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GI II > Immuno-Pathogenic Mechanisms of Inflammatory Bowel Disease (IBD) (part 2 of 2) > Flashcards

Immuno-Pathogenic Mechanisms of Inflammatory Bowel Disease (IBD) (part 2 of 2) Flashcards

1
Q

the prevalence of IBD varies among different populations; UC is less common in what populations?

A

UC is 10-fold less common in Asian and African populations

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2
Q

the prevalence of IBD varies among different populations; CD seems very uncommon in what populations?

A

Asia and africa

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3
Q

the genetic risk of getting IBD is increased when?

A

among first-degree relatives

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4
Q

when is there a greater concordance rate for IBD?

A

in monozygotic twins vs. dizygotic twins

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5
Q

what is associated with a predisposition for developing IBD?

A

there have been over 200 single nucleotide polymorphisms (SNPs) that are associated with a predisposition for developing IBD; NOT MUTATIONS, but SNPs!

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6
Q

what are SNPs?

A

they are defined as loci variants with alleles that differ at a single base

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7
Q

what is the susceptibility locus for IBD found on chromosome 16?

A

IBD-1

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8
Q

what does the IBD-1 locus contain?

A

CARD15/ NOD2 genes

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9
Q

where is CARD15 primarily expressed?

A

in macrophages/ dendritic cells

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10
Q

defects in what have been found in 17-27% of cases of CD?

A

defects in CARD15/NOD2

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11
Q

what is CARD15?

A

an intracellular PPR (pattern recognition receptor)

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12
Q

what does CARD15 recognize?

A

MDP (muramyl dipeptide- a peptidoglycan constituent of both gram positive and gram negative bacteria)

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13
Q

CARD15 triggers activation of what?

A

NF-kB

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14
Q

What are 3 broad mechanisms of Crohn’s disease caused by NOD2 mutations?

A

1) defective function of macrophages; 2) defective epithelial-cell responses; 3) defective “conditioning” of APCs

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15
Q

what does defective function of macrophages lead to?

A

persistent intracellular infection of macrophages and chronic stimulation of T cells by macrophage-infecting organisms

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16
Q

what does defective epithelial-cell responses lead to?

A

loss of barrier function and increased exposure to the mucosal microflora

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17
Q

what does defective “conditioning” of APCs lead to?

A

inappropriate activation of APCs and disruption of the homeostatic balance of effector and regulatory cells

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18
Q

what does colonization of the GI with beneficial bacteria induce?

A

the development of GALT

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19
Q

during homeostasis, the gut microbiota has important roles in what?

A

permeability of the GI tract and intestinal immunity

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20
Q

the microbiota maintains the basal level of what?

A

Th17 and Th1 cell activity in the lamina propria

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21
Q

beneficial subsets of commensal bacteria tend to have what?

A

anti-inflammatory activities

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22
Q

what do beneficial commensal bacteria suppress? and how?

A

pathobionts; partly through the induction of Treg cells and stimulation of IL-10 production by immune cells

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23
Q

what do commensal bacteria ferment?

A

nondigestible polysaccharides ingested in the diet (eg cellulose) to produce SCFAs

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24
Q

what are the qualities of SCFAs?

A

they have anti-inflammatory properties in macrophages, dendritic cells, CD4+ T cells and intestinal epithelial cells

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25
Q

what is the receptor for SCFAs?

A

GPR43

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26
Q

a colonization of intestinal cells with segmented filamentous bacteria (SFB), bacteroides fragilis, clostridium spp. results in what?

A

induction of Treg cells in the lamina propria

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27
Q

besides Treg cell induction, what is the other role of SFBs?

A

maintenance of the basal activation level of Th17 cells, which are important for the integrity of the epithelial barrier

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28
Q

what represents the primary barrier limiting contact between the microbiota and host tissue preventing microbial translocation?

A

mucus

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29
Q

what do epithelial cells produce that also play a significant role in limiting exposure to the commensal microbiota?

A

antimicrobial peptides

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30
Q

what are translocating commensals rapidly eliminated by?

A

tissue-resident macrophages

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31
Q

presentation of commensal Ags by the DCs leads to what?

A

the differentiation of commensal-specific Treg cells, Th17 cells, and IgA-producing B cells

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32
Q

commensal-specific lymphocytes traffic to what?

A

the lamina propria and Payer’s patches

33
Q

in peyer’s patches, Tregs can further promote what?

A

class switching and IgA generation against commensals

34
Q

what comprises the mucosal firewall?

A

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

35
Q

what is the purpose of the mucosal firewall?

A

it limits the passage and exposure of commensals to the gut-associated lymphoid tissue, preventing untoward activation and pathology

36
Q

what does the commensal microbiota suppress?

A

the NF-kB pathway

37
Q

what is the immune tolerance of the microbiota related to?

A

to DCs and macrophages which do not sense the presence of microflora and thus do not secrete pro-inflammatory cytokines; IN IBD THE TOLERANCE IS LOST

38
Q

what occurs in IBD in association with immune tolerance and the microbiota?

A

tolerance is lost; consequently, a chronic immuno-inflammatory response is triggered in the mucosa

39
Q

dysbiosis results in what?

A

a loss of protective bacteria and/or in the accumulation of colitogenic pathobionts, which leads to chronic inflammation

40
Q

chronic inflammation involves what?

A

hyperactivation of Th1 and Th17 cells and inhibition of Treg cells producing IL-10

41
Q

what is the tipping point associated with IBD?

A

if an acute inflammation cannot be resolved by anti-inflammatory mechanisms, it leads to chronic intestinal inflammation

42
Q

chronic inflammation may cause complications of IBD such as what?

A

fibrosis, stenosis, abscess, fistula, cancer, etc.

43
Q

the process of T cell activation and differentiation is modulated by what?

A

co-stimulatory signals (cytokines and ligands) between APCs and naive (or memory) T cells

44
Q

crohn’s disease is characterized by the activation of what?

A

Th1 and Th17 cell response

45
Q

what are the th1 and th17 cell responses driven by?

A

IL-12, IL-6, and IL-23 produced by DCs and macrophages

46
Q

what do Th1 cells secrete?

A

IL-2, IFN-gamma, and TNF

47
Q

what do Th17 cells secrete?

A

IL-17

48
Q

ulcerative colitis is characterized by an atypical activation of what?

A

Th2 cell and natural killer T cells (NKT)

49
Q

what do Th2 cells produce?

A

IL-5 and IL-4 and IL-13

50
Q

what do NKT cells produce?

A

IL-13

51
Q

what cytokine causes an activated T cell to become a Th1 cell?

A

IL-12

52
Q

what product of Th1 cell leads to crohn’s disease?

A

IFN-gamma

53
Q

what cytokine causes an activated T cell to become a Th2 cell?

A

IL-4

54
Q

what products of Th2 cells lead to ulcerative colitis?

A

IL-4, IL-5, IL-13

55
Q

what cytokines cause an activated T cell to become a Th17 cell?

A

IL-6, IL-23, TGF-beta

56
Q

what products of Th17 cells lead to crohn’s disease?

A

IL-17

57
Q

what is IL-23 produced by?

A

activated APCs (macrophages and DCs)

58
Q

what is IL-23 closely related to?

A

IL-12

59
Q

what cytokines are needed for inhibition of IBD and maintenance of tolerance?

A

IL-10 and TGF-beta

60
Q

what would happen if you lost function of the SNPs for IL-10 and TGF beta?

A

you would be predisposed to IBD

61
Q

what would happen if you gain function of the SNPs for IL-10 and TGF-beta?

A

you would be protected from IBD

62
Q

what cytokines are important for the cell-mediated inflammation and CD in IBD?

A

TNF-alpha, IFN gamma, IL-1, IL-6, IL-2, IL-17, and IL-22

63
Q

what happens if you lose the function of the SNPs for the cell mediated inflammation and CD?

A

you would be protected from CD

64
Q

what happens if you gain function of the SNPs for the cell mediated inflammation and CD?

A

you would be predisposed for CD

65
Q

what are the cytokines important for antibody-mediated inflammation and UC?

A

IL-4, IL-5, and IL-13

66
Q

what happens if you lose the function of the SNPs for antibody mediated inflammation and UC?

A

you would be protected from UC

67
Q

what happens if you gain the function of SNPs for antibody mediated inflammation and UC?

A

you would be predisposed to UC

68
Q

immune responses in the intestinal lumen GI are tightly regulated; how??

A

there is tolerance to resident commensal bacteria and dietary antigens present; there is also a rapid immune response against pathogenic microbes; there is active suppression by Treg cells

69
Q

IBD is believed to be the result of a breakdown of what?

A

tolerance to resident enteric bacteria (microbiota)

70
Q

what do Treg cells secrete?

A

Il-10 and TGF-beta

71
Q

limited expression of pro-inflammatory cytokines by APCs and excess of TGF-beta results in what?

A

differentiation of naive T cells into T reg cells

72
Q

where can Treg cells act?

A

locally in various tissues and draining lymph nodes

73
Q

Treg cells become activated by what?

A

APC presenting auto-Ag

74
Q

what do Treg cells constitutively express?

A

CTLA-4 and an alpha-subunit of IL-2 receptor (CD25) which render IL-2R a high affinity binding

75
Q

how do Treg cells suppress APCs?

A

directly through cell-to-cell interactions or indirectly by inhibitory cytokines

76
Q

Treg cells might act directly on activated T cells via what?

A

CTLA-4 and by IL-2 deprivation

77
Q

what are the current treatment options for IBD?

A

TNF blockers

78
Q

what are TNF blockers?

A

they are humanized monoclonal Ab that bind TNF

79
Q

besides TNF blockers, what is on the horizon for treatment for IBD?

A

fecal microbiota transplantation

GI II (20 decks)

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