IBD: mechanisms and new treatments Flashcards
What are the types of IBD?
UC and Crohns; Behcets; vasculitis
What is the important differential diagnosis in UC?
amoebic colitis
What is the important differential diagnosis in Crohn’s?
yersinia and TB
How many genetic loci have been identified to be associated with IBD?
163
How many of the genetic loci associated with IBD in general are shared between CD and UC?
110
What other diseases share the 110 IBD loci associated with both CD and UC?
common pathways in leprosy; mycobacterial susceptibility; lots of other immune mediated diseases
What are the important genes implicated in CD risk?
NOD2 and PTPN22
What is the important gene implicated in UC?
MHC- chromosome 6
What makes gut immology a difficult balance?
the gut is constantly bombarded with foreign antigens- some such as food and commensals we want no response- tolerance whereas we do want immune activation to pathogens
What is seen in the gut inflamamtory state?
exists in a state of controlled or physiological inflammation- lymphocytes in the lamina propria and epithelium is unique and are stimualted
What indicates that there is always some immune activation in the gut?
cytokine production levels are high even in physiological states- especially IFNy
What controls the state of inflamamtion in the gut?
immune suppression and effective barrier function
What in the gut protects against GI pathogens?
saliva; stomach acid and enzymes; bile; water and electryolye secretion/persitalsis; epithelial barrier; bacterial flora
What is the realtionships between the gut microbiota and the host?
symbiotic relationship; immunologically distinct
Give an exmaple of how the gut flora prevent colonisation by pathogens?
if give antibiotics and get rid of commensal bacteria, C.diff gains a foothold and produces toxins that cause mucosal injury and the leakge of nuetrophils and RBCs into the gut between injured eptihelial cells
What happens when there is breakdown of the epithelial barrier?
dominant N-cadherin negative chimeric mice had patchy disruption of E-cadherin expression leading to focal increases in intestinal permeability-chornic focal intestinal inflammation even with normal immune system –Hermiston and Gordon
What suggests that IBD is not solely a problem with the adaptive immune system as suggested by biopsy with massive lymphocyte infiltration?
NOD2 and CARD15 are innate mechanisms implicated
What are the different types of GALT?
tonsils; adenoids; peyers patches; appendix
What is the function of M cells?
interspersed between enterocytes and in close contact with lymphocytes and DCs; they take up antigen from the gut lumen by endocytosis and release to APCs
How are gut immune repsonses iniated?
M cells provide antigen to APCs which then migrate to mesenteric lymphoid tissue where they activate T cells who then move back to mucosa
How may intestinal epithelial cells be involved in the immune repsonse?
act as non-professional APCs; present antigens to and stimulate lymphocytes using the non-classical pathways of stimulation
Where are lamina propria lymphocytes found?
under the epithelium in the stroma
Where are intraepithelial lymphocytes found?
between intestinal epithelial cells
What type of T cell are intraepithelial lymphocytes?
many are TCRyd
What do the intraepithelial lymhocytes produce?
IL-2 and IFNY
What type of lymphocyte are the lamina propria lymphocytes mainly?
CD4- Th1; Th2 and Th3/Tr1- regulatory
What suggests that Crohns disease may be a Th1 mediated disease?
granulomata are seen-cellular immunity; CD patietns have increased mucosal levels of IL-6; IL8- IL-12; IFNy and TNFa; may regress in AIDs; antibodies that block Th1 cytokiens improve CD
Why may UC be a Th2 disease?
increased levels of IgG1; elevated IL-5 BUT lots of Th1 cytokiens as well
What cytokine stimulates Th2 differentiation?
IL-4
What are the transcription factors of Th2 cells?
GATA-3; STAT-6
What stimulates Th1 differentiation?
IL-12
What stimualtes Th17 differenation?
TGF-b; IL-23; IL-6
What are the transcription factors for Th1 cells?
T-bet; STAT4
What is the trascnription factor for Th17?
STAT-3
What suggests that Crohns and UC are Th17 mediated diseases?
mouse model IL-23 is essential for inflammation; both Th1 and Th17 cells can be found in CD- Annunziato; IL-23 if necessary for chronic inflammation in the IL-10 KO but IL-12 isn’t -Yen; IL-23R polymorphisms are associated iwth CD and UC- Duerr
What is the relative risk of homozygot for mutations in NOD2 for ileal disease?
30.3 -Ahmad
What is the function of NOD2?
intracellular receptor for muramyl dipeptide of bacterial cell wall
What domain does muramyl dipeptide of bacterial cell wall bind to on NOD2?
LRR
What happens when the LRR of NOD2 is activated?
CARD15 is activated
What are hte possible reasons for why NOD2 increases CD risk?
defective NOD2 resutls in defective Caspase 9 mediated apoptosis induced by CARD15; or in Paneth cells results in redued antimicrobial peptides and uncontrolled microbiota
What are the genes associated with Crohns disease?
MHC- esp. MHC-II; CARD15- Ahmad; IL-23R polymorphisms- Duerr; TCR polymorphisms;
How may CARD15 interact with Th17 cells in CD?
MDP stimualtes IL-17 production by DCs via CARD15 which is lost in CARD15 deficiency- not sure what the digniscance
What is the first line therapy for mild to mod UC?
aminosalicylates
When is nutritional therapy in Corhns typically used?
in children- to avoid harmful immunsuppression
Give an example of an immunomodulator in IBD?
azathioprine
Why are biologics needed in IBD?
steroids have a lot of SEs, don’t result in mucosal healing; immunosuppressives have SEs; slow onset
What are the possible biologic targets in IBD?
prevent the initial triggering of inflammation by gut microbiota; prevent migration and adhesion of inflam cells; prevent activation of T cells; upregulation of immunoregulatory cells/ cytokines
Why does vedolizumab- ant-integrin take 10-12 weeks to work?
prevents further migration; length of time reflects life span of cells already in the gut
What are hte concerns about anti-TNF treatment?
malignancy- reduced immune surveillance; bad in heart failure?
What is the mechanism of ustekinemab?
targets the common subunity of IL-12 and IL-23
Whati s the efficacy of infilximab in IBD?
remarkable mucosal healing after 6 weeks
What is the best marker of clinical benefit in IBD?
mucosal healing
What is the common subunit of IL12 and IL23?
p40
What is ustekinemab currently licensed for?
psoriasis
When is ustekinemab used?
anti-TNF resistant CD - increased clinical remission and clinical repsonse
What does vedolizumab target?
a4b7 integrin and inhibits lymphocyte tracking to the gut
What is the function of tofacitinib?
blocks phosphorylation of STAT by Jak and downstream activation
What are hte different biologics being trailled in IBD?
anti-TNF: inflixumab; anti-integrins- vedolizumab; anti-12/23- ustekinemab; tofacitinib
What has been the effect of tofacitinib ?
improved clinical response; remission; endoscopic response-Sandborn
What is hte function of SMAD7?
downregulated the phosphorylation of SMAD3, which mediates TGFb related immune regulation
What was the in vitro efficacy of SMAD7 inhibitor?
reduced SMAD7 and increased phosphorylation of SMAD3 restoring TGFb signalling and reducing expression of IL1 and TNFa
What does the effect of sekukinumab on CD suggest about the role IL-17 in the gut?
anti-IL-17 made CD worse usggesting some underlying IL-17 is needed for gut integrity?
What are the mechanisms of CD and UC?
genetic susceptibility and environmental triggers which cause unregualted activation of hte immune response and inflammation with both the innate and adaptive immune reponses implicated
What is inflammatory bowel disease?
chronic inflammatory state of the GI tract that is classified in 2 main clinical phenomena- CD and UC
What suggests taht Th17 is implicated in IBD?
STAT3 and IL-17 are increased in inflamed colon tissue; massive infiltration of th17 cells in their mucosa; GWAS studies implicate Th17 pathways
What is the effect of IL-18 in Crohns disease?
increased in the mucosa of CD patietns and increases the Th1 response whilst reducing IL-10 release from T cells
What is the effect of IL-33 in UC?
stimualtes mucus secretion to protect the epithelium and upregulates IL-5 and IL-13 as part of hte Th2 repsonse- upregulated in UC
How does TNFa relate to IBD?
clinical severity is correlated with serum TNFa levels; increases expressiong of IL-1b; IL6 and IL-33
What relates Th17, gut microbiota and IBD?
biopsy samples have shown that changes in the composition of hte microbiota may be associated with IBD pathogenesis; the process of Th17 cells, implicated in IBD progression is impacted by microbiota- segmented filamentous bacteria induce Th17 cells; and Th17 differentation is decreased in germ free system and in antibortiocs
How can IL-17 be used as a marker of clinical severity?
expression in PMBCs of IL-17 corrrelates with UC severity
What suggests that importance of Tregs in IBD?
mutations in CD25 and IL-10 lead to increased susceptibility to IBD; ablation of Treg cells increases colitis expression
How could Tregs be used therapeutically?
in a Rag1 KO mouse model, transfer of Tregs decreased intestinal inflammation
What are new avenues of research in IBD?
specific mixtures of macronutrients and emulsifiers within the diet affect intestinal permeability, gut microbiota desnity and predispose to intestinal inflam; allogeneic expadned adipose-derived stem cells result in long-term clinical and radiological healing in treatment-refractory perianal Crohns
