Lec13 Mucosal Immunity

Question 1

What is largest lymphoid organ in body

Answer 1

gastrointestinal mucosa

Question 2

2 parts of mucosal immune system

Answer 2

inductive sites effector sites

Question 3

function of innate immune mech in mucosal immune system? what makes it up?

Answer 3

function is to keep microbiota contained - antimicrobial peptides produced by epithelial cells - regulatory cytokines [TGF-beta and IL-10] help control inflammation in intestine - specialized cytokine-producing innate lymphoid cells in intestine - unique features of intestinal dendritic cells that promote induction of regulatory T cells

Question 4

function of adaptive immune response in gut? what makes it up?

Answer 4

regulatory/suppressive function = immune tolerance - IgA keeps antigens from being absorbed - regulatory T cells keep immune response contained

Question 5

What antigens are in gut?

Answer 5

dietary protein: 100 g daily bacteria: 10 bacteria cells per human cell in body

Question 6

What separates mucosal immune system from intestinal lumen?

Answer 6

• single layer epithelial cells act as gatekeepers - secreted mucins and antibodies - digestive enzymes that break down antigens

Question 7

What are the inductive sites of mucosal immune system?

Answer 7

where initial immune response takes place - lymphoid structures where immune cells found - peyer’s patches - isolated lymphoid follicles - mesenteric lymph nodes

Question 8

What are the effector sites?

Answer 8

GI mucosa where B/T lymphocytes, macrophages, dendritic cells, eosinophils, mast cells densely scattered in normal intestine

Question 9

Can intact protein antigens get from GI lumen into body? How?

Answer 9

Yes - cross epithelial cells - taken up by M cells, specialized antigen sampling cells, and taken to peyer’s pathces - taken up by dendritic cells that reach into lumen

Question 10

Which cytokines are involved in gut innate immune?

Answer 10

TGF-beta IL-10

Question 11

Why are oral vaccines not often successful?

Answer 11

It is difficult to generate a good protective response in the intestine

Question 12

What do adjuvants do to adaptive immune response?

Answer 12

• Adjuvants can break oral tolerance and allow the gut to generate an immune response

Question 13

Celiac disease

Answer 13

• innapropriate innate and adaptive immune reactivity to gluten that causes to attack epithelial cells — from Il-15 by intestinal epithelial cells, IFN-gamma by T cells - flattening of villi on upper small intestine, crypt hyperplasia, intraepithelial lymphocytes - due to DR3/7-DQ2/8 genetic mut - get fat and vit malabsorption, weight loss, osteoporosis, iron deficiency, diarrhea, abdominal bloating - most effective therapy: avoid gluten

Question 14

Food allergy mech

Answer 14

hypersensitivity reaction to food

Question 15

Oral tolerance

Answer 15

• don’t get reaction to antigen taken orally - this is what allows to separate commensal from pathogen - soluble antigen better at producing tolerance

Question 16

peyer’s path

Answer 16

• oval or round lymphoid follicle in lamina propria/submucosa - contain T and B cells

Question 17

What antibodies in mucosal immunity?

Answer 17

IgA production in setting of suppression of systemic IgG/IgM

Question 18

adjuvant and antigen experiment with mouse

Answer 18

treat mouse with antigen subcutaneously then 10 days later give antigen and adjuvant subcutaneously –> immunity treat moust with antigen orally then 10 days later give antigen and adjuvant subcutaneously –> tolerance - transfer T cell from tolerance mouse to another mouse then give antigen and adjvuant subcutaneously –> tolerance

Question 19

Factors involved oral tolerance

Answer 19

Nature of antigen: protein >> carb >> lipid Form of antigen: soluble protein is best at producing tolerance, particulate does not give as much tolerance Genetics of host: some mouse strains harder to tolerize Dose of antigen: – low dose –> regulatory T cells turn on – high dose –> anergy and deletion of T cells Age of host: neonates do not tolerize well

Question 20

What specific changes in immune cells [macrophages, lymphocyes, dendritic cells] occur in gut to make gut immune less reactive?

Answer 20

macrophages/dendritic cells: fewer toll like receptors, less signaling lymphocytes: difficult to activate, undergo apoptosis after activation Treg cells: activated to suppress response

Question 21

What is immune exclusion?

Answer 21

• IgA binds bacteria and neutralizes them

Question 22

What is function of SIgA?

Answer 22

• inhibits adhesion of virus and bacteria to the epithelium, protects epithelial cells

Question 23

3 Methods Antigens captured from gut into body?

Answer 23

1. Dendritic cells telescoping: dendritic cells telescope through and can see antigen in lumen and takes some in, eventually dendritic cells exit lamina propria and go to lymph nodes 2. M cells: M cell overlies peyer’s patch and transports antigen in and brings it to peyer’s patch, leading to formation of larger immune rxn 3. antigen transports through or between epithelial cells

Question 24

Th1 cell cytokine

Answer 24

IFN-gamma

Question 25

Th2 cell cytokines

Answer 25

IL-4, IL-13, IL-5

Question 26

TH17 cell cytokine

Answer 26

IL-17

Question 27

3 types of Tregs and their cytokines

Answer 27

CD4+Foxp3+CD25+ TR1: produce IL10 TH3: produce TGFB

Question 28

Cause of IBD

Answer 28

• Inflammatory bowel disease caused by dysregulated mucosal immune response to enteric bacterial antigens in genetically susceptible host - 2 types: crohns, ulcerative colitis

Question 29

Effect of extra TH1 response

Answer 29

• get extra IFN-gamma and IL-2 - cell-mediated granulomas

Question 30

Effect of extra TH2 response

Answer 30

• get extra IL-4, IL-5, IL-10 - hypersensitivity reactions

Question 31

Effect of lack of TR1 cells?

Answer 31

• not as much TGF-B and IL-10 - get increase in both TH1 and TH2 response - granulomas and hypersensitivity

Question 32

Function of IL-17/IL-22

Answer 32

• normally expressed by immune cells to repair - help recruit neutrophils - reduce expression of microbicidals

Question 33

Crohn’s Disease

Answer 33

• Faulty genes and specific bacterial antigen –> lots of inflammation, granuloma - due to TH1/TH17 problem

Question 34

Ulcerative collitis

Answer 34

• segmented disease - sometimes goes through whole wall of gut - happen in colon - ulcerates = lose epithelial cells from surface - dense inflammation - unconfrolled reaction to bacteria in context of genetic predispostion - due to TH2/TH17

Question 35

Food allergy

Answer 35

• food specific - contrary to other allergic rxns: not always associated with eosinophils - affects many parts of bowel - associated wtih urticaria [hives] - elevated IgE, tryptase - get diarrhea or anaphylaxis - vasoactive compounds released