La2- Mucosal Immune System Flashcards
How are ilc non specific
No ag receptor
So how are they stimulated
Cytokines release by epi, mac, dc or dying cells
Give example of a parasite controlled by ilc2 response
Helminths
Give example of a leukocyte required in this process
Eosinophils (attracted by il5)
What are the 4 main roles of ilc
Link adaptive
Inflammation
Barrier function
Tissue remodelling/repair
What is the tuft cell- ilc2 loop for protists/helminths/ec
Stimulation of tuft cells like succinate produced by pathogen metabolism
Causes release of il25
Thsi stimulates ilc2 and release il13
Il13 able to skew differentiation into more tuft and goblet cells
Means efficient trapping in mucus barrier
Which intracellular protozoan killed efficiently by il12 induced cells ilc1,th1,NK
Toxoplasma gondii
How do cytokines signal for their development
Cytokine y chain receptor
Do they have the same tf like th1,2,17 induced by the cytokines
Yes
Which cytokines from ilc2 required for m2 development antiinflam
13,4
How does it induce healing (ilc2)
Through amphireglin (areg)
Which subset of ilc3 can present MHC for T cells
Ccr6+ ilc3
Other than amp increase what else does il22 do
Induced formation of tj (effective barrier eg claudin 2)
Induced amp exp and release
Induce mucin exp
Which type of ilc upreg in giardia lamblianinfection
Ilc3
What’s the diff between inductive and effector sites
Inductive is where ag uptake and presentation to naive cells occurs
Effector is where they migrate to for clearance eg from the circulation back to lp/subepithelium
Give 2 reasons microvilli exist
For sa for absorption or for sensing in tuft cells
What are tj for and made of
Keep cell polarity
Claudins, occludin, jams, zonulin
What other types of junctions are there cell to cell
Desmsoomes linking if together
Adheren junctions linking actin (made of cadherins )
What is there cell to basal Lamina
Hemidesmosomes and actin linked matrix junctions
What 3 trafficking occur in cells meaning polarity needed
Recycling back from endosome
Transcytosis
Degradation pathway (lysosome fusion)
What does the lymphoid lineage vs myeloid contain
B,t, NK and ilc
Myeloid is granulocytes and macrophages/dc/monocytes
What makes up the malt
Nalt- walldeyers ring (adenoids in nose and tonsils in mouth)
Balt- bronchus associated
Galt - lymphoid follicles and pp
No ugt
Give some unique features to mucosal immune system
M cells in nalt and galt
Siga
Constant active memory and T cells in absence of pathogen
Regulatory pathways/tolerance
Close contact with epithelium and the galt
Specific homing
Where do immune cells go from pp eg after ag presented
Draining to mesenteric Ln
Then through lymph to the circulation
Where via hev ag mucosal tissues can extravasate to their mucosal effector site
What adhesion molecule do hev at mucosal surfaces have for extravasation of lymphocytes
Madcam1 (bind integrins like a4:b7 or L-Selectins for naive)
(Lung tissue has pnad for l-selectin or vcam1 for a4:b1
How is balt diff to this
Has pnad or vcam1 instead
Which receptor marks lymphocytes mainly of si origin so they can home back via teck chemokine
Ccr9
What do iga+ plasma cells usually have (some T cells too)
Ccr10 (eg from nasal, salivary , mammary, intestine)
Where can they home to
Other mucosal sites like bronchi, mammary glands, large intestine
Through which chemokine at these sites
Mec
What marker for systemic homing do lymphocytes from nalt have (also naive before they are marked)
Ccr7 and L-selectin
Is homing established in ugt
No but evidence of systemic and mucosal immunity there
What does immunisation orally do
Mount Siga in gi tract , mammary and urt (salivary,lacrimal glands)
What does immunisation nasally do
Siga and igG at ugt and resp tract (lower and upper)
Do colons have isolated lymphoid follicles
Yes for some iga responses but local
Which receptor type in nasal immune cells are there for this response by vaccine
Ccr10 (so can migrate to resp tract which has mec)
Give some ways ag can cross barrier
M cell transcytosis
Cross epithelial dc or macrophages
Through Apoptotic cells
Through goblet cells (if soluble)
What do m cells have for recognition
Prion protein receptors
What 2 types of cd8 cell are there
CD8 ab- for killing of infected cell
CD8 ydelta- killing stressed cells eg in the coeliac disease gluten response
Which antibodies are specific to mucosal immunity
Polymeric
Dimeric iga
Pentameric igm
Why are resp tract and ugt different
They have majority igG unlike the other mucosal with mainly iga
How are iga / igm transported
Using pigr unidrectionally from baso lateral to apical side
Secreted with the sc via protease cleavage of pigr
How is igG different
It is bidirectionally through fcrn receptor instead
Also can be exp on placental endothelial cells (for maternal blood to foetal blood transfer) not just epi cells
Which disease associated with reduced iga specifically because of pigr polymorphism
Ibd
What is seen in gf mice colonised for first time
Hypertrophic pp and increased Siga+ plasma cells
Inducing which tlr causes coating of iga of Microbiota eg b and f
5 (induced th17 response and therefore iga release)
How does il17 from th17 diff (by Microbiota) cause pigr exp
Il17 activates nfkb can cause pigr exp by binding an element in intron 1
What else causes this nfkb binding
Tlr signalling in general through myd88 and activation of nfkb binding to pigr
Mice Il-17r deficient caused what
Lower levels of pigr exp
How else do Microbiota influence b cells/antibodies
Aid expression
And tslp sexretion from epi cells
Give 4 roles of iga
Neutralise ag/ suppress motility of pathogens in lumen
Neutralise ag already endocytosed within endosome of epithelium
Export out using their pigr any toxins that crossed the epithelial barrier
Modulate innate immune responses
How can they be anti inflammatory via innate modulation
Suppress complement activation
What can they induce
Better phagocytosis eg of neutrophils or macrophages
Fcr stimulation on eosinophils for degranulation
How do they interact with mucins to trap pathogens
Through cysteine residues
What is the difference between classic and natural iga
Classic is T cell dependant activation and class witching high affinity fab region
Natural are present T cell independently and exhibit low affinity
What cytokines help plasma cell and b cell survival and isotype switching in T cell independent (via dc)
April and baff
What induced these cytokines in first place
Tslp (induced by Microbiota…)
Explain t cell dep response for high affinity
First signal is via bcr and ag
Then second is via cd40-cd40l binding aswell as mhc on B-cell with tcr holding ag
= class switching and high affinity shm
Can tlr stimulation also induce t-inde classswitching
Yes via nfkb signalling downstream to induce aid expression
Natural iga can allow for tolerance how
Low affinity because probably reduced somatic hypermutation/activity
Would pathogens induce shm
Yes likely through T cell responses better stimulation of macrophages
Eg cholera toxin
What is the differences between iga1 and iga2
Iga1 has longer hinge region making it more flexible for cross linking
Also glycosylation via both o and n glycosylation
Iga2 shorter and only n glycosylation
Iga1 in majority of mucosal surfaces except colon where iga2 is more
Why is n glycans present on the secretory component also important
Can bind bacteria instead of fab region
Why would Colin need more iga2
More Microbiota and some have protease activity which can cleave epitopes of the longer hinge sequence of iga1 but can’t cleave iga2
What happens for fcrn igG trafficking instead ef in lung or ugt especially in acidic ph from apical to baso lateral
Acidic ph apically causes recetor mediated endocytosis
Endosome trafficking
And then out by a transport vesicles where fcrn releases igG at neutral ph
What can happen both ways in neutral ph
Pinocytosis and transcytosed and then released from fcrn in neutral ph
What type of proteins are fcrn
MHC class 1
In which disease is it upregulated unlikeniga
Ibd (because of adcc potentially and also complement activation = inflammatory )
How many bacteria in colon
10^11 (the most)
What would happen / happens in gf mice to immune system of mucosa
Reduced siga production and serum iga
Decreased T cell
Reduced cd8 cytotoxicity
Reduced lp size
Impaired rh17 responses
Normally nfkb will cause inflammation via eg tlr system by microbes. Which butyrate induced molecule stops this system
Ppary
How
Blocks it’s binding to genes and causes export out of nucleus
Alternatively what can be done to block nfkb eg scfa do this (butyrate) and salmonella = tolerance
Block ikb degradation
How can saa from sfb cause dc maturation
Gmcsf exp
Which cytokines inducing ilc3 can non-disclosed / identified Microbiota induce release of by epi cells aswell as tslp
Il25 and 33
How are ilc3 seen in Ibd crohns
Because gmcsf released blocks m2 development and induces more m1
= reduced antiinflam cytokines like tgfb which also needed for tissue repair
Why is m1 bad
Can secrete proinflam like tnf, il23,il12, which can induce th1 and th17 responses = pro inflammatory and seen in Ibd
Low affinity of natural IgAs can cause what
Binding to wide range of epitopes/microbes potential instead of highly specific
Although Microbiota induced ilc3 which produces gmcsf can stimulate inflammatory m1, how can it also cause tolerance
Release of RA and IL10 (for treg differentiation)
Which 3 malt sites have m cells for ag uptake
Tonsils, adenoids and pp
How is PSA recognition by tlr2 example of tolerance
Induces cd4 cell release of il10 which is anti inflam
Whcih 2 markers do naive lymphocytes have which allows their homing systemically to lymphoid tissues via HEV
Ccr7 and l-selectin
What is the difference between cxr9 and 10
Ccr9 is majority only T cells and is specific to homing mainly in the small intestine via TECK chemokine released from those hev
Some b cells will have Ccr9 to home to si too but very little amount
Ccr10 is majority only b cells/iga plasma blasts from nalt, si,colon,stomach which then homes to diff mucosal sites like li, bronchi, mammary and salivary glands through MEC chemokine
Dc will activate switching to the specific homing receptors eg Ccr9,10 a4:b7 or a1:b7. How
Retinoic acid release
What does pnad and vcam1 bind in the bronchi
Pnad binds l-selection
Vcam bind a4:b1 integrin on some immunocytes eg from nalt
Which markers instead are induced at the nalt which makes mucosal interact with systemic immunity
A4:b1 ine grin (binds vcam in bronchi)
Also systemic induction of Ccr7 and l-selectin (binds madcam) = systemic
Why would gut immunisation not give immunity to airways
A4:b7 not important here
What can iga - pathogenic or commensal complexes be recognised by which induces anti inflammatory il10 release vs downregulated inflam tnfa etc
Dc-sign expressing dendritic cells
Give example where this has been shown
Shigella flexneri complexes (helps downregulate the inflammation)
