Mucosal Immunity Flashcards
what are the 4 physiological functions of mucosal tissue?
- gas exchange
- food absorption
- sensory activities
- reproduction
why id the mucosal tissue highly vulnerable?
What does trans and paracellular transport mean?
= due to fragility and permeability
Trans - through cells
Para - in tight junctions
what feature of a lymph node brings the antigen into the lymph node?
= afferent lymphatic vessels
what feature of a lymph nodes causes the antigens to leave the lymph nodes?
= efferent lymphatic vessels
describe 3 anatomical features of gut mucosal immune system?
1) intimate relationship between mucosal epithelial and lymphoid tissue
2) organised lymphoid tissue structure unique to mucosal site
3) specialised antigen uptake mechanism
what are the effector mechanisms used in the GUT?
- activated/memory T cells
- effector/regulatory T cells
describe the immuno-regulatory environment of the gut.
- down regulation of immune response
- inhibitory macrophages and tolerating dendritic cells
where are intestinal lymphocytes found?
= in organised tissue where immune responses are induced, and scattered throughout the intestine, where they carry out effecter functions.
what are Peyer’s patched covered by?
= an epithelial layer containing specialised cells called M cells which have characteristic membrane ruffles.
why does the M cells have ruffles one the membrane?
increase the surface area
what shape do Peyers patches form? and what colour are they?
= dome shape
= purple
meaning lots of nuclei
how do M cells take up antigens?
= by endocytosis and phagocytosis
how are antigens transported across the M cells and where are they released?
Transported = in vesicles and Released = at basal surface
what is the antigen bound by?
= dendritic cells, activating T cells
Yes or No.
can dendritic cells extend processes across the epithelial layer?
Yes.
why do dendritic cells extend processes across the epithelial layer?
= two capture antigen from lumen of the gut
what 2 components does the mucosal of the immune system consist of?
1) epithelium
2) lamina propria
what type of immune cells are contained in the epithelia?
intra-epithelial lymphocytes
how do T cells enter Peyer’s patches?
from blood vessels, directed by the homing receptor CCR7 and L-selectin
what do these T cells in the Peyer’s patch then encounter?
= encounter antigens transported across M cells and become activated by dendritic cells.
what do the activated T cells then?
= drain via mesenteric Lymph nodes to thoracic duct and returns to gut via bloodstream
what do acivated T cells express?
alpha 4; beta 7 integral
and
CCR9 ome ot lamina propria and intestinale epithelium of small intestine
what do gut-homing effector T cells bind?
= bind MAdCAM-1 on endothelium
what do gut epithelial cells express?
chemokine specific for gut-homing T cells
where else is MAdCAM also found?
= in vasculature of other mucosal sites.
what can lymphocytes primed in the guts do?
= migrate to other mucosal sites
how do passive immunity transfer?
in breast milk
what are 3 humeral intestinal responses?
IgA = 80%
= dimeric
IgM = 15%
IgG = 5%
Yes or No.
Reversal of systemic humeral immune response; IgG, IgM, IgA monomeric?
Yes
where does IgA bind?
= to receptor on basolateral face of epithelial cells
what does IgA binding to receptor on baso-lateral face of epithelial cells cause?
= endocytosis
what happens after endocytosis?
= transcytosis to apical face of epithelial cells
after transcytosis to apical face of epithelial cells, what happens?
= release of IgA dimer at apical face of epithelial cells
what can secreted IgA on the gut surface do?
= bind and neutralise pathhogens and toxins
what is IgA also able to bind and neutralise?
antigens internalised in endoscomes
what can IgA export?
toxins and pathogens from lamina propria while being secreted
what does the activated appearance on special T cells contain?
full killing machinery
describe the antigen receptor repertoire on special T cells?
= restricted antigen receptor repertoire
describe the different recognition mechanisms.
2 types with different recognition mechanisms
describe the different recognition mechanisms.
2 types with different recognition mechanisms
what type of lymphocytes lie within epithelial lining of gut?
= intra-epithelial lymphocytes (IELS)
what are intra-epithelial lymphocytes positive?
CD8-positive T cells
at higher magnification, what can the ILEs be seen to lie within?
the epithelial layer between epithelial cells
what happens after the virus has infected mucosal epithelium cells?
infected cells display viral peptide to CD8 IEL via MHC class I
what do activated IEL kill?
infected epithelial cells by perform/granzyme and Fas dependent pathway
what do epithelial cells undergo as a result of infection, damage or toxic peptide?
= stress and express MIC-A and MIC-B
what binds to MIC-A,B and as a result activated IEL?
NKG2D on IELs bind
what else binds o TL?
CD8Alpha:alpha homodimers
what do activated IELs kill?
the stressed cell via perforin/granzyme pathway
what needs to happen to maintain the balance between protective immunity and homeostasis?
= discriminating between pathogen and innocuous antigens
what happens after oral administration of protein state of specific peripheral unresponsiveness = oral tolerance?
= default response
What is inhibited more - T cell &IgE mediated responses or serum IgG responses?
T cells and IgE mediated responses are inhibited more than serum IgG responses both locally and systemically
proposed mechanism
proposed mechanism
proposed mechanism
proposed mechanism
proposed mechanism
proposed mechanism
proposed mechanism
proposed mechaism
how does pathogen recognition occur by and what does this initiate?
= TLRs, initiating a cascade of signals that activate IKK
what does IKK phosphorylate?
= IKB, targeting it to be degraded
- NFKB translocates to the nucleus to activate gene transcription
what blocks gene transcription, by activated PRARgamma, which removes NFKB from nucleus?
some commensal bacterial
what can some commensal bacteria block?
degradation of phosphorylated IKBs, preventing NFKB trans-location to the nucleus
look at slide 29
look at slide 29
what are 5 roles of intestinal mucosal in imm unity in disease?
- infectious disease
- primary immunodeficiency
- allergy
- coeliac disease
- IBD
what type of immune mechanism eliminates most intestinal infections rapidly?
= innate mechanisms
how does the immune mechanism work?
= activation though ligation of pattern recognition receptors
= intracellular sensors in epithelial cells, PRR, activate NFkB pathway
= gene transcription and production of cytokines, chemokines an defensives
= activation of underlying immune response
what is the outcome of infection by intestinal pathogens determined by?
= complex interplay between micro-organism and host
See slide 32 on diagram.
See slide 32 on diagram
what do infected dendritic cells shuttle?
= shuttle virus from site of exposure to regional lymph nodes where they concentrate virus particle and infect CD4+ T cells
what are 5 mucosal disorders associated with primary immuno-deficiency?
1) Selective IgA deficiency -2/3 asymptomatic remainder recurrent sinopulmonary infections (Coeliac disease 10x)
2) CVID - recurrent sinopulmonary and GI infections
= failure to differentiate into Ig secreting cells
= Low IgG, IgA, IgM and IgE
= Defective antigen specific antibody response
3) XLA - Sinopulmonary and GI infections+ devastating systemic manifestations of chronic enteroviral infections
No B cells/ agammaglobulinaemia
4) CGD - Staphlococcus aureus/inflammatory granulomas- pneumona, liver abscess, perianal abscess and skin abscess.
Failure of phagocyte respiratory burst
5) SCID- Profound defect in T and B cell immunity
oral candidiasis/chronic diarrhoea/interstitial pneumonitis
GI- CMV/rotavirus/EBV
what type of hypersensitivity is associated by food allergy?
= type I hypersensitivity reaction
how is type I hyper-sensitivity reaction initiated by?
= cross linking allergen specific IgE on surface of mast cells with the specific allergen
= memory response-immune system must be primed
what does IgE secreted by plasma cells bind to?
a high-affinity Fc receptor FcgammeRI on mast cell
what do activated mast cells provide?
= contact and secreted signals to B cells to stimulate IgE production
see IgE mediated allergic reactions slide 37
see IgE mediated allergic reactions slide 37
see slide 38
see slide 38
what is coeliac disease/gluten sensitive enteropathy?
= genetically linked, (auto) immune disorder, causing damage to small intestine leading to malnutrition
- life long, incurable
- NOT an allergy
what genes make you susceptible to coeliac disease?
HLADQ2
HLADQ8
describe gamma interferon in coeliac disease?
Gamma interferon from Gluten specific T cell activate epithelial cells which produce IL-15 which induces proliferation and activation of IEL
- Both T cells and IEL can then kill epithelial cells
see slide 41 on diagrams
see slide 41 on diagram
describe transamination of gliadin peptide and activation of gliadin-specific T cell.
leads to activation of plasma cells and other lymphocytes.
- cytokines released by activated lymphocytes lead to damage to intestinal epithelium
look at slide 44 diagrams.
look at slide 44 diagram
how do you diagnose coeliac disease?
= biopsy
= serology, useful as screening test IgA anti-tissue trans-glutaminase auto-antibodies
what is Crohn’s disease
= can affect any part of the GI tract from mouth to anus - commonly distal ileum and colon
= focal and discontinuous inflammation with deep and eroding fissures +/- granulomas
how is Crohn’s disease mediated by?
= Th1 CD4+ T cells/gamma interferon/IL-12/TNF alpha
Yes or No.
Is it a multiple genetic deficiency and immunological mechanism - multi-factorial - HLA.
Yes.
what gene is identified in Crohn’s disease?
= NOD2
- intracellular PRR muramyl dipeptide of bacterial peptidoglycan
describe the interleukins identified in Crohn’s disease?
IL-8 and neutrophil function
AND
IL-23/atuophagy
what is ulcerative colitis restrictive to?
= retracted to rectum and colon
- starts in rectum and moves proximally and contiguously (and develops extra-intestinal manifestations)
- inflammation and ulceration just in surface mucosa
what infiltrates the distortion of crypts?
= infiltration of monocytes/neutrophills and plasma cells
Yes or No.
Does immuno-pathology fit into Th1/Th2?
= no
- postulated may be an NK T cell mediated disease via IL-13
what do both conditions produce large amounts of?
= large amounts of inflammatory cytokines IL-1, IL-6 and TNF alpha
how would you treat these conditions?
= non-specific anti-inflammatory and immune-suppressive drugs steroids, azathioprine, cyclosporin, methotrexate
= anti-TNF alpha
