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GI II Exam 1 > Immunology of IBD > Flashcards

Immunology of IBD Flashcards

1
Q

What is IBD and what conditions cause it?

A

IBD: chronic, relapsing idiopathic inflammation of the GI tract.

  • 1. Ulcerative colitis
  • 2. Crohn’s Disease
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2
Q

What is Ulcerative Colitis?

A

Ulcers in the innermost lining of the colon and rectum

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3
Q

What is Crohn’s disease?

A

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%

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4
Q

IBD is chronic, relapsing, idiopathic.

What does this cause?

A
  • ↑ permeability of epithelial barrier in intestines because we cant form tight junctions => irreversible impairment of structure and function
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5
Q

What explains the ↑ incidence of IBD?

A

Hygiene hypothesis of allergic and AI disease.

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6
Q

What is the mechanism at which IBD occurs?

A
  1. NL commensal bacteria in the intestines causes inflammation
  2. Cross the mucosal barrier => contact immune cells => + innate and adaptive immune responses
    • Cellular and humoral immune responses occu
  3. Cause self-sustained mucosal inflammation and dysbiosis
  4. Increase permeability of the epithelial barrier of intestines bc tight junctions cant be formed.
    1. UC => disruption of function of barrier
    2. CD =>dysfunction of microbe sensing.
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7
Q

In other words, IBD is due to a persistant and inappropriate pertubation between _____________ and __________ of the NL microbiome, causing ________ and ________.

A

Immune system and commensal bacteria

Mucosal inflammation & dysbiosis

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8
Q
  • Disruption of function of the barrier => ______.
  • Dysfunction of microbe sensing => _____.
  • Both have what?
A
  • UC
  • CD
  • Both have changes in immunoregulation
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9
Q

In IBD, we see _______ of protective bacteria and _______ of inflammatory agents

A
  • loss
  • accumulation
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10
Q

Crohns Disease

  1. Signs and sx:
  2. GI involvement:
  3. Pathology:
  4. Diagnosis:
  5. Cancer risk:
  6. Management and tx:
  7. Lab tests:
A
  1. Abdominal pain, obstruction and fever
  2. Mouth => anus (rectum is spared)
  3. Abscesses, fistulas, strictures, granulomas, transmural inflammation
  4. Barium XR (string sign), Skip lesions, Endoscopy (Cobblestone appearance)
  5. Increases after 15 years
  6. Medical; surgery does NOT cure
  7. 80% of patients are ASCA (+)
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11
Q

Ulcerative Colitis

  1. Signs and sx:
  2. GI involvement:
  3. Pathology:
  4. Diagnosis:
  5. Cancer risk:
  6. Management and tx:
  7. Lab tests:
A
  1. Bloody diarrhea and urgency
  2. Colon and/or rectum
  3. Pseudopolyps, toxic megacolon, mucosal/submucosal inflammation
  4. Barium XR (Lead-pipe colon), ulcerations, edema, red mucosa in colon; (-) stool cultures, continous disease
  5. Increases after 10 years
  6. Medical and surgery CAN cure
  7. 50-70% are p-ANCA (+)
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12
Q

Define the role of environmental factors in IBD

A

Low concordance rate in identical twins (50% for CD & 10% for UC), suggesting environment is important and NEEDED to initiate or reactivate disaese.

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13
Q

Both a (+) ASCA test and (-) p-ANCA test tells us what?

A

96% predictive value for CD

97% specificity for CD

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14
Q

UC: less common in ____ and ____ populations

CD: very uncommon in ___ and ____ population

A

Asia and Africa

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15
Q

Role of genetic factors in IBD (2)

A
    1. Risk in increased in 1st degree relatives
    1. Greater concordance rate in monozygotic twins vs dizygotic
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16
Q

______________ are associated with a predisposition for developing IBD.

A

Single nucleotide polymorphisms (SNPs), NOT mutations

* SNPs => local variants with alleles that differ at a single base

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17
Q

What SNPs are associated with predisposition for developing Crohn’s Disease?

A
  • IBD-1 suspectibility locus on Chr16q12, which contains genes CARD15/NOD2.
    • Defects in CARD15/NOD2 is found in 17-27% of cases.
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18
Q

CARD15/NOD2 encode for _________.

A

immuno-inflammatory components

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19
Q

What is CARD15/NOD2?

A
  • CARD15 is a intracellar PRR that recognizes MDP (a peptidoglycan in gram +/i bacteria) expressed in MO/DCs
    • _​_triggers (+) of NF-kB
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20
Q

Homozygous individuals with SNPs of CARD15 => ____x increased risk of developing ____

A

20x risk of developing Crohns

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21
Q

A defect CARD15/NOD2 causes ________, which is a risk factor for IBD.

A

inhibits NF-kB pathway ( which causes inflammation)

Q: Hmm… why? Shouldnt it be protective if it reduces inflammation?

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22
Q

Why does defect in CARD15/NOD2 (=> inhibition of NF-kB), increase risk of IBD?

A

3 mechanisms

  1. Defective function of macrophages--> persistent intracellular infection of macrophages–> chronically stimulate T cells
  2. Defective epithelial-cell responses–> loss of barrier function–>increased exposure to mucosal microflora
  3. Defective “conditioning” of APCs–>inappropriate +APCs–>disruption ofbalance of effector and regulatory cells
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23
Q

Gut microbiome is made up of mainly _____________ or ____________

A
  • Bacteroidetes (Bacteroides or Prevotella)
  • Firmicutes (Clostridium and Lactobacillus)
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24
Q

IBD develops in what types of areas?

A

Areas with high concentration of bacteria (terminal ileum and colon)

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25
Q

How does the concentration of bacteria change, causing dybiosis in UC and CD?

A
  • UC
    • ↑ proteobacteria and actinobacteria than NL.
    • ↓ bacteroidetes
  • CD
    • ↑ firmicutes and actinobacteria than NL.
    • ↓ bacteriodetes
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26
Q

What prevents intestinal inflammation?

A

Surgical diversion of poop; reestablishment will cause inflammation to reoccur.

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27
Q

_______ and ______ help IBD

A

ABX and probiotics

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28
Q

What is detected in IBD?

A

Circulating Abs to fecal bacterial antigens.

  • Lymphocytes will then react to fecal Ags.
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29
Q

What experiment is proof that the intestinal microbiota is important in IBD pathologies?

A
  • Mice in germ-free environment–> no spontaneous colitis
  • Give them commensal bacteria–> spontaneous colitis
  • Give them microbiota from IBD donors–>worse colitis
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30
Q

What is the main predictor of the diversity of an infants microbiota.

A

Maternal IBD

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31
Q

What do we see in babies that are born from IBD women?

A

Altered bacterial composition of intestinal microbiota

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32
Q

What happens with we get GFM is inoculated with [IBD-mother and babies stool]?

A

Altered adaptive immune system of the intestines.

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33
Q

What has a MAJOR effect on gut microbiota?

A
  • Diet
  • Other environmental factors
  • Hosts genetics
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34
Q

Dysbiosis leads to what?

A
  1. Dysregulation of the immune system
  2. Inflammation in genetically susceptible host
35
Q

Dysbiosis may be caused by ________.

A

various environmental factors.

36
Q

High fiber diet

A
  • ↑ bacteroidetes, firmicutes, and actinobacteria
  • ↓ proteobacteria
37
Q

High protein diet

A
  • ↑ bacteroidetes, firmicutes, and proteobacteria
38
Q

High fat diet

A

↓ bacteriodetes, fimicutes and proteobacteria

39
Q

High carb diet

A
  • ↑ bacteriodes, firmicutes, actinobacteria
40
Q

Infections by what orgnaisms contribute to the development of IBD?

*Not def. proven

A
  1. M. Paratuberculosis
  2. Paramyxovirus (persistant measles infection)
  3. Listeria monocytogenes
41
Q

Ppl diagnosed with ________ have a ↑ risk of getting IBD.

A

Acute gastroenteritis (salmonella and campylobacter)

42
Q

Have any microbial organisms been conclusively linked in development in IBD?

A

NO

43
Q

Prevelance of IBD is inversely associated with ________.

A

Helminth colonization

*Important immunoregulatory role in intestinal flora.

44
Q

Lots of good flora in the gut, greatest diversity in what parts?

A

Ileum, colon and cecum

45
Q

What restricts the numbers and types of microorganisms in the gut?

A
  1. O2 levels
  2. Bile acid concentrations
  3. Intestinal motility
  4. Antimicrobial peptides
  5. pH of the lumen
46
Q

_________________ bacteria–> proximal part of GI tract

A

Aerobic and facultative anaerobic bacteria

47
Q

_________ bacteria –> distal small intestine (ileum) and colon

A

Obligate anaerobe bacteria

48
Q

Colononization of the GI with beneficial bacteria induces the development of ________

A

GALT

49
Q

During homeostasis, what is the role of the microbiota?

A
    1. Permeability of GI tract
    1. Intestinal immunity
    1. Maintains basal levels of Th17 and Th1 cell activity in the lamina propria
50
Q

Beneficial bacteria in the microbiome do what?

A
  1. ↑ Treg cells
  2. ↑ IL-10
51
Q

During homeostasis, what happens to pathobionts (any pathogenic organism that harms symobiosis)?

A
  • Suppressed by beneficial commensal bacteria through ↑ Treg cells and IL10.
52
Q

Commensal bacteria ferment ________, which makes ________.

A

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
53
Q

Commensal bacteria ferments nondigestable polysaccharides in our diet to make SCFA. What do SCFA do?

A
  1. 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
  2. Also: ↑ IgA and mucus secretion from goblet cells => ↑ integrity of epithelial barrier & prevent pathogen colonization
54
Q

What happens when Segmented Filamentous Bacteria (SFB; Bacteriodes fragilis or Clostridium) colonize the intestines?

A
  1. ↑ Treg cells in lamina propria
  2. Maintain basal activation of Th17 cells–> keep epithelial barrier intact
55
Q

_________ helps to form GALT and secondary forms of bile acids

A

Beneficial bacteria

56
Q

How does the microbiota cause immune tolerance to commensal bacteria (bacteriodes)?

A
  1. MAMPS (microbe-associated molecular patterns)
  2. PSA (polysaccharide signaling)
  3. Indirectly by SCFA production
  4. Expression of epithelial IAL (intestinal alkaline phosphatase), which detoxifies luminal LPS
57
Q

What makes up the mucosal firewall and what is its purpose?

A

Limits the passure and exposure of commensals to the GALT, which prevents unwanted activation and pathology.

  1. Epithelial barrier
  2. Mucus layer
  3. IgA
  4. DCs
  5. T cells
58
Q

If commensals are translocated into the lamina propria, what happens?

A

Rapidily eliminated by tissue-resident MO.

59
Q

What happens if commensal/commensal antigens are captured by DCs?

A
  1. DCs take from lamina propria => mLN
  2. Presentation causes the differentiation of specific [T-reg, Th17, IgA producing B cells)
  3. Commensal lymphocytes go to lamina propria and peyer’s patches
    1. In Peyers patches, T-reg cells can cause class-switching and make IgA AGAINST commensals.
60
Q

There is a _____ relationship between host and commensal microbiota.

How?

A

Symbiotic

  • Microbiota regulates inflammatory immune response to food antigens and microbes
  • Commensal bacteria suppresses NF-kB pathway.
61
Q

What is responsible for TOLERANCE of commensal bacteria?

A

DC and MO; do note sense their presence and secrete inflammatory cytokines

62
Q

In IBD, what is lost?

A

TOLERANCE of MO and DC to the commensal bacteria => inflammation.

& chronic immuno-inflammatory response is triggered.

63
Q

In the absence of commensal Bacteroides, what happens?

A
  1. Salmonella flagellin binds to TLR5 intestinal epithelial cells (IECs) =>
  2. + IKK =>
    • and nuclear translocation of NF-kB =>
  4. + transciption of proinflammatory genes
64
Q

In the presence of Bacteroides, what happens?

A
  1. S. enteritidis does not initiated pro-inflammatory response
  2. Peroxisome Proliferation Activated Receptor (PPAR)–> exports activated

NF-kB from nucleus

65
Q

what are the 4 major phases in the development of IBD?

A
  1. Genetics + environemnt impairs the mucosal firewall/barrier.
  2. Impaired barrier allows commensal bacterial to enter pass through the barrier => enter lamina propria => + immune cells, which make cytokines
  3. RESOLUTION OR CHRONICITY: if a acute inflammation cannot be fixed by anti-inflammatory mechanisms => chronic intestinal inflamation
  4. Chronic inflammation => complications like [fibrosis, stenosis, abcess, fistula, cancer]
66
Q

Chrohns diseases is characterized by the activation of what cells?

A

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
67
Q

Ulcerative Colitis diseases is characterized by the activation of what cells?

A

TH2 and NK Cells

  • IL4 => [TH2 & NK Cells*] => IL4, 5, 13* => UC
    • NK cells only release IL13
  • => MUCOSAL ULCERATION
68
Q

IL-23 is produced by ____________ and it is closely related to IL-12

A

APC (MO and DCs)

69
Q

LOF SNPs–> _______ CD

GOF SNPs–> _______ CD

A

LOF SNPS => protect from CD

GOD SNPS => predispose to DC

70
Q

Loss of function SNPs–>_____ from UC

Gain of function SNPs–>______ UC

A

Protect

Predispose

71
Q

IBD is believed to be the result of a BREAKDOWN OF TOLERANCE

to _____-

A

resident enteric bacteria (microbiota).

72
Q

LOF of SNPS in _______ = predisopse to IBD

A

IL10

TGFB

73
Q

GOF of SNPS in _______ = protect from IBD

A

IL10

TGFB

74
Q

What SNPs can protect us from CD?

A

LOF SNPS in TNFa, IFN-y, IL1, 2, 6, 17, 22 = protect from CD

GOF would predisose up to them

75
Q

What SNPs can protect us from UC?

A

LOF SNPs in IL4, 5, 13 = protect from UC

GOF in thsese would predispose us to UC

76
Q

How are immune responses in the intestinal GI lumen tightly regulated?

A
  • 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.
77
Q

How do T-reg actively supress immune responses in the GI tract => decrease IBD?

A
  1. T-reg cells directly suppresses APCs through cell-to-cell interactions and indirectly by releasing inhibitory cytokines
  2. Treg cells act directly on activated T cells via CTLA-4 and IL-2 deprivation

Overall prevent IBD

78
Q

How do T-reg cells prevent the Crohns Disease?

A

T reg cells inhibit TH17 by releasing Retanoic acid.

79
Q

_____ allow us to reach homesteostasis by releasing ______

A

Treg Cell

IL10 and TGF-B

80
Q

Up to 10% of Tcells in GALT are _______

A

Treg cells

81
Q

How are Treg cells activated?

What are the jobs of T-reg cells?

A
  • 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.
82
Q

If we do not supress _______ => inflammation and IBD

A

effector T cells

83
Q

Current treatments for IBD?

SE?

What is on the horizon?

A
  • 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)

GI II Exam 1 (19 decks)

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