Gut Immunity, Nutrition, and Adverse Food Reactions Flashcards
Describe gut immunity
the mucosal barriers are thin and very vulnerable to pathogenic infection, so the immune system must discriminate between protective immunity and tolerance
What are the gut associated lymphoid tissues (GALT)?
- tonsils
- adenoids
- Peyer’s patches
- isolated lymphoid tissue
- appendix
How do peyer’s patches and isolated lymphoid tissues receive antigens?
directly from epithelial surface - via Ag-transporting DCs
What are ILFs? How are they activated?
- single B-cell follicles that act as inductive site for IgA production
- MAMPs sensed by PRRs on intestistinal epithelial cells and DCs adjacent to cryptopatches recruit B cells and T cells. Cryptopatches mature into ILFs.
How do microbes enter Peyer’s patches?
Microbes cross epithelium through M cells to enter Peyer’s Patches. The microbes are endocytosed by DCs in the subepithelial dome. Ag-loaded DCs interact with lymphocytes to induce T cell differentiation and T cell dependent B cell maturation in multiple germinal centers —> induction of IgA producing plasma cells.
What do MAMPs stimulate?
proliferation of intestinal epithelial cells in crypts —> increased depth and increased density of Paneth cells
What are special challenges of the GI tract immune system?
- tolerance of food antigens
- tolerance of commensal microbiota but responsive to rare pathogens
- enormous surface area
What are special anatomic structures of the GI immune system?
- tonsils
- Peyer’s patches
- lamina propria follicles
What are the specialized cells or molecules of the GI immune system?
- intestinal epithelial cells: mucus secretion
- M cells: luminal antigen sampling
- Paneth cells: defensin production
- Secretory IgA, IgM: neutralization of microbes in the lumen
- Dendritic cell subsets:
What are the functions of DCs in GI immunity?
- luminal antigen sampling
- lamina propria sampling
- T cell tolerance induction
- effector T cell activation
- induction of B cell IgA class switching
- imprinting gut-homing phenotypes of B and T cells
The effector lymphocytes that are generated in the draining GALT of a partigular regional immune system will enter _____ and preferentially ____ to _____.
the blood; home back; lamina propria of the same organ
What are 3 major ways that the gut prevents infections?
- the presence of a thick mucus layer that keeps most organisms in the lumen away from the intestinal epithelium
- antibiotic peptides produced by intestinal epithelial cells that kill pathogens in the lumen or reduce their entry into the epithelium
- IgA produced by plasma cells that kill pathogens in the lumen or reduce their entry into the epithelium
What are the layers of GI tract starting at the lumen?
- secreted mucus
- epithelial cell layer: intestinal epithelial cells, dendritic cells, M cells, goblet cells
- lamina propria: innate sentinel cells and lymphocytes; mucosal associated lymphoid tissues: Peyers patches; plasma cells
What are the types of intestinal epithelial cells? Where are they found?
- mucus-secreting goblet cells: top of intestinal villi
- antigen-sampling M cells: in specialized dome structures overlying lymphoid tissues
- antibacterial peptide secreting Paneth cells: bottom of crypts
What is innate immune protection in the gut mediated by?
-physical and chemical barrier provided by mucosal epithelial cells and their mucus secretions
What block the movement of microbes between adjacent intestinal epithelial cells into lamina propria?
tight junctions
What types of cells in the mucosa are capable of mounting inflammatory and anti-viral responses?
- epithelial cells
- DCs
- macrophages
- innate lymphoid cells
What is secreted from goblet cells?
mucins - extensively glycosylated proteins that form a viscous physical barrier that prevents microbes from contacting the epithelial lining of GI tract
What are the physical barriers of the GI tract?
- mucus layer - mucins
- glycocalyx - dense macromolecular layer
What stimuli increases mucin production?
- cytokines: IL-1, IL-4, IL-6, IL-9, IL13, TNF, type I interferons
- neutrophil products: elastase
- microbial adhesive proteins
What are defensins?
What are major defensins in the small bowel? What are they produced by?
What are major defensins in the colon?
peptides produced by various cell types that exert lethal toxic effects on microbes by inserting into and causing loss of integrity of their outer phospholipid membranes
- alpha defensins (HD5, HD6) produced by Paneth cells at the base of crypts between microvilli
- beta defensins produced by absorptive epithelial cells in intestinal crypts (constitutively or in response to IL-1 or bacteria)
What do Paneth cells produce?
- defensins
- trypsin
- C0type lecins called regenerating islet-derived proteins
What TLRs are expressed by intestinal epithelial cells?
2, 4, 5, 6, 7, 9
What does TLR signaling do?
- increases intestinal epithelial motility and proliferation
- stimulates secretion of defensins, REGIII lectins, and IgA
What are the functions of DCs and macrophages in the lamina propria of healthy people?
- inhibit inflammation:
- macrophages stimulated by TGF beta: secrete IL-10
- maintain homeostasis
What stimulates innate lymphoid cells in the intestinal mucosa?
alarmins from injured or infected epithelial ceslls
What is the function of IL-17 and IL-22?
- IL-17 promotes acute inflammatory response to microbes
- both IL-17 and IL-22 enhance intestinal mucosal barrier function by stimulating production of defensins and enhancing epithelial tight junction function
What are the features of the adaptive immune system in GI?
- major form of adaptive immunity is humoral immunity directed at microbes in the lumen
- dominance of IgA in mucosal secretions
- protective cell-mediated immune responses against microbes in the gut are mediated by helper T cells
- major mechanism for controlling inflammatory reactions in the gut is activation of Tregs.
Where are Peyer’s Patches usually found? What do their germinal centers contain?
- distal ileum
- B lymphocytes, follicular helper T cells, follicular dendritic cells, macrophages
Where are M cells?
regions of the gut epithelium called follicle-associated (dome) epithelium that overlie Peyer’s patches and other GALT structures
What is the major function of humoral immunity in the GI tract?
- neutralize luminal microbes
- mediated by IgA produced in lamina propria and transported across the mucosal epithelium into the lumen
What cytokine is required for IgA isotype switching?
TGF-beta produced by inestinal epithelial cells and DCs in GALT
Where are T cells found in GI tract?
- gut epithelial layer
- scattered throughout the lamina propria and submucosa
- around and within follicles in Peyer’s patches and other GALT structures
What cytokines do Th17 produce?
IL-17 and IL-22
What induces Th2 responses? What cytokines do Th2 produce?
- helminth
- IL-4 and IL-13
What disease process has increased Th1 cells in the gut?
IBD
What is the function of Treg in GALT?
prevent inflammatory reactions against intestinal commensal microbes
What cytokines do Tregs produce?
IL-10
What are Treg markers?
CD4+, CD25+, Foxp3+
What are the 2 types of Treg cells? Where are they developed?
- nTreg in the thymus
- iTreg in the periphery from CD4+ Foxp3- conventional T cells
What cytokines promote homeostasis in the gut system?
TGF-beta, IL-10, IL-2
-deficiencies result in pathologic bowel inflammation
What is oral tolerance?
suppression of immune responses to Ags that have been administered by the oral route
- peripheral tolerance
- anergy
- apoptosis
- suppression by Treg
What are the main inductive sites for oral tolerance?
lamina propria and mesenteric lymph node
What is the process of oral tolerance?
- macrophages directly take up small or soluble Ags from intestinal lumen
- macrophages transfer the acquired Ags to DCs
- Ag-loaded DCs move from lamina propria to mesenteric lymph node
- DCs stimulate native CD4+ T cells to differentiate into Foxp3 expressing Ag specific Tregs via release of RA, TGF-beta, and IDO
What is RA? What’s its role in oral tolerance?
retinoic acid - a metabolite of vitamin A
- capable of inducing Treg cell differentiation
- expression of gut homing receptors
What is TGF-beta’s role in oral tolerance?
mediates Foxp3 upregulation in Treg differentiation
-sustains IDO expression on DCs
What is IDO? What is its role in oral tolerance?
indoleamne 2,3-dioxygenase
- drives Foxp3+ Treg development
- downregulates Th1 and Th17 differentiation
- inhibits colitis
Commensal organisms in the intestines are required for and regulate _____ in the gut and also influence _____
innate immune responses; systemic innate immunity
What does malnutrition effect?
both immune system and microbiota
What is the microbiota a barrier to?
enteropathogen infection
Is undernutrition associated with defects in innate or adaptive immunity?
BOTH
What is an outcome of recurrent enteric infections?
- nutrient deficiency
- impaired intestinal mucosal barrier function
What are undigested dietary carbohydrates fermented into?
SCFAs - stimulate production of mucus
- acetate: increases IL-10 colonic Tregs
- propionate: enhance expression of effector molecules including IL-10 and TGF-beta
- butyrate: directly act on Tregs or modulate DCs to enhance Treg inducing ability
What type of hypersensitivity?
- IgE mediated
- non IgE mediated
IgE mediated: type I
non IgE mediated: type III or type IV
How long does it take for signs of a non IgE T-cell mediated reaction to start?
4-28 hours after the ingestion of food
Describe the sensitization and secondary response to a food allergy
Allergen sensed by DC causes induction of Th2 cell by IL-4. Th2 produces IL-4 that induces Bcells and induction of IgE upon second exposure (after 7-10 days from first exposure). Th2 also produces IL-3, IL-4, IL-5, IL-9, IL-13 to activate basophils, eosinophils, and mast cells.
What is the role of mast cells in food allergy?
activation triggers mast cells to release granules
-proteases: tryptase for tight junction rearrangement
-histamine
de novo synthesis
-cytokines: IL-1beta, TNF-alpha
What is the effect of histamine and tryptase in food allergy?
- increases vascular permeability resulting in exudation containing C3 and C5
- tryptase released from mast cells generate C3a and C5a to activate the complement system
What suppresses inflammation and what promotes inflammation?
suppression: Vitamin D, A, and folate
promotion: high fat diet
What suppresses basophils and mast cells?
microbiota
What suppresses Th2 cells?
iTregs
What is the most common food allergy?
milk in 2% of infants
What mediates local acute GI response to allergy exposure?
PAF and serotonin
What foods are most frequently associated with anaphylaxis?
peanuts, tree nuts, seeds, seafood, spices, celery, eggs, milk, some fruit
What is anaphylaxis?
most severe form of systemic reaction which several different parts of the body experience allergic reaction at the same time.
-results from sudden release of multiple chemical mediators as a result of IgE antibodies
- severe itching, hives
- swelling of throat
- bronchoconstruction
- low BP
- unconsciousness and sometimes death
Describe type IV hypersensitivity
t cell mediated
- CD4+ T cells
- CD8+ CTLs
- macrophage activation, cytokine-mediated inflammation
- direct target cell lysis, cytokine mediated inflammation
What are major triggers of type IV hypersensitivity reactions?
- autoimmunity
- environmental Ags
- microbial Ags
How is tissue injury caused in type IV hypersensitivity?
-macrophage activation and inflammation induced by ctyokines produced mainly by DC4+ Th1 cells and Th17 cells or by killing of host cells by CD8+ CTLs
What are the mechanisms of type III hypersensitivity?
- Fc receptor binds to Ab reacted with toxoid.
- Classical complement pathway activated
- Ab and cells transported to site(s) of antigen deposition
- anaphylatoxins C3a, C5a, adn C4a attract macrophages and neutrophils to cause tissue damage
What are causes of food intolerance?
-lactose intolerance
- IBS
- muscle contractions in the intestin
- NS
- severe infection
- inflammation
- changes in microflora
- food poisoning
- sensitivity to food additives
- recurring stress or psychological factors
- celiac disease
What is celiac disease (CD)
an immune-mediated systemic disorder elicited by gluten in genetically susceptible individuals and characterized by gluten dependent manifestations, CD specific antibodies, HLA-DQ2 or HLA-DQ8, and enteropathy
Type IV hypersensitivity
What are non GI findings in celiac disease?
- failure to thrive
- delayed puberty
- autoimmune disorder
- inflammation
- neurological disorder
- metabolic disorder
Describe antigen processing in MCH II
- microbial Ags are taken up by professional APCs via phagocytosis or endocytosis
- protein Ags undergo enzymatic degredation into peptides
- peptide Ags loaded into class II MHC and presented to CD4+ Th lymphocytes
What is gluten?
proline rich protein that is poorly digested in SI due to lack of prolyl endopeptidases
-also rich in glutamine residues
What causes gluten to be potent to people with CD?
crosslinking and deamidation of gluten peptides by TG2 creates potent immunostimulatory epitopes that are presented to HLA-DQ2 or -DQ8 on APCs
-activated CD4 T cells secrete Th1 cytokines such as INF gamma to induce release of MMPs by myofibroblasts resulting in mucus remodel and villus atrophy
