What is largest lymphoid organ in body
2 parts of mucosal immune system
inductive sites effector sites
function of innate immune mech in mucosal immune system? what makes it up?
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
function of adaptive immune response in gut? what makes it up?
regulatory/suppressive function = immune tolerance - IgA keeps antigens from being absorbed - regulatory T cells keep immune response contained
What antigens are in gut?
dietary protein: 100 g daily bacteria: 10 bacteria cells per human cell in body
What separates mucosal immune system from intestinal lumen?
- single layer epithelial cells act as gatekeepers - secreted mucins and antibodies - digestive enzymes that break down antigens
What are the inductive sites of mucosal immune system?
where initial immune response takes place - lymphoid structures where immune cells found - peyer's patches - isolated lymphoid follicles - mesenteric lymph nodes
What are the effector sites?
GI mucosa where B/T lymphocytes, macrophages, dendritic cells, eosinophils, mast cells densely scattered in normal intestine
Can intact protein antigens get from GI lumen into body? How?
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
Which cytokines are involved in gut innate immune?
Why are oral vaccines not often successful?
It is difficult to generate a good protective response in the intestine
What do adjuvants do to adaptive immune response?
- Adjuvants can break oral tolerance and allow the gut to generate an immune response
- 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
Food allergy mech
hypersensitivity reaction to food
- don't get reaction to antigen taken orally - this is what allows to separate commensal from pathogen - soluble antigen better at producing tolerance
- oval or round lymphoid follicle in lamina propria/submucosa - contain T and B cells
What antibodies in mucosal immunity?
IgA production in setting of suppression of systemic IgG/IgM
adjuvant and antigen experiment with mouse
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
Factors involved oral tolerance
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
What specific changes in immune cells [macrophages, lymphocyes, dendritic cells] occur in gut to make gut immune less reactive?
macrophages/dendritic cells: fewer toll like receptors, less signaling lymphocytes: difficult to activate, undergo apoptosis after activation Treg cells: activated to suppress response
What is immune exclusion?
- IgA binds bacteria and neutralizes them
What is function of SIgA?
- inhibits adhesion of virus and bacteria to the epithelium, protects epithelial cells
3 Methods Antigens captured from gut into body?
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
Th1 cell cytokine
Th2 cell cytokines
IL-4, IL-13, IL-5
TH17 cell cytokine
3 types of Tregs and their cytokines
CD4+Foxp3+CD25+ TR1: produce IL10 TH3: produce TGFB
Cause of IBD
- Inflammatory bowel disease caused by dysregulated mucosal immune response to enteric bacterial antigens in genetically susceptible host - 2 types: crohns, ulcerative colitis
Effect of extra TH1 response
- get extra IFN-gamma and IL-2 - cell-mediated granulomas
Effect of extra TH2 response
- get extra IL-4, IL-5, IL-10 - hypersensitivity reactions
Effect of lack of TR1 cells?
- not as much TGF-B and IL-10 - get increase in both TH1 and TH2 response - granulomas and hypersensitivity
Function of IL-17/IL-22
- normally expressed by immune cells to repair - help recruit neutrophils - reduce expression of microbicidals
- Faulty genes and specific bacterial antigen --> lots of inflammation, granuloma - due to TH1/TH17 problem
- 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
- 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