Barrier Immunology in the Gut Flashcards
Different cytokines secreted by T-helper cells will induce ________
Class switching
What does Th1 secrete? what does it stimulate?
- Secretes: IFN-gamma
- Class switching to IgG subtypes, macrophage activation, CT cell activation
TGF-beta and retinoic stimulate class switching to what?
IgA
What does Th2 secrete? what does it stimulate?
- Secretes IL-4 and IL-5
- Class switching to IgE
Antibody secreted as a monomer in small quantities?
IgE
Function of IgE?
- Binds cells with Fc receptor = triggers granulation of granulocytes
Antibody predominantly found as a dimer secreted in the GI and respiratory tract mucous?
IgA
Functions of IgA? (2)
- Neutralizing and aggregating pathogens
- Developing tolerance within mucosal immune system
Antibody produced in highest quantities in our body?
IgA
ILCs that are cytotoxic monitors of
and responders to abnormal-looking or stressed cells?
NK Cells
Where are resident ILCs found?
Barrier tissues
ILCs that secrete cytokines such as IFN-gamma and TNF-alpha?
ILC1
ILCs that secrete cytokines such as IL-4, IL-5, IL-9, IL-13?
ILC2
ILCs that secrete IL-17 and IFN-gamma?
ILC3
What are type 3 ILCs effective against?
Extracellular bacteria
Trans-membrane proteins that can act as channels for small molecules (paracellular)
Claudins
Trans-membrane protein, function not clear
Occludin
Trans-membrane protein that may mediate permeability to larger molecules
Junctional Adhesion Molecules (JAMs)
Protein important in tight junction formation, interact with the cytoskeleton
ZO-proteins
Large collections of lymphoid nodules in the ileum?
Peyer’s patches
What is the luminal surface of a Peyer’s patch lined with?
M (microfold) cells
MALT nodules without capsules found throughout the gut?
Isolated lymphoid follicles (ILFs)
Gut cells with immune function? (4)
- Enterocytes
- Goblet cells
- Paneth cells
- Microfold cells
Where are PRRs generally on enterocytes?
Tend to be intracellular or
located at the basolateral surface (come on luminal surface)
How do enterocytes translocate IgA? (3)
- enterocyte grabs IgA from plasma cells in LP
- Assemble with secretory component and J-chain
- Exocytosis
What is the e receptor that binds to secreted IgA at the basolateral surface of the enterocyte?
Polymeric IgA receptor
Cells found all throughout the intestine, but the highest population in the colon?
Goblet cells
Function of goblet cells? (3)
- Secrete mucous = barrier to invasion
- Secrete anti-microbial peptides (AMPs)
- Can transport antigen from lumen to APCs in LP
What cells are located in the crypts that secrete large quantities of AMPs?
Paneth cells
Very specialized cells present over the surface of Peyer patches and isolated lymphoid follicles (ILFs)?
Microfold cells (M cells)
Apical surface of M cell?
Smooth = captures antigen
What part of M cells intimately contacts PACs and lymphocytes?
Large basolateral “pocket”
Is more or less mucous found over sites with M-cells?
Less
What is the M cell basement membrane like?
Sieve
The GI tract must? (2)
- maintain commensal bacteria and be exposed to potentially antigenic macros
- fight off pathogenic molecules
The GI tract must not?
Develop an inflammatory response to potentially antigenic macronutrients or healthy commensals
Mucous in the lumen impairs bacterial ________ and makes it difficult for bacteria to penetrate the __________
mobility; epithelial barrier
What in the mucous of the lumen impairs bacterial mobiity?
Mucins and glycoproteins
What layer is very thick in the large intestine? What does it contain a lot of?
- Mucous layer
- Goblet cells
What can degrade bacterial cell walls or create pores in them? (3)
- Defensins
- Phospholipases
- Lysozymes
Secreted mostly by Paneth cells, mainly toxic against gram (+)-ve bacteria but also seems to have some activity
against gram (-)-ves?
REG3 - unique to GI tract
What is “unshuffled” IgA?
The antibody sequence has not undergone affinity maturation - broadly specific for wide range of microbes
What do unshuffled IgA generally inhibit?
Microbe penetration into mucosa
What does it mean for unshuffled IgA to be somewhat tolerogenic?
Reduces the likelihood of inflammation in the mucosa
What is shuffled high-affinity IgA?
The antibody sequence has undergone affinity maturation due to Th-B cell interactions
Why are shuffled IgA more deadly?
They have higher affinity for pathogens that have been recognized as pathogenic
Are shuffled or unshuffled IgA more likely to be related to overall gut inflammation?
Shuffled
4 methods for bringing antigen from lumen to APC?
- M cell dependent
- FcR dependent
- Goblet cell dependent
- Direct APC contact
Methods of antigen presentation may be tolerogenic or cause the development of inflammation and this depends on what?
The activation state of APC and presence of messengers
If a microbe penetrates the epithelial barrier, what response is likely?
Pro-inflammatory response
Tolerogenic features and molecules in a non-inflammatory gut environment? (3)
- Low/No molecules that promote type 1 or 2 inflammation
- Low levels of signals associated with Th17 and ILC3 activation
- normal levels of anti-inflam cytokines and Th cells
Signals associated with maintenance of tolerance in the gut? (3)
- IL-10, retinoic acid, TGF-beta
- APRIL, BAFF
- Low levels of Th-17 cytokines
What do IL-10, retinoic acid, TGF-beta do? (2)
- Enhance Treg and IgA production
- inhibit inflammation
What do APRIL and BAFF do? (2)
- Pro-B cell messengers
- Enhance T-independent B cell production of IgA
What are Th17-type cytokines and what do they do?
- IL-23, IL-17, IL-22
- Enhance production of anti-microbial proteins
IgA is secreted from plasma cells from what 3 major sources?
- ILFs
- Peyer’s patches
- Plasma cells in mesenteric lymph nodes around abdominal aorta
Most of the IgA secreted in the lumen is from what 2 sources?
ILFs and Peyer’s patches
T-dependent IgA class switching?
Tfh induce IgA class switching in B cells via TGF-beta and CD40L/iCOS interactions
What is the result of T-dependent IgA class switching?
The production of ONE or A FEW specific antibodies
T-independent IgA class switching?
BAFF and APRIL are secreted by the mucosal dendritic cells and enterocytes
What are the results of T-independent IgA class switching? (2)
- Low affinity Ab’s quickly produced
- MANY different types of Ab’s produced
Where is T-independent IgA class switching likely to take place?
Much more likely to be produced in a tolerogenic environment
There are quite a few _____ and _____ cells in a healthy gut, and less _______ or _______
ILC3 and Th17; ILC2/ILC1 or TH1/Th2 cells
Human ILC3 cells seem to respond to…? (2)
- Directly to microbes via TLRs
- To RA and IL-23 released from innate immune cells and enterocytes
What do ILC cells do when activated? (3)
- Secrete IL-22 and IL-17 = produce AMPs by enterocytes and Paneth cells
- Secrete factors that induce Peyer’s patch, ILF, and IgA production
- Amplify Th17 response in gut
How does Th17 response facilitate IgA production? (2)
Can be induced and become either:
- Tfh = Ab production in follicles and lymph nodes
- Treg = anti-inflam cytokine prod = down regulate APCs
Does SI or LI have larger microbial community?
Large Intestine
What are there more of in the SI?
- Paneth cells
- M cells
- Peyer’s patches
What are there more of in the LI?
- Goblet cells
- ILFs
Commensal microbiome tends to…? (2)
- Stimulate development and accumulation of Tregs
- Aid in development of MALT
3 major commensals in the SI?
- Firmicutes
- Actinobacteria
- Bacteroidetes
Development and accumulation og Tregs can be through the secretion of what?
Short Chain Fatty acids (SCFAs)
How can commensals aid in the development of MALT?
ILC3 can detect commensals through TLR signalling
What bacterial family by themselves enhance IgA production and Th17 development?
Firmicutes
What is the degradation product that is resistant to proteolytic degradation by pancreatic enzymes in celiac disease?
Alpha-gliadin
What chemokine receptor does gliadin being to and what is the result?
CXCR3 = produces and releases zonulin extracellularly
What does zonulin do?
Binds to its receptor, disassembles ZO proteins = disassembles TJs
What does gliadin cause to be produces by enterocytes and what does it do?
IL-15 = causes intra-epithelial lymphocytes to express NK cells activating receptors
APCs phagocytose gliadin and some individuals will express _____ that present gliadin in a way that activates Th1 or Th17
HLA2
HLA-DQ2 or HLA-DQ8 are necessary for what?
Perpetuate inflammation and destruction of villi
What does destruction of intra-epithelial lymphocytes, TJ integrity, and ongoing inflammation lead to? (3)
- Development of self-antibodies (tissue-transglutaminase Ab’s)
- Destruction of villi
- Migration of immune cells into crypts and lamina propria
Adult presentation of celiac disease (5)
- Anemia
- Chronic diarrhea
- Bloating
- Fatigue
- Deficiencies in B12 and iron
Pediatric presentation of celiac disease (5)
- Irritability
- Anorexia
- Chronic diarrhea
- Weight loss/malabsorption
- Some with abdominal pain, nausea, vomiting, bloating, constipation
Extra-intestinal manifestations of celiac disease all ages (4)
- Joint pain/arthritis
- Aphthous somatitis
- Iron deficiency anemia
- Dermatitis herpetiformis
Extra-intestinal manifestations of celiac disease in children (2)
- seizure disorders
- pubertal delay and short stature
Gold standard diagnostic test for celiac disease?
Duodenal biopsy
What antibodies have a >95% specificity and sensitivity for celiac disease diagnosis?
Anti-tissue transglutaminase Ab’s
