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GI/GU II Exam 1 > IBD Immunology > Flashcards

IBD Immunology Flashcards

1
Q

NB! what is a characteritic that really sets UC and CD apart

A

CD- rectum spared (40%)

UC - rectum always involved

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2
Q

what are the key concepts of IBD

A

chronic relapsing idiopathic inflammation of GI tract

genetics and immune mechanisms play imp role

irreversible impairment of GI structure and function –> increased intestinal permeability bc impaired formation of tight jxns

hygiene hypothesis- -> increased incidence of IBD

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3
Q

What is the role of commensal bacteria in IBD

A

cause inflam rxn –> self-sustained mucosal inflam

bacterial components cross the mucosal barrier and induce innate and adaptive responses

both cellular and humoral immune responses to a variety of antigens in IBD

persistent & inappropriate perturbation of highly regulated interaxn btn immune system and commensal bacteria of normal microbiome causes dysbiosis and mucosal inflam

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4
Q

What are the aberrant responses that are genetically determined

A

disrupt barrier fxn- UC
dysfxn of the microbe sensing - CD
changes in immunoregulation in both disorders

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5
Q

what are the respective lab tests for CD and UC

A

CD = (+) ASCA

UC = pANCA test (+)

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6
Q

what is the role of environmental factors in IBD

A

= initiate and reactivate dz

environmental factors imp bc low cordance rate in identical twins

genetics - influence luminal microbiota

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7
Q

what is gut microbiota & what is its role in the host

A

=symbiotic & reciprocal interaxn w/ host cells - make complex & regulated ecosystem

fxnal roles =

  1. protection: against invasion/colonization
  2. facilitation: digestion & abs
  3. immunological surveillance signals
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8
Q

what is the role of microbiota in IBD

A

develops in high bacterial concentration

surgical diversion of fecal stream –> prevent intestinal inflamm - IF reestablish –> recurrence!

ABx and probiotics = beneficial effects on IBD

circulating Abs against fecal Ag detected ; lymphocytes show reactivity to these

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9
Q

what phyla make up the gut microbiome

A

Bacteroidetes
Firmicutes

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10
Q

wht dysbiosis occurs in CD

A

increase Firmicutes (majority) and Actinobacteria

decrease bacteroidetes

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11
Q

What is the dysbiosis that occurs in UC

A

increased Proteobacteria

decreased Bacteroidetes

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12
Q

how do we know that intestinal microbiota may be imp for IBD pathogenesis

A

spontaneous colitis doesnt occur in mutant mouse strains when kept in a germ free environment
BUT it develops rapidly when mice are colonized by commensal bacteria
GFM colonized w/ intestinal microbiota from IBD donors show exacerbated dz

____________________________________________

Babies born from IBD women –> lower bacterial diversity & altered composition [maternal IBD = main predictor of diversity of infant microbiota]

GFM injected w/ IBD mother & infant ==> stools show sig altered adaptive immune system of intestines in GFM

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13
Q

what can cause dysbiosis & lead to dysregulation of the immune system and inflam in genetically susceptible host

A

host genetics

maternal transfer & early colonization

ABx & meds

infxn

inflam

stress

hygiene

age

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14
Q

how doe diet control the microbiota diversity

A

High fiber: increases all besides proteobacteria (decreases)
High protein: increases all except actinobacteria (dysbosis bc increase proteobacteria!)
High carb: increases all except Proteobacteria
High fat: decreases all except actinobacteria (dysbosis bc decrease in bacteriodetes & firmicutes)

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15
Q

what is the role of infxn in IBD

A

no specific organisms conclusively linked to development
gastroenteritis, such as Salmonella and campylobacter, possible etiology of IBD
prevalence of IBD is inversely related to prevalence of helminth colonization (imp immunoregulators)

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16
Q

what are the roles of genetic factors in IBD

A

Asia & Africa: UC is 10x less** & CD if **very uncommon

risk increase w/ 1st degree relative

greater concordance rate in monozygotic vs dizygotic

NB! over 200 SMPs associated w/ predisposition ( NOT mutations )

NB! all genes encode for immunoinflam components

17
Q

what is the IBD-1 gene

A

in chromosome 16q12
contains CARD15/NOD2 genes = CAspase Recruitment Domain family member 15 also known as Nucleotide-binding Oligomerization Domain 2 gene)

18
Q

what are the fxns and characteristics of CARD15/NOD2

A

expressed in macrophages/DCs
defects in CD (17-27%)
ppl homozygous for susceptible variant (SNPs) have > 20x increased risk for CD
= intracellular PRR and recognizes MDP, a peptidoglycan constituent of both gram (+) & (-) ==> triggers activation of NF-kB

19
Q

What is the possible mechanism for mutations of CARD15/NOD2 that cause CD

A
  • *Defective functions of macrophages**–> persistent intracell infxn & stimulate T cells
  • *Defective epithelial-cell responses** –> loss of barrier fxn & increased exposure to mucosal microflora
  • *Defective conditioning of APCs**–> inappropriate activation of APCs & disrupte the homeostatic balance of effectors and regulatory cells
20
Q

how does normal microbiota maintain homeostasis

A

colonization of the GI w/ beneficial bacteria –> induce development of GALT

maintains the basal levels of Th17 & Th1 in lamina propria

increased barrier fxn (maintain permeability)

pathobionts suppressed by commensal bacteria via Treg & IL-10

21
Q

what is the role of SCFAs in the GI system

A

produced by commensal bacteria

anti-inflam properties in macrophages, DCs, CD4+ T cells, and intestinal epithelial cells

GPR43 is the receptor for SCFAs that induces Treg cells and IL-10 production

induce IgA and mucus secretion into lumen

promotes epithelial barrier integrity & prevent pathogen colonization

22
Q

what happens whtn the GI tract is colonized by segmented filamentous bacteria

A

(Bacteroides fragilis and Clostridium spp)
= induce Treg cells in the lamina propria
and maintain basal level activation of Th17 - imp for the integrity of the epithelial border

23
Q

how does the microbiota induce host immune tolerance to commensal bacteria

A

microbe-associated molecular patterns (MAMP)
polysac signaling (PSA)
indirectly through production of SCFAs
potentially by expression of intestinal Alkaline phosphatase (IAP), which detoxifies luminal LPS

24
Q

describe the “mucosal firewall”

A

primary barrier limiting contact btn microbiota & host tissue = mucus

epithelial cells –> make antimicrobial peptides –> also limit exposure to commensal microbiota

tissure resident macrophages - quickly eliminated translocating commensals

DC can capture commensal Ags that traffic to the mLN from lamina propria –> Ag presentation –> differentiation of Treg, Th17 and IgA producing B cells

combo of mucus, DC, IgA and T cells = firewall - limit passage & exposure of commensals to the gut associated lymphoid tissue

25
Q

what happens to immune tolerance to microbiota in IBD

A

lost tolerance –> chronic immuno-inflammatory response in the mucosa

26
Q

What is the role of NF-kB in the absenceand presence of commensal bacteroides?

A

absence

salmonella flagella binds to TLR5 intestinal epithelial cells
- Activates IkB kinase, activating NF-kB –> transcription of proinflammatory genes

presence
attenuated proinflam response caused by S. enteritidis & induction of peroxisome proli activated receptor –> export activated NF-kB from nucleus

27
Q

What is phase I of the development of IBD?

A

Genetic and environmental factors induce impaired barrier function in the mucosa

28
Q

What is phase II of the development of IBD?

A

Translocation of commensal bacteria –> activate immune cells and cytokine production

29
Q

What is phase III of the development of IBD?

A

Tipping point: “resolution or chronicity”
If acute inflam cannot be resolved by anti-inflammatory mechanisms –> chronic intestinal inflam

30
Q

What is phase IV of the development of IBD?

A

Chronic inflam may cause complications of the disease such as fibrosis, stenosis, abscess, fistula, cancer, etc

31
Q

What are the cytokines that contribute to Crohn’s disease?

A

IL-12 –> (+) Th1 cells –> (+) IL-2, IFN-y and TNF
IL-6, IL-23 & TGFB –> (+) Th17 cells–> (+) IL-17
initiating factors made by DCs and macrophages

32
Q

What are the cytokines that contribute to Ulcerative colitis?

A

Th2 –> (+) IL-4, IL-5, and IL-13

Natural Killer T cell –> (+) IL-13

33
Q

Which cytokines activate the offending type of T cells in IBD?

A

IL-12 activates Th1 response
IL-4 activates Th2 response
IL-6, IL-23, and TGFß activates Th17 response

34
Q

What would a LOF or GOF SNP in IL-10 and TGF-ß result in?

A
  • *LOF** would predispose to IBD
  • *GOF** would protect from IBD
35
Q

What would a LOF or GOF SNP in TNF-a, IFN-y, IL-1, IL-6, IL-2, IL-17. and IL-23 result in?

A
  • *LOF** would protect from CD
  • *GOF** would predispose CD
36
Q

What would a LOF or GOF SNP in IL-4, 5, and 13 result in?

A
  • *LOF** would protect from UC
  • *GOF** would predispose UC
37
Q

Which cytokines produced by Treg cells contribute to homeostasis?

A

IL-10 and TGF-ß

38
Q

What are the properties of Treg cells?

A

act locally in many tissues and draining LNs

activated by APC presenting auto-Ags

constitutively express CTLA-4 and a-subunit of IL-2R (CD25) –> render IL-2 a high affinity binding

suppress APCs directly by cell-to-cell interactions or indirectly by inhibitory cytokines

May act directly on activated T cells via CTLA-4 and by IL-2 deprivation

39
Q

What are the currently immuno-therapeutic treatment options for IBD?

A

TNF blockers -monoclonal Ab bind TNF & neutralize it –> reduce inflam

Infliximab, Adalimumab, golimumab, etanercept, certolizumab pegol

some blockers bind to both forms (soluble and membrane bound) % block interaction w/ receptors

GI/GU II Exam 1 (16 decks)

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