Immunology of IBD Flashcards
What is IBD and what conditions cause it?
IBD: chronic, relapsing idiopathic inflammation of the GI tract.
- 1. Ulcerative colitis
- 2. Crohn’s Disease
What is Ulcerative Colitis?
Ulcers in the innermost lining of the colon and rectum
What is Crohn’s disease?
Deep inflammation of the lining of the GI tract and may occur in any part of the GI tract, BUT rectum is spared in 40%
IBD is chronic, relapsing, idiopathic.
What does this cause?
- ↑ permeability of epithelial barrier in intestines because we cant form tight junctions => irreversible impairment of structure and function
What explains the ↑ incidence of IBD?
Hygiene hypothesis of allergic and AI disease.
What is the mechanism at which IBD occurs?
- NL commensal bacteria in the intestines causes inflammation
- Cross the mucosal barrier => contact immune cells => + innate and adaptive immune responses
- Cellular and humoral immune responses occu
- Cause self-sustained mucosal inflammation and dysbiosis
-
Increase permeability of the epithelial barrier of intestines bc tight junctions cant be formed.
- UC => disruption of function of barrier
- CD =>dysfunction of microbe sensing.
In other words, IBD is due to a persistant and inappropriate pertubation between _____________ and __________ of the NL microbiome, causing ________ and ________.
Immune system and commensal bacteria
Mucosal inflammation & dysbiosis
- Disruption of function of the barrier => ______.
- Dysfunction of microbe sensing => _____.
- Both have what?
- UC
- CD
- Both have changes in immunoregulation
In IBD, we see _______ of protective bacteria and _______ of inflammatory agents
- loss
- accumulation
Crohns Disease
- Signs and sx:
- GI involvement:
- Pathology:
- Diagnosis:
- Cancer risk:
- Management and tx:
- Lab tests:
- Abdominal pain, obstruction and fever
- Mouth => anus (rectum is spared)
- Abscesses, fistulas, strictures, granulomas, transmural inflammation
- Barium XR (string sign), Skip lesions, Endoscopy (Cobblestone appearance)
- Increases after 15 years
- Medical; surgery does NOT cure
- 80% of patients are ASCA (+)
Ulcerative Colitis
- Signs and sx:
- GI involvement:
- Pathology:
- Diagnosis:
- Cancer risk:
- Management and tx:
- Lab tests:
- Bloody diarrhea and urgency
- Colon and/or rectum
- Pseudopolyps, toxic megacolon, mucosal/submucosal inflammation
- Barium XR (Lead-pipe colon), ulcerations, edema, red mucosa in colon; (-) stool cultures, continous disease
- Increases after 10 years
- Medical and surgery CAN cure
- 50-70% are p-ANCA (+)
Define the role of environmental factors in IBD
Low concordance rate in identical twins (50% for CD & 10% for UC), suggesting environment is important and NEEDED to initiate or reactivate disaese.
Both a (+) ASCA test and (-) p-ANCA test tells us what?
96% predictive value for CD
97% specificity for CD
UC: less common in ____ and ____ populations
CD: very uncommon in ___ and ____ population
Asia and Africa
Role of genetic factors in IBD (2)
- Risk in increased in 1st degree relatives
- Greater concordance rate in monozygotic twins vs dizygotic
______________ are associated with a predisposition for developing IBD.
Single nucleotide polymorphisms (SNPs), NOT mutations
* SNPs => local variants with alleles that differ at a single base
What SNPs are associated with predisposition for developing Crohn’s Disease?
-
IBD-1 suspectibility locus on Chr16q12, which contains genes CARD15/NOD2.
- Defects in CARD15/NOD2 is found in 17-27% of cases.
CARD15/NOD2 encode for _________.
immuno-inflammatory components
What is CARD15/NOD2?
-
CARD15 is a intracellar PRR that recognizes MDP (a peptidoglycan in gram +/i bacteria) expressed in MO/DCs
- __triggers (+) of NF-kB
Homozygous individuals with SNPs of CARD15 => ____x increased risk of developing ____
20x risk of developing Crohns
A defect CARD15/NOD2 causes ________, which is a risk factor for IBD.
inhibits NF-kB pathway ( which causes inflammation)
Q: Hmm… why? Shouldnt it be protective if it reduces inflammation?
Why does defect in CARD15/NOD2 (=> inhibition of NF-kB), increase risk of IBD?
3 mechanisms
- Defective function of macrophages--> persistent intracellular infection of macrophages–> chronically stimulate T cells
- Defective epithelial-cell responses–> loss of barrier function–>increased exposure to mucosal microflora
- Defective “conditioning” of APCs–>inappropriate +APCs–>disruption ofbalance of effector and regulatory cells
Gut microbiome is made up of mainly _____________ or ____________
- Bacteroidetes (Bacteroides or Prevotella)
- Firmicutes (Clostridium and Lactobacillus)
IBD develops in what types of areas?
Areas with high concentration of bacteria (terminal ileum and colon)
How does the concentration of bacteria change, causing dybiosis in UC and CD?
-
UC
- ↑ proteobacteria and actinobacteria than NL.
- ↓ bacteroidetes
-
CD
- ↑ firmicutes and actinobacteria than NL.
- ↓ bacteriodetes
What prevents intestinal inflammation?
Surgical diversion of poop; reestablishment will cause inflammation to reoccur.
_______ and ______ help IBD
ABX and probiotics
What is detected in IBD?
Circulating Abs to fecal bacterial antigens.
- Lymphocytes will then react to fecal Ags.
What experiment is proof that the intestinal microbiota is important in IBD pathologies?
- Mice in germ-free environment–> no spontaneous colitis
- Give them commensal bacteria–> spontaneous colitis
- Give them microbiota from IBD donors–>worse colitis
What is the main predictor of the diversity of an infants microbiota.
Maternal IBD
What do we see in babies that are born from IBD women?
Altered bacterial composition of intestinal microbiota
What happens with we get GFM is inoculated with [IBD-mother and babies stool]?
Altered adaptive immune system of the intestines.
What has a MAJOR effect on gut microbiota?
- Diet
- Other environmental factors
- Hosts genetics
Dysbiosis leads to what?
- Dysregulation of the immune system
- Inflammation in genetically susceptible host
Dysbiosis may be caused by ________.
various environmental factors.
High fiber diet
- ↑ bacteroidetes, firmicutes, and actinobacteria
- ↓ proteobacteria
High protein diet
- ↑ bacteroidetes, firmicutes, and proteobacteria
High fat diet
↓ bacteriodetes, fimicutes and proteobacteria
High carb diet
- ↑ bacteriodes, firmicutes, actinobacteria
Infections by what orgnaisms contribute to the development of IBD?
*Not def. proven
- M. Paratuberculosis
- Paramyxovirus (persistant measles infection)
- Listeria monocytogenes
Ppl diagnosed with ________ have a ↑ risk of getting IBD.
Acute gastroenteritis (salmonella and campylobacter)
Have any microbial organisms been conclusively linked in development in IBD?
NO
Prevelance of IBD is inversely associated with ________.
Helminth colonization
*Important immunoregulatory role in intestinal flora.
Lots of good flora in the gut, greatest diversity in what parts?
Ileum, colon and cecum
What restricts the numbers and types of microorganisms in the gut?
- O2 levels
- Bile acid concentrations
- Intestinal motility
- Antimicrobial peptides
- pH of the lumen
_________________ bacteria–> proximal part of GI tract
Aerobic and facultative anaerobic bacteria
_________ bacteria –> distal small intestine (ileum) and colon
Obligate anaerobe bacteria
Colononization of the GI with beneficial bacteria induces the development of ________
GALT
During homeostasis, what is the role of the microbiota?
- Permeability of GI tract
- Intestinal immunity
- Maintains basal levels of Th17 and Th1 cell activity in the lamina propria
Beneficial bacteria in the microbiome do what?
- ↑ Treg cells
- ↑ IL-10
During homeostasis, what happens to pathobionts (any pathogenic organism that harms symobiosis)?
- Suppressed by beneficial commensal bacteria through ↑ Treg cells and IL10.
Commensal bacteria ferment ________, which makes ________.
Nondigestible polysaccharides in diet => make short chain fatty acids (SCFAs)
- SCFA have anti-inflammatory properties in MO, DCs, CD4+ T cells, and intestinal epithelial cells
- Induce production of Treg cells, which release IL10 => + effector Tcells and block inflammation
- Aso: Induce IgA and mucus secretion–>epithelial barrier integrity, prevent pathogen colonization
Commensal bacteria ferments nondigestable polysaccharides in our diet to make SCFA. What do SCFA do?
- SCFA have anti-inflammatory properties in MO, DCs, CD4+ T cells, and intestinal epithelial cells
- Induce production of Treg cells, which release IL10 => + effector Tcells and block inflammation
- Also: ↑ IgA and mucus secretion from goblet cells => ↑ integrity of epithelial barrier & prevent pathogen colonization
What happens when Segmented Filamentous Bacteria (SFB; Bacteriodes fragilis or Clostridium) colonize the intestines?
- ↑ Treg cells in lamina propria
- Maintain basal activation of Th17 cells–> keep epithelial barrier intact
_________ helps to form GALT and secondary forms of bile acids
Beneficial bacteria
How does the microbiota cause immune tolerance to commensal bacteria (bacteriodes)?
- MAMPS (microbe-associated molecular patterns)
- PSA (polysaccharide signaling)
- Indirectly by SCFA production
- Expression of epithelial IAL (intestinal alkaline phosphatase), which detoxifies luminal LPS
What makes up the mucosal firewall and what is its purpose?
Limits the passure and exposure of commensals to the GALT, which prevents unwanted activation and pathology.
- Epithelial barrier
- Mucus layer
- IgA
- DCs
- T cells
If commensals are translocated into the lamina propria, what happens?
Rapidily eliminated by tissue-resident MO.
What happens if commensal/commensal antigens are captured by DCs?
- DCs take from lamina propria => mLN
- Presentation causes the differentiation of specific [T-reg, Th17, IgA producing B cells)
- Commensal lymphocytes go to lamina propria and peyer’s patches
- In Peyers patches, T-reg cells can cause class-switching and make IgA AGAINST commensals.
There is a _____ relationship between host and commensal microbiota.
How?
Symbiotic
- Microbiota regulates inflammatory immune response to food antigens and microbes
- Commensal bacteria suppresses NF-kB pathway.
What is responsible for TOLERANCE of commensal bacteria?
DC and MO; do note sense their presence and secrete inflammatory cytokines
In IBD, what is lost?
TOLERANCE of MO and DC to the commensal bacteria => inflammation.
& chronic immuno-inflammatory response is triggered.
In the absence of commensal Bacteroides, what happens?
- Salmonella flagellin binds to TLR5 intestinal epithelial cells (IECs) =>
- + IKK =>
- and nuclear translocation of NF-kB =>
- + transciption of proinflammatory genes
In the presence of Bacteroides, what happens?
- S. enteritidis does not initiated pro-inflammatory response
- Peroxisome Proliferation Activated Receptor (PPAR)–> exports activated
NF-kB from nucleus
what are the 4 major phases in the development of IBD?
- Genetics + environemnt impairs the mucosal firewall/barrier.
- Impaired barrier allows commensal bacterial to enter pass through the barrier => enter lamina propria => + immune cells, which make cytokines
- RESOLUTION OR CHRONICITY: if a acute inflammation cannot be fixed by anti-inflammatory mechanisms => chronic intestinal inflamation
- Chronic inflammation => complications like [fibrosis, stenosis, abcess, fistula, cancer]
Chrohns diseases is characterized by the activation of what cells?
Th1 and Th17 cells
DC and MO =>
- [IL12] => + TH1 => IL-2, IFN-y and TNF => CD
- [IL6, IL23 and TGFB] => + TH17 => IL-17 => CD
- => CD gut-like inflammation
Ulcerative Colitis diseases is characterized by the activation of what cells?
TH2 and NK Cells
- IL4 => [TH2 & NK Cells*] => IL4, 5, 13* => UC
- NK cells only release IL13
- => MUCOSAL ULCERATION
IL-23 is produced by ____________ and it is closely related to IL-12
APC (MO and DCs)
LOF SNPs–> _______ CD
GOF SNPs–> _______ CD
LOF SNPS => protect from CD
GOD SNPS => predispose to DC
Loss of function SNPs–>_____ from UC
Gain of function SNPs–>______ UC
Protect
Predispose
IBD is believed to be the result of a BREAKDOWN OF TOLERANCE
to _____-
resident enteric bacteria (microbiota).
LOF of SNPS in _______ = predisopse to IBD
IL10
TGFB
GOF of SNPS in _______ = protect from IBD
IL10
TGFB
What SNPs can protect us from CD?
LOF SNPS in TNFa, IFN-y, IL1, 2, 6, 17, 22 = protect from CD
GOF would predisose up to them
What SNPs can protect us from UC?
LOF SNPs in IL4, 5, 13 = protect from UC
GOF in thsese would predispose us to UC
How are immune responses in the intestinal GI lumen tightly regulated?
-
T-reg cell actively supresses immune responses in the intestinal tract to prevent IBD
- We have tolerance for commensal bacteria and dietary antigens
- Immune system responds rapidly against pathogens.
How do T-reg actively supress immune responses in the GI tract => decrease IBD?
- T-reg cells directly suppresses APCs through cell-to-cell interactions and indirectly by releasing inhibitory cytokines
- Treg cells act directly on activated T cells via CTLA-4 and IL-2 deprivation
Overall prevent IBD
How do T-reg cells prevent the Crohns Disease?
T reg cells inhibit TH17 by releasing Retanoic acid.
_____ allow us to reach homesteostasis by releasing ______
Treg Cell
IL10 and TGF-B
Up to 10% of Tcells in GALT are _______
Treg cells
How are Treg cells activated?
What are the jobs of T-reg cells?
- APC present auto-Ag to T-reg cells => + T-reg cells => inhibit inflammation
- T-reg cells can act on inhibit APC directly or release immunosuppressive cytokines (IL4, 10, TGFB) => inhibit inflammation and IBD
- T-reg cells constitutively express inhibitory molecule (CTLA-4) and alpha subunit of CD25 ( IL-2R) => binds to IL2 and CTLA on +Tcells => inhibit effector T cells and prevent inflammation/IBD.
If we do not supress _______ => inflammation and IBD
effector T cells
Current treatments for IBD?
SE?
What is on the horizon?
-
TNF blockers => monoclonal AB that bind to TNF in moderate to severe UC/CD; administered IV/SubQ.
- SE: Worsening HF, reactivation of infections and malignancy.
- Fecal Microbiota Transplantation (FMT) => Give your poop to someone else (how generous)
