L12 - Mucosal immunology 2 Flashcards
MESENTERIC LYMPH NODES 1
i) where are they located?
ii) give two main roles
iii) what is oral tolerance? how can it be harnessed in allergy?
iv) are they an organ?
v) where does lymph from the rectum drain into? how is this important in rectal cancer?
i) located at the base of the mesentery
ii) collect lymph, cells and antigens from the intestinal mucosa
- main site of oral tolerance induction
iii) oral tolerance - aavoidance of an immune response to foodstuffs and other matter
- can use oral tolerance induction as a therapeutic option in allergy
v) lymph from rectum drains to inguinal LNs
- in rectal cancer > can met to inguinal LNs
MESENTERIC LYMPH NODES - DRAINAGE
i) where do MLNs drain lymph from?
ii) what type of vessel allows abs of fat and nutrients from the small intestine? why are these different to other lymphatic vessels?
iii) what is the role of immune cells in liver sinuses? (2)
iv) what goes wrong in alcoholic liver cirrhosis which leads to a build up of endotoxin?
i) MLNs drain lymph from the intestinal mucosa
ii) lacteals allows abs of fat and nutrients
- different to other lymph vessels as they regenerate during adulthood
iii) immune cells in the liver sinuses maintain food tolerance
- protect from microbes/microbial products in the portal vein eg LPS
iv) alcoholic liver cirrhosis > increased resistance in the P vein
- splenic vein acts as a bypass > swamped with endotoxin
LAMINA PROPRIA AND INTRAEP LYMPHOCYTE COMPART
i) where are intraepithelial lymphocytes situated?
ii) what shape do IELs have? what allows close contact with neighbour cells?
iii) which cells are they mixed with?
iv) what two main groups can IELs be divided into?
i) basolateral portion of the epithelium
ii) irregular shape and long extensions to allow close contact with neighbour epithelial cells
iii) mixed with eosinphils - up to 12% eosino in IEL preps
iv) divided into tissue resident memory T cells and innate like/innate lymphocytes
NK CELLS
i) what receptors do NK cells carry? where are they found
ii) apart from NK cells - which other cells can carry NK cell receptors such as NKG2D?
iii) what type of receptors does NKG2D bind? what are these called (2) what situation does this happen in and what can be the cause?
iv) how do IELs expressing NKG2D kill their target? (2)
v) what do intraepethelial CD8 T cells produce? what type of pathogen is this important in killing?
i) NK cells in the gut carry the NK receptor
ii) unconventional T cells eg TCRab+CD8aa can carry NK receptors eg NKG2D
iii) NKG2D binds stress receptors on damaged gut epithelial cells = MIC-A and MIC-B
- happens in situations of stress which can be caused by toxins
iv) cells expressing NKG2D can kill target by secreting perforins which put holes in the cell mem
- or by secreting granzyme > apop > phago of debris
v) intraep CD8 T cells produce IFNy
- important in killing epithelial cells infected with virus (express on MHCI)
MECHANISMS OF DAMAGE
i) when a virus infects a cell - which MHC is it presented on? which type of cell targets this?
ii) name three molecules that are used to destroy a viral infected cell?
iii) what does invasion of a toxic peptide to an epithelial cell cause? what receptor do cells then express? what does this bind on the infected cell? (2)
iv) name two things that are released to destory a toxic peptide infected cell?
i) virus presented on MHC I
- targeted by CD8+ T cells
ii) perforin, granzyme and fas > apoptosis of cell
iii) toxic pep > ep cell causes stress
- NK or CD8aa cells express NKG2D which bind MIC-A/B on the infected cell
iv) granzyme and perforin
T HELPER CELLS IN THE GUT
i) what is Th cell differentiation in the gut influenced by?
ii) name two cytokines that the non toxic Th17 cells can produce?
iii) name two cytokines the toxic variant of Th17 can produce?
iv) what do these cytokines interact with? what does this regulate and ultimately lead to?
i) influences by epithelial and dendritic cells
ii) non toxic Th17 produce IL-17 and IL-22
iii) toxic Th17 produce IL-17 and IFNy > kill endothelial cells
iv) cytokines can interact with receptors on ep cells to regulate production of mucins/defensins > stabilise intestinal epthelial barrier
v)
T REGULATORY CELLS AND DENDRITIC CELLS IN THE GUT
i) what are T reg cells produced in response to? which two molecules are present to allow this?
ii) which two things can Tregs regulate?
iii) what IL do Tregs produce? what is this crucial for?
iv) where do dendritic cells sit? how do some of these cells sample the contents of the intestinal tube?
v) what cells will be activated if dendritic cells sense danger? what does this allow?
i) Tregs produced in response to harmless commensals in the presence of retinoic acid and TGF
ii) regulate immune food tolerance and B cell class switch
iii) Tregs produce IL-10 > maintain tolerance to commensals and food
iv) dendritic cells sit in the lamina propria
- some have extensions reaching through the epithelium to sample the intestinal contents
v) DCs activate cytotoxic response if sense danger
- allows response to danger before there is damage
INDUCTION OF T CELLS
i) where does priming and functional imprinting of T cells happen?
ii) which two molecules cause T reg differentiation? what does this allow?
iii) which two factors released from dendritic cells transform CD4 cells into cytotoxic T cells?
i) in gut associated lymphatic tissue eg peyers patch
ii) retinoic acid and TGFb
- allows T reg differen to allow tolerance
iii) DCs reelase IL-6 and TGFb to cause CD4 > cytotoxic T cell
MUCOSAL B CELLS AND IGA 1
i) once B cells are primed, where do they head to before reaching the mucosal effector site?
ii) once at the effector site - where do B cells sit? what Ig do they produce?
iii) what is the main antibody in secretions?
i) primed B cell > thoracic duct > blood > effector site
ii) sit int he lamina propria and produce IgA
iii) IgA is the main antibody in secretions
IgA
i) what is immune exclusion?
ii) how strongly does IgA activate complement?
iii) what structure does IgA have that is trasported through epithelial cells? what chain joins this molecule?
iv) which receptor allows IgA to bind gut endothelial cells? which surface does it bind?
i) immune exclusion = certain antigens cant invade an organism but no immune response is triggered by them
- prevents invasion by a mucosal barrier
ii) igA weakly activates complement
iii) IgA is dimeric and coupled by a J chain
iv) poly Ig receptor allows IgA to bind the basolateral surface of gut endothelial cells
POLY IG RECEPTOR
i) what does this receptor bind to? what does it allow?
ii) what characteristic does a portion of the receptor have/? what does this allow?
iii) where is the receptor found?
iv) what does the mechanism help to aid in relation to IgA?
i) binds the J chain of IgA and also IgM
- allows trans-endotheoial transport of dimeric IgA and petameric IgM
iii) receptor is found on basolateral surface of ep ells
iv) mech helps enrich the Igs in the mucus where they can exert function of immune exclusion
GUT HOMING OF B AND T CELLS 1
i) what does homing mean for lymphocyes? where does it happen?
ii) where are gut homing properties of effector cells imprinted? what also happens here?
iii) where will T cells primed in a specific induction site then re-enter? is this the same or a different tissue?
i) homing means that T and B cells are instructed to return to effector sites
- happens in all tissues
ii) gut homing properties of effectir cells are imprinted in the gut associated lymphoid tissue
- this is also where they have undergone differen from naive precusors
iii) T cells primed at a spec induction site then re enter the same tissue at an effector site
MECHANISM OF T AND B CELL HOMING
i) which site does a naiive T cells enter?
ii) what happens at this site?
iii) where does the cell then leave via? (2)
iv) what does the T cell then bind on the effector site? what allows this to happen?
v) what happens if a T cell primed in a different tissue tries to enter the effector site? why does this happen?
i) naiive T cell > induction site
ii) surface adhesion molecules are imprinted onto the cell in the induction site
iii) T cell then leaves via thoracic duct and then blood
iv) T cell then binds a receptor on the effector site by its surface adhesion molecule
v) if a T cell primed in a different tissue tries to enter then it will not bind to the effector site as it will have different surface adhesion molecules
GUT HOMING - NUTRITION AND LOCAL FACTORS
i) what enzyme is produced by dendritic cells in gut assoc lymph tissues are induced by local factors? what is the function of this enzyme?
ii) what molecule allows upregulation of adhesion molecules on lymphocytes in MLNs/PPs?
iii) which two ligands will the lymphocyte express if it is primed in the presence of retinoic acid? which two sites will the T cell then be able to travel to and bind?
i) dendritic cells produce RALDH
- converts vitamin A > retinoic acid
ii) retinoic acid allows upreg of adhesion molecules on lympho
iii) lymphocyte will express CCR9 and a4/b7 if priming takes place in the pres of RA
- can then travel to effector sites = lamina prop and epithelium
PROCESS OF GUT HOMING OF B AND T CELLS
i) which two things do the lamina propria dendritic cells capture from the gut lumen? where do they then migrate to?
ii) which cells are then activated? what molecule is required for this? where does that molecule come from?
iii) when T cells are activated - which two things are expressed on its surface? what type of molecule is each?
iv) where do the cells then travel? where do they end up?
v) which two molecules are expressed on the lamina prop venular endothelial cells during inflammation? what does this allow?
vi) what does the cell ultimately end up as? give two fates for this cell
i) LP dendritic cells capture antigen + vitamin A
- then migrate to a mesenteric LN or peyers patch
ii) activation of B or T cells in the presence of retinoic acid
- RA from vitamin A (due to RALDH enz)
iii) activated T cells express CCR9 (chemokine receptor) and a4b7 (an integrin)
iv) cells then travel via the lymphatic system, thoracic duct and blood stream back to the ‘home’ in the gut
v) during inflam > express CCL25 (lig for CCR9) and MADCAM (lig for a4b7) on endo cells to allow access to the homed cells (lock and key binding)
vi) cell becomes a lamina propria T cell
- can be a resident memory cell or continue to recirculate
SUMMARY PART I
i) what site plays a major role as an induction site in the gut apart from peyers patches? where is this site found? name one other role it plays
ii) name the two broad groups of intraepithelial lymphocytes? what makes these cells so important?
iii) what are the two subtypes of IEL CD8 cells?
iv) what are the two main types of IEL CD4 T cell? what is the role of each and what do they each secrete?
v) what are Tregs important for? why does this matter?
i) mesenteric LNs - found at the base of the mesentery
- major role in inducing tolerance to foods
ii) two main groups of IEL
- resident memory T cells
- innate like/innate cells
iii) CD8 T cells = convential CD8 cells (alpha and beta) unconventional CD8 (2x alpha)
iv) two main types of CD4 T cell are
- non toxic Th17 - produce IL-17 and IL-22 - stabilise intestinal barrier by TJs and mucus secretion
- toxic Th17 - produce IFNy - tissue damage
v) Tregs are important for tolerance to food antigens
- important as abs of nutrients and inflammation are incompatible
SUMMARY PART II
i) where are mucosal B cells located? what do they do here?
ii) what is the main Ig secreted in mucus? what structure does it have?
iii) what mechanism is this Ig secreted by? what additional transport molecule does this require? what receptor does this molecule originate from?
iv) how strongly does this Ig activate complement? what are its main roles (2)
v) what does commensal gut flora induce? what does this aim to do?
i) mucosal B cells located in the lamina propria
- secrete Ig
ii) main Ig secreted is IgA
- dimeric IgA joined by a J chain
iii) IgA is secreted by transcellular transport and requires the secretory component of the poly Ig receptor
- poly Ig receptor expressed on basal surface of gut ep cells
iv) IgA weakly activates complement
- can neutralise toxins and prevent microbial invasion
v) commensal gut flora induces low affinity IgA response aimed at immune exclusion
SUMMARY PART III
i) which cells do antigen primed B and T cells originate from? where is their recirculation pattern restricted to? (2)
ii) how do naiive B and T cells reach peyers patches and MLNs?
iii) which two events happen to naiive cells before they travel back to the blood stream? how do they get to the blood?
iv) where do they ultimately return to?
v) how do they leave the blood stream? what mediates this? where do they go?
i) antigen primed B and T cells orig from naiive b and t cells
- recirc restricted to blood and lymph nodes
ii) naiive b and t cell > PP and MLNs via high endothelial venules
iii) naiive cells have antigen contact (induction) and tissue specific imprinting > then back to blood
- get to blood via lymphatic system and thoracic duct
iv) ultumately return to the gut via the blood
v) leave the blood by adhesion to the endothelium small venules (NOT HEVs) expressing ligands for CCR9 and a4b7
- then transmigration to the lamina prop and intraep sites
