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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
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
26
What prevents **intestinal inflammation?**
**Surgical diversion of poop**; reestablishment will cause inflammation to reoccur.
27
\_\_\_\_\_\_\_ and ______ help **IBD**
**ABX** and **probiotics**
28
What is detected in **IBD**?
**Circulating Abs** to fecal bacterial antigens. * Lymphocytes will then react to fecal Ags.
29
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
30
What is the main predictor of the **diversity** of an infants microbiota.
**Maternal IBD**
31
What do we see in babies that are born from IBD women?
**Altered bacterial composition** of intestinal microbiota
32
What happens with we get GFM is inoculated with [IBD-mother and babies stool]?
**Altered adaptive immune system** of the intestines.
33
What has a MAJOR effect on gut microbiota?
* Diet * Other environmental factors * Hosts genetics
34
**Dysbiosis** leads to what?
1. **Dysregulation** of the immune system 2. **Inflammation** in genetically susceptible host
35
Dysbiosis may be caused by \_\_\_\_\_\_\_\_.
**various environmental factors.**
36
**High fiber diet**
* ↑ bacteroidetes, firmicutes, and actinobacteria * ↓ proteobacteria
37
**High protein diet**
* ↑ bacteroidetes, firmicutes, and proteobacteria
38
**_High fat diet_**
↓ bacteriodetes, fimicutes and proteobacteria
39
**_High carb diet_**
* **↑ bacteriodes, firmicutes, actinobacteria**
40
Infections by what orgnaisms contribute to the development of **IBD?** ## Footnote **\*Not def. proven**
1. **M. Paratuberculosis** 2. **Paramyxovirus** (persistant measles infection) 3. **Listeria monocytogenes**
41
Ppl diagnosed with ________ have a ↑ risk of getting IBD.
**Acute gastroenteritis** (salmonella and campylobacter)
42
Have any microbial organisms been conclusively linked in development in IBD?
**NO**
43
Prevelance of IBD is inversely associated with \_\_\_\_\_\_\_\_.
**Helminth colonization** \*Important immunoregulatory role in intestinal flora.
44
Lots of good flora in the gut, greatest diversity in what parts?
**Ileum**, **colon** and **cecum**
45
What restricts the numbers and types of microorganisms in the gut?
1. O2 levels 2. Bile acid concentrations 3. Intestinal motility 4. Antimicrobial peptides 5. pH of the lumen
46
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ bacteria--\> **proximal part of GI tract**
**Aerobic** and **facultative anaerobic bacteria**
47
\_\_\_\_\_\_\_\_\_ bacteria --\> distal small intestine (ileum) and colon
**Obligate anaerobe** bacteria
48
Colononization of the GI with beneficial bacteria induces the development of \_\_\_\_\_\_\_\_
**GALT**
49
During **homeostasis**, what is the role of the microbiota?
* 1. **Permeability** of GI tract * 2. **Intestinal immunity** * 3. Maintains **basal levels of Th17** and **Th1** cell activity in the lamina propria
50
**Beneficial bacteria** in the microbiome do what?
1. **↑ Treg cells** 2. **↑ IL-10**
51
During homeostasis, what happens to **pathobionts** (any pathogenic organism that harms symobiosis)?
* **Suppressed** by beneficial commensal bacteria through **↑ Treg cells** and **IL10**.
52
**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
53
**Commensal bacteria** ferments nondigestable polysaccharides in our diet to make SCFA. What do SCFA do?
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
What happens when **Segmented Filamentous Bacteria** (SFB; Bacteriodes fragilis or Clostridium) colonize the intestines?
1. **↑ Treg cells** in lamina propria 2. Maintain basal activation of **Th17 cells**--\> keep epithelial barrier intact
55
\_\_\_\_\_\_\_\_\_ helps to form GALT and secondary forms of bile acids
**Beneficial bacteria**
56
How does the microbiota cause immune tolerance to **commensal bacteria (bacteriodes)?**
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
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. 1. Epithelial barrier 2. Mucus layer 3. IgA 4. DCs 5. T cells
58
If **commensals** are translocated into the lamina propria, what happens?
**Rapidily eliminated** by tissue-resident MO.
59
What happens if commensal/commensal antigens are **captured** by DCs?
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
There is a _____ relationship between **host** and **commensal microbiota.** ## Footnote **How?**
**Symbiotic** * **Microbiota** regulates inflammatory immune response to food antigens and microbes * **Commensal bacteria** suppresses NF-kB pathway.
61
What is responsible for **TOLERANCE** of commensal bacteria?
**DC** and **MO**; do note sense their presence and secrete inflammatory cytokines
62
In **IBD**, what is lost?
**TOLERANCE** of MO and DC to the commensal bacteria =\> inflammation. & chronic immuno-inflammatory response is triggered.
63
In the **absence** of commensal Bacteroides, what happens?
1. **Salmonella** flagellin binds to TLR5 intestinal epithelial cells (IECs) =\> 2. **+ IKK** =\> 3. + and nuclear translocation of **NF-kB** =\> 4. **+** transciption of **proinflammatory genes**
64
In the presence of **Bacteroides**, what happens?
1. S. enteritidis **does not** initiated pro-inflammatory response 2. **Peroxisome Proliferation Activated Receptor (PPAR)**--\> exports activated NF-kB from nucleus
65
what are the 4 major phases in the development of IBD?
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
**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**
67
**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**
68
**IL-23** is produced by ____________ and it is closely related to **IL-12**
**APC (MO and DCs)**
69
LOF SNPs--\> _______ CD GOF SNPs--\> _______ CD
LOF SNPS =\> protect from CD GOD SNPS =\> predispose to DC
70
Loss of function SNPs--\>\_\_\_\_\_ from UC Gain of function SNPs--\>\_\_\_\_\_\_ UC
Protect Predispose
71
IBD is believed to be the result of a BREAKDOWN OF TOLERANCE to \_\_\_\_\_-
**resident enteric bacteria (microbiota).**
72
**LOF** of **SNPS** in _______ = predisopse to **IBD**
**IL10** **TGFB**
73
**GOF** of **SNPS** in _______ = protect from **IBD**
IL10 TGFB
74
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
75
What SNPs can **protect** us from **UC**?
**LOF SNPs** in **IL4, 5, 13** = **protect** from **UC** GOF in thsese would predispose us to UC
76
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.
77
How do T-reg actively supress immune responses in the GI tract =\> decrease IBD?
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
How do T-reg cells prevent the Crohns Disease?
T reg cells inhibit TH17 by releasing **Retanoic acid.**
79
\_\_\_\_\_ allow us to reach **homesteostasis** by releasing \_\_\_\_\_\_
**Treg Cell** **IL10** and **TGF-B**
80
Up to 10% of Tcells in **GALT** are \_\_\_\_\_\_\_
Treg cells
81
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.
82
If we do not supress _______ =\> inflammation and IBD
effector T cells
83
Current treatments for IBD? SE? What is on the horizon?
* **TNF blocker**s =\> 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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