Chapter 14 - GI Immunity Flashcards by Alex Hamidi

What has a multilayer epithelial barrier?

oral cavity and vagina

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What immune system is the largest?

how many lymphocytes does it have?

50 x 10^9

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what utilizes M cells?

GI, tonsils, adenoids

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Where do DCs travel to to present Ag to naive T cells?

draining LN

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what happens at GALT sites

adaptive immune responses specialized for the particular mucosa are initiated

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what happens to effector lymphocytes generated in LN or GALT?

enter the blood and home back to same organ

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where are M cells present?

gamma delta T cells?

gut

epithelia

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what specialized cells are restricted to 1 or more regional immune systems but not present throughout?

M cells
gamma delta T cells
subsets of IgA producing B cells
plasma cells

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what are regional immune systems important for?

regulatory functions that prevent unwanted responses to nonpathogenic microbes and foreign substances

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where is the number of microflora the highest, small or large intestine?

large intestine

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what is the lamina propria?

under the epithelium, loose CT in the gut

contains blood and lymphatic vessels, MALT

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what are the function of commensals (microflora)?

degradation of dietary components we cannot digest

compete with pathogenic microbes in the gut to prevent harmful infections

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how can commensal organisms become lethal?

if they cross the mucosal barrier

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what are the 2 forms of innate immune protection

physical and chemical

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what are the physical barriers?

mucosal epithelial cells held together by tight junctions and their mucous secretions

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what are the chemical barriers

anti-microbial peptide defensins

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what is present in the lamina propria which can induce inflammation?

DCs, Macrophages, neutrophils

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what do mucins do?

what do they include?

prevent microbes from contacting epithelial cells

secreted and cell surface glycoproteins

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what are the layers of mucins?

outer less-dense layer with bacteria

dense inner layer that is bacteria free

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the apical surface of GI epithelial cells is coated with what?

membrane-bound mucin proteins called the glycocalyx

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what does the glycocalyx do?

physical barrier to prevent microbial contact

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how and by what are mucins produced?

constitutively by epithelial cells and submucosal glands

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how often are mucins replaced?

every 6-12 hours

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what cytokines increase mucin production during inflammation?

IL-1, IL-4, IL-6, TNF, IFN-alpha, elastase, microbial adhesive proteins

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What do inflammatory molecules do?

inc. mucin production and alter their glycosylation which inc. barrier function against pathogens

what do epithelial and Paneth cells produce? for what

defensins constitutively to provide innate immunity protection against luminal bacteria

how do defensins work?

exert lethal toxic effects on microbes by inserting into and causing loss of integrity of their outer phospholipid membranes

what are the major defensins in the small bowel? colon?

alpha-defensins made by Paneths beta-defensins made by epithelial

what are defects in defensin linked to?

Crohn's disease

What are TLRs and NLRs expressed by for what?

intestinal epithelial cells to promote immune responses to invasive pathogens limit inflammatory responses to microflora

what may microflora express?

lipopolysaccharide (-) peptidoglycans (+) CpG DNA flagellin

what do functional responses to TLR signaling do?

increase barrier function, not inflammation

TLR5 recognizes what? expressed where?

flagellin basolateral surface

where is NLR for flagellin expressed?

cytosol of intestinal epithelial cells inflammatory response activated only when microbe enters cytosol

how is adaptive immune response initiated?

APC with mucosal epithelial cells and lymphocytes

what is the pathway of Ag delivery from lumen to GALT? what is major form?

M cells humoral immunity

what does the dominant, cell-mediated immune response consist of? what can control responses in the gut?

Th 17 cells Treg cells

what are the characteristics of M cells and what do they do?

have shorter villi, engage in transport of intact microbes or molecules across the mucosal barrier into GALT where they hand off to DC

how are DCs in GALT induced and what do they convert

thymic stromal lymphopoietin (TSLP) Vit A to Retinoic acid

what are naive B or T cells exposed to retinoic acid and activated by Ag, induced expression of what occurs?

CCR9 and intergrin alpha4-beta7 on plasma cells and effector T cells

what causes effector lymphocytes to enter circulation and home back into the gut lamina propria?

CCL25 and MadCAM displayed on lamina propria endothelial cells

in T-dependent IgA class switching, where do DCs capture Ags delivered by M cells and where do they migrate to?

subepithelial dome of Peyer's patches | migrate to interfollicular zone where they present Ag to naive CD4 T cells

what do the activated T cells differentiate into?

Th cells with a T follicular helper phenotype

what is B cell class switching to IgA stimulated through? what does TD pathway yield?

CD40L binding to B cell CD40 with TGF-Beta high affinity IgA Abs

what does T-independent IgA class switching involve? what does this pathway yield?

B-1 cells, DC secrete BAFF, APRIL, and TGF-Beta which induces the switch low affinity IgA Ab

what does IgA produced in the lamina propria bind to? how is it released into lumen

poly-Ig receptor proteolytic cleavage

what is the lamina propria of the small bowel rich in? where are there no Th17 cells?

Il-17 producing cells colon

what is the function of Th 17 cells? what cytokines does it produce?

maintains mucosal epithelial barrier IL-17 and IL-22

what do IL-17 and IL-22 act on? function?

intestinal epithelial cells, induce expression of mucins and Beta-defensins protect the epithelial cells against microbe-induced injury

what is abundant in GALT, what do these cells do?

Treg, prevent inflammatory reactions against intestinal commensal microbes

what factors contribute to the generation of Treg cells in the GI? how do these cells suppress immune responses?

DCs retinoic acid (promotes FoxP3) TGF-Beta (promotes FoxP3) production of IL-10

what cytokines are important for homeostasis? what do deficiencies of these result in?

TGF-Beta, IL-10, and IL-2 pathological bowel inflammation

what is associated with colitis in children?

mutation in IL-10 and IL-10R

what does a defect in IL-2 or IL-2R lead to?

IBD, due to defect of development of Treg cells

what mechanisms of oral tolerance are there?

anergy deletion Treg-mediated suppression

what % of T cells in GALT are Treg cells?

10%

what are PAMPs and TLRs they bind on epithelial cells needed for?

proliferation and repair of the intestinal barrier after injury

what do microflora stimulate?

mucins and anti-microbial peptides that prevent gram(+) bacterial colonization

what do short-chain FAs from gut do? peptidoglycycan from commercials?

dampen neutrophil inflammatory response enhances ability of circulating neutrophils to kill gram(+) bacteria

what is microflora required for?

systemic anti-viral functions of macrophages, DCs, and NK cells

IgA production is dependent on what? what do commensal organisms induce?

luminal flora IgA switch factors (BAFF, APRIL, retinoic acid)

what does IgA in the gut do?

reduce innate response to commensals limits B cell activation and Ab responses to other isotypes

what do dietary products do?

shape the microbial community

what do microbiota do?

change the nutritional value of the consumed food

what happens to unmodified dietary components?

absorbed in the intestine, interact with immune cells

what does MAMP/PAMP signaling via TLR do?

modifies local mucosal immunity

what does microbe-modified dietary components (ex. acetate)

stimulate IL-10 production regulating metabolic activities in the lamina propria

what are the 2 main types of IBD?

Crohn's - affects entire thickness, involves terminal ileum ulcerative colitis - patchy damage, restricted to colonic mucosa

what are treatments of IBD?

anti-inflammatories sulfasalazine, corticosteroids, TNF antagonists, and antimetabolites

Defects in innate immunity to gut commensals

defective expression of defensins --> increased commensal invasion inadequate negative regulation

what is Crohn's characterized by?

granulomatous inflammation drive by IFN-gamma producing Th1 cells

what are possible causes of IBD?

inadequate Treg-mediated suppression absence or depletion of Treg IL-2, IL-2R, FoxP3 mutation

what causes IPEX? symptoms?

FoxP3 mutation severe gut inflammation

what are the 2 alleles people with Celiac have? what type of cells involved in the pathogenesis?

HLA-DQ2 and HLA-DQ8 CD4 T

what does cross-linking and deamindation of gluten peptides?

transglutaminase 2 (TG2)

what releases MMPs? what is the result?

myofibroblasts mucosal remodeling and villus atrophy

what does IL-15 do?

links adaptive immune system to innate immune response