigestible polysaccharides –> SCFAs
have anti-inflammatory properties in macrophages, DCs, CD4+ Tcells and intestinal epithelial cells
induce IgA and mucus secretion
What receptor on Treg cells recognizes SCFAs?
GPR43
What are segmented filamentous bacteria and what do they do in gut immunity?
bacteroides, clostridium spp.
induce Treg cells in lamina propria
play role in basal activation of Th17 = integrity of barrier
What happens in the absence of commensial bacteroides?
What about in the presence?
absence: salmonella flagellin binds TLR5 –> activates IKK –> NF-kB activation and proinflammation
presence: proinflammatory response is attenuated, induction of PPAR exports activated NF-kB from the nucleus
What immune things predominate in crohn’s Dz?
UC?
Crohns: Th1 and Th17 –> IFNgamma, TNF, IL-17
UC: Th2 –> IL-4, 5, and 13
What cytokines drive Th1 an 17 response?
IL-12, IL-6, IL-23
How might Tregs be involved in IBD?
Tregs actively suppress immune response to commensals in normal ppl
might have breakdown in IBD
How do Tregs generally work?
activated by APC presenting auto-Ag
express CTLA-4 and IL-2R (CD25) –> can deprive T cells of IL-2 so there aren’t as many of them
directly suppress APCs via cell-cell contact
