Immunologic Mechanisms Of IBD

Question 1

What is IBD?

Answer 1

A term used to describe two disorders that involve chronic inflammation of the GI tract
Includes ulcerative colitis and Crohn’s disease

Question 2

What is ulcerative colitis characterized by?

Answer 2

Chronic inflammation and ulcers in the innermost lining of the colon and/or rectum

Question 3

What is Crohn’s disease characterized by?

Answer 3

Inflammation of the lining of the GI tract which often spreads deep into affected tissues and may occur in any part of the GI tract
Rectum is usually spared

Question 4

IBD is associated with an increased permeability of what?

Answer 4

The epithelial barrier caused by impaired formation of tight junctions

Question 5

IBD develops as a result of what?

Answer 5

A persistent inappropriate perturbation of highly regulated interaction between the immune ssytem and commensal bacteria of the normal micro biome resulting in dysbiosis and mucosal inflammation

Question 6

The aberrant responses in IBD are to a large degree genetically determined and may include what?

Answer 6

Disruption of the barrier function (mainly in UC)
Dysfunction of microbe sensing (mainly in CD)
Changes in immunoregulation of innate and adaptive immune responses (both)

Question 7

A low concordance rate in identical twins suggests what?

Answer 7

Imporatnace of environmental factors

50% for CD and 10% for UC

Question 8

What are the functional roles of gut microbiota?

Answer 8

Protection of the host against invasion or colonization by pathogens
Facilitation of nutrient digestion and absorption in humans
Providing the immunological surveillance signals at the gut mucosa lumen interface

Question 9

IBD develops in areas with high concentrations of what?

Answer 9

Bacteria (terminal ileum and the colon)

Question 10

Surgical diversion of the fecal stream prevents what?

Answer 10

Intestinal inflammation

Reestablishment of the flow leads to recurrence of IBD

Question 11

What has beneficial effects on IBD?

Answer 11

Use of abx and probiotics

Question 12

Circulating Abs against what are detected in IBD?

Answer 12

Fecal bacterial antigens

Question 13

What is the gut micro biome primarily comprised of?

Answer 13

The phyla bacteroidetes (largely bacteroides or Prevotella species) or Firmicutes (largely clostridium and Lactobacillus species)

Question 14

Which factors have a major effect on gut microbiota?

Answer 14

Diet and other environmental factors + host genetics

Question 15

What maintains gut homeostasis?

Answer 15

Symbiosis (a balanced microbial composition)

Question 16

What does dysbiosis lead to?

Answer 16

Dysregulation of the immune system and to inflammation in a genetically susceptible host
May be caused by various environmental factors

Question 17

True or false: no specific microbial organisms have been conclusively linked to the development of IBD

Answer 17

True

Question 18

Which disease may play a role in the etiology of IBD?

Answer 18

Gastroenteritis (such as salmonella and campylobacter)

Individuals diagnosed with an acute gastroenteritis have been shown to have an increased risk of developing IBD

Question 19

The prevalence of IBD is inversely associated with the prevalence of what?

Answer 19

Helminth colonization

Helminths are thought to play an important immunoregulatory role with the intestinal flora

Question 20

Describe the prevalence of UC and CD in Asian and African populations

Answer 20

UC is 10 fold less common in Asian and African populations

CD seems very uncommon in Asia and Africa

Question 21

If a first degree relative has IBD are the changes increased or decreased in an individual with that relative?

Answer 21

Increased

Question 22

There is a greater concordance rate in which types of twins?

Answer 22

Monozygotic vs dizygotic twins

Question 23

Describe the IBD1 gene

Answer 23

Found on chromosome 16

Contains CARD15/NOD2 genes

Question 24

Describe CARD15?

Answer 24

Primarily expressed in macrophages and DCs
It’s an intracellular PPR
Recognizes MDP (a peptidoglycan constituent of both gram + and - bacteria)
Triggers activation of NF-kB

Question 25

Individuals homozygous for susceptible variant (SNPs) of CARD15 have more than a 20 fold increased risk of developing what?

Answer 25

Crohn’s disease

Question 26

What are the 3 possible mechanisms that CARD15/NOD2 mutations can lead to Corin’s disease?

Answer 26

Defective function of macrophages
Defective epithelial cell responses
Defective conditioning of APCs

Question 27

Commensal bacteria ferment non-digestible polysaccharides ingested in the deity to produce what?

Answer 27

SCFAs which have anti inflammatory properties in macrophages, DCs, CD4 T cells, and intestinal epithelial cells

Question 28

The microbiota induces host immune tolerance to commensal bacteria directly via what?

Answer 28

A microbe associated molecular pattern (MAMP)
Polysaccharide (PSA) signaling
Indirectly through the production of SCFAs
Potentially through expression of epithelial intestinal alkaline phosphatase (IAP) which detoxifies luminal LPS

Question 29

What comprises the mucosal firewall of the GI tract?

Answer 29

The combination of the epithelial barrier, mucus layer, IgA, DCs and T cells

Question 30

What is the function of the mucosal firewall?

Answer 30

Limits the passage and exposure of commensal pts to the GALT preventing untoward activation and pathology

Question 31

Which pathway do commensal microbiota suppress?

Answer 31

NF-kB

Question 32

Describe immune tolerance in the GI tract

Answer 32

The tolerance is related to DCs and macrophages which do not sense the presence of microflora and thus dont secrete pro-inflammatory cytokines
In IBD the tolerance is lost

Question 33

What happens in the absence of commensal bacteroides?

Answer 33

Salmonella flagellin binds to TLR5 intestinal epithelial cells (IECs)
Activates IkB kinase (IKK) —> activation and nuclear translocation NF-kB

Question 34

What happens in the presence of commensal bacteroides?

Answer 34

Proinflammatory response caused by S enteritidis is attenuated
Induction of peroxisome proliferation activated receptor (PPAR) which exports the activated NFkB from the nucleus

Question 35

Crohn’s disease is characterized by the activation of which types of T cells?

Answer 35

Th1 and Th17 cell responses driven by IL-12, IL-6 and IL-12 produced by DCs and macrophages

Question 36

Which cytokines do Th1 cells secrete?

Answer 36

IL-2, IFN-gamma, TNF

Question 37

Which cytokines do Th17 cells secrete?

Answer 37

IL-17

Question 38

Ulcerative colitis is characterized by an atypical activation of which cell?

Answer 38

Th2 cell and natural killer T cell (NKT) which produce IL-5 and IL-4 (Th2) and IL-13 (Th2 and NKT cells)