Barrier Immunology in the Gut (Week 11) Flashcards
REVIEW: What are the major cytokines that induce Treg cell development?
- IL-2
- TGF-beta
REVIEW: What effector cytokines do Treg cells usually secrete?
- IL-10 (a good antiinflammatory cytokine –> suppresses immune response)
- TGF-beta
Note: Treg cells are important for gut homeostasis
REVIEW: What are the major cytokines that induce Th17 cell development?
- IL-23
- Il-6
- TGF-beta
REVIEW: What effector cytokines do Th17 cells usually secrete?
- IL-17A
- IL-17F
- IL-22
Note: these are usually associated with an increased secretion of antimicrobial peptides
Note: too much Th17 activation can be pro-inflammatory, but mild Th17 activation can be anti-inflammatory… therefore Th17 and Treg cells can both contribute to keeping things “under control”
REVIEW: Which T helper cells “turn up” the immune response?
- Th2
- TFH
- Th1
REVIEW: What cytokine induces development of Th2 cells?
IL-4
REVIEW: What do Th2 cells secrete?
- IL-4
- IL-5
- IL-13
Note: associated with eosinophil activation, allergic response, parasitic/worm response, polarization of B cells to make IgE
REVIEW: Which cytokines induce development of Th1 cells?
- IL-12
- IFN-y
- IL-18
REVIEW: What do Th1 cells secrete?
- IFN-y
- TNF
Note: associated with viral response/activatation of cytotoxic T cells, fighting intracellular pathogens, class-switching to IgG subtypes, macrophage activation
REVIEW: What cytokine induces development of TFH cells?
IL-12
REVIEW: What is the effect of TFH cells?
- iCOS
- CD40 interactions
Note: associated with antibody production
TGF-beta and retinoic acid stimulate class-switching to ______
IgA
IL-4 and IL-5 stimulate class switching to ______
IgE
Note: large amounts of IL-4 and IL-5 can stimulate class switching to IgM
What type of cells does IgE bind to?
eosinophils, basophils, and mast cells
Note: IgE binds to the Fc receptor which triggers degranulation of granulocytes
Which antibody type is predominantly found as a dimer and secreted into the GI and respiratory tract, and in tears, saliva, and breastmilk?
IgA
True or False: IgA is produced in the highest quantity in our body (5g/day)
True
What are the functions of IgA?
- neutralizing and aggregating pathogens
- developing tolerance within the mucosal immune system*
REVIEW: What are the major types of innate lymphoid cells (ILCs)?
- NK cells
- “resident” ILCs
Which of the following ILCs help with the development of gut tolerance?
a) ILC1
b) ILC2
c) ILC3
c) ILC3
Type 3 ILCs (ILC3) secrete IL-17 and are effective against extracellular bacteria, however they also contribute to lymphoid tissue development at the barrier and developing gut tolerance
REVIEW: What are some of the key proteins associated with tight junctions?
- claudins
- occludin
- junctional adhesion molecules (JAMs)
- ZO-proteins
REVIEW: Which tight junction protein interacts with cytoskeleton?
ZO-proteins
Which tight junction proteins are transmembrane proteins?
- claudins
- occludin
- junctional adhesion molecules (JAMs)
- large collections of lymphoid nodules in the ileum
- a few cm in length, can be palpated
- most people have about 100
- MALT is very thick and well-developed
- luminal surface lined by M (microfold) cells
What type of immune structure in the gut is this describing?
Peyer’s patches
- found throughout the gut
- MALT nodules without capsules
- smaller than Peyer’s patches
- luminal surface lined by M (microfold) cells
What type of immune structure in the gut is this describing?
isolated lymphoid follicles (ILFs)
True or False: Enterocytes themselves have immune functions. For example, they have many PRRs, which tend to be intracellular or at the basolateral surface. Enterocytes also translocate IgA from the lamina propria to the luminal layer of mucus
True
the receptor that binds to secreted IgA at the basolateral surface of the enterocyte, allowing the enterocyte to take it up and later exocytose it
polymeric IgA receptor
IgA is secreted by enterocytes bound to what?
the secretory component and J chain
True or False: Goblet cells are only found in the colon
False
They are found all throughout the intestine but highest population = in the colon
___________ cells secrete mucous, acting as a barrier to bacterial invasion and also secrete anti-microbial peptides (AMPs) that prevent bacteria from getting too close to teh epithelial lining
Goblet
__________ cells, located in the crypts, secrete large quantities of AMPs
Paneth
very specialized cells that are present over the surface of Peyer’s patches and ILFs, with a smooth apical surface that captures antigen, and has a large basolateral “pocket” that allows intimate contact between APCs and lymphocytes
microfold cells (aka M cells)
True or False: Less mucous is found over sites with M cells
True
___________ are glycoproteins that impair bacterial mobility (make it difficult for bacteria to penetrate the epithelial barrier)
Mucins
True or False: Defensins, phospholipases, and lyzosymes can all degrade bacterial cell walls or create pores in them
True
What is predominantly secreted by Paneth cells, is toxic against gram (+) bacteria, but has some activity against gram (-) bacteria and is unique to the GI tract
REG3 (a type of lectin)
via punching holes in bacterial cell walls
Two types of IgA are secreted in the gut. What is the difference between unshuffled IgA and shuffled IgA?
unshuffled IgA = the antibody sequence has not undergone affinity maturation (more broadly specific for a wide range of microbes); generally inhibits microbe penetration into the mucosa (either commensal or pathogenic microbes)
shuffled IgA = the antibody sequence has undergone affinity maturation due to Th-B cell interactions; aka “high-affinity IgA”; fights off pathogens
If a microbe penetrates the epithelial barrier, is a pro-inflammatory response more or less likely?
more likely
A ____________ (inflammatory/non-inflammatory) gut environment results from tolerance (to “nonself” molecules) in the GI tract
non-inflammatory
What are some tolerogenic features of a happy, non-inflammatory gut?
- very low or zero levels of molecules that promote type 1 or type 2 inflammation
- low levels of signals associated with Th17 and ILC3 activation
- “normal” levels fo anti-inflammatory cytokines and regulatory Th cells
What are some signals that are associated with the maintenance of tolerance in the gut?
- IL-10, retinoic acid (RA), TGF-beta
- APRIL, BAFF
- low levels of Th17-type cytokines (IL-23, IL-17, IL-22)
Which signals associated with tolerance in the gut:
- are produced by many immune and non-immune cells
- tend to enhance Treg and IgA production, as well as inhibiting inflammation
IL-10, retinoic acid (RA), and TGF-beta
Which signals associated with tolerance in the gut:
- are pro-B cell messengeres released by epithelial cells and resident APCs
- enhance T-independent B cell production of IgA
APRIL and BAFF
Low levels of Th17 cytokines (e.g., IL-23, IL-17, IL-22) enhance production of _____________
antimicrobial proteins
What are the three major sources IgA is secreted by plasma cells?
1) ILFs (isolated lymphoid follicles)
2) Peyer’s patches
3) Mesenteric lymph nodes around the abdominal aorta
Note: most of the IgA secreted in the lumen is from 1) and 2)
How do T cells induce IgA class switching?
via TGF-beta, retinoic acid, and CD40L/iCOS interactions
How does IgA class switching occur without the help of T cells (T-independent)?
BAFF and APRIL are secreted by mucosal dendritic cells and enterocytes
Note: “BAFF and APRIL are pro-B cell activating cytokines”
True or False: ILC3 (innate lymphoid cell type 3) secretes similar cytokines as Th17 (e.g., IL-17, IL-22)
True
IL-17 and IL-22 thought to increase enterocyte/Paneth cell ability to secrete antimicrobial peptides (keeping that protective distance)
True or False: ILC2, ILC1, Th1, and Th2 cells are commonly found in a healthy gut
False
You would see more ILC3 and Th17 cells in a healthy gut
Human ILC3 cells respond to what?
- directly to microbes via TLRs (UNLIKE mice)
- retinoic acid and IL-23 (released from innate immune cells and enterocytes)
Once activated, what do ILC3 cells secrete?
IL-22, IL-27 –> leads to increased production of AMPs by enterocytes and Paneth cells
factors that induce the full development of Peyer’s patches and ILFs (isolated lymphoid follicles), and IgA production
ILC3 activation can amplify the _______ response in the gut
Note: This can be tolerogenic (good) or pathogenic (bad), depending on the presence of pro- or anti-inflammatory cytokines
Th17
Th17 cells can be induced to become what type of cells?
Tfh and Treg
True or False: Although Th17 and ILC3 are strongly implicated in autoimmunity and inflammatory disease, they are also crucial for tolerance in the gut (when in an anti-inflammatory environment)
True
Even though they can be pro-inflammatory, they still have an important role in a healthy gut (when in an anti-inflammatory/more tolerogenic environment)
anti-inflammatory environment = high in IL-10 and TGF-beta, and low IL-6 (pro-inflammatory)
Does the small or large intestine have a more diverse microbial community?
large intestine = greater microbial diversity
The _____________ (small/large) intestine has
- many Paneth cells
- prevalent M cells
- Peyer’s patches are present
- fewer ILFs
- few goblet cells
small intestine
The ________ (small/large) intestine has
- lots of goblet cells
- lots of ILFs
- no Paneth cells
- few M cells
large intestine
Excess large intestinal bacteria in the small intestine is known as __________________
small intestine bacterial overgrowth
True or False: The same microbes invade the small and large intestines
False
Different microbes
True or False: Different autoimmune disorders affect the large vs. small intestine
True
Example: Celiac disease doesn’t touch the large intestine
Example: Ulcerative colitis doesn’t touch the small intestine
What are the three major species of commensal bacteria in the gut?
1) Firmicutes
2) Actinobacteria
3) Bacteroidetes
Commensals tend to stimulate the development and accumulation of ______ cells
Treg
Commensels aid the development of MALT via __________
TLR signalling
Humans ILC3s can detect commensals via TLR signaling
_____________ (segmented and filamentous bacteria) enhance IgA production and Th17 development
Firmicutes
True or False: Without ILC3 cells, we don’t really develop mature Peyer’s patches or lymphoid follicles
True
What is the complex, multi-step way that gluten can mess with our intestinal immune system in Celiac Disease?
1) a degradation product known as alpha-gliadin is resistant to proteolytic degradation by pancreatic enzymes
2) Gliadin binds to a chemokine receptor (CXCR3) –> leads to production and release of zonulin extracellularly –> zonulin binds to its receptor –> leads to disassembly of ZO proteins –> and therefore diassemby of tight junctions (= “leakiness”)
3) Gliadin ALSO causes production of IL-15 by enterocytes –> which causes intra-epithelial lymphocytes to express NK cell “activating receptors that bind to stress proteins on the enterocyte” (Note: binding to stress proteins on enterocyte = this will kill the enterocyte)
4) Gliadin and other pro-inflammatory molecules likely leaks through the damaged tight junctions
5) APCs phagocytose gliadin and some individuals will express HLA-2 molecules that present glidin ina. way that activates Th cells (usually Th1 or Th17)
Note: step 5 = the “kiss of death”
____________ expression is strongly linked to the development of celiac disease
HLA-DQ2 or DQ8
a combination of enterocyte destruction by intra-epithelial lymphocytes (NKG2D recognzies stress proteins), loss of tight junction integrity, and ongoing inflammation driven by gliadin as an antigen
This is the pathogenesis of what?
celiac disease
Note: these mechanisms lead to the development of self-antibodies (i.e., transglutaminase antibodies), destruction of villi, crypt hyperplasia, and migration of immune cells into teh crypts and lamina propria
How does celiac disease present in adults?
- anemia
- chronic diarrhea
- bloating
- fatigue
- deficiences in B12 and iron
How does celiac disease present in children?
- irritability
- anorexia
- chronic diarrhea
- weight loss
- muscle wasting (malaborption)
- some also present with abdominal pain, nausea, vomiting, bloating, or constipation
What are some extra-intestinal manifestations that are common in celiac disease (for all ages)?
- arthritis or joint pain
- apthous stomatitis
- iron deficiency anemia
- dermatitis herpetiformis (itchy, erythematous, blistering macular-vesicular lesion often on torso, up to 10% of patients)
What are some extra-intestinal manifestations that are common in celiac disease in CHILDREN?
- seizure disorders
- pubertal delay
- short stature
How do you diagnose celiac disease?
- anti-tissue transglutiminase antibodies (>95% specificity and sensitivity); most labs detect IgA tTG - if IgA deficiency, then need to look for IgG
- duodenal biopsy = GOLD STANDARD (but not always available)
What is the prognosis of celiac disease?
- very good prognosis if gluten can be avoided
- continual exposure to gluten will result in intestinal and extra-intestinal manifestations that don’t seem to get better… and in a small minority, may develop a B-cell lymphoma (due to excess B cell activation) –> eventually can develop into malignancy
