Mucosal Defense Flashcards
What are muscosal surfaces? What is mucus?
surfaces bathes in a layer of thick fluid/mucus they secrete which helps protect epithelial cells from damage and stop infection. Mucus containing:
- glycoproteins
- peptides
- enzymes
- proteoglycans
Where in the body can muscosal surfaces be found?
The line the
- GI tract
- respiratory tract
- urogenital tract
Exocrine glands of pancreas, salivary glands. mammary glands.
Why are mucosal tissues important?
- They act as sites of communication
- gas exchange
- food absorption
- sensory
- reproduction
Why are mucosal surfaces vulnerable to pathogens?
They are dynamic, thin and have permeable barriers.
-There is a very large surface area largely of monolayer of epithelial cells; 200x bigger than skin
There are Ab producing cells on mucosal surfaces
More antibody made for muscosal defense than all other Ab production. This is energy expensive as 5-15g of Ab made.
Mucosal defense is separate from circulating defence
In the GI tract, how does immune response eliminate pathogens but not food?
there are large populations of commensal microorganisms which need to be limited.
To co-ordinate this response, GI has secondary lymphoid tissues throughout gut and other tissues, in epithelium and connective tissues.
Waldeyer’s ring: where the tonsils (ccand adenolds form a ring of lymphoid tissue around gut entrance.
What is lamina propria?
secondary lymphoid tissues underlying the connective tissues
What are the mesentric lymph nodes?
Largest node arranged in a chain within the gut connective tissue
What is GALT?
Gut associated lymphoid tissue
In the GI tract, how does immune response eliminate pathogens but not food?
there are large populations of commensal microorganisms which need to be limited.
To co-ordinate this response, GI has secondary lymphoid tissues throughout gut and other tissues, in epithelium and connective tissues.
Waldeyer’s ring: where the tonsils (palatine and adenolds, lingual) which form a ring of lymphoid tissue around gut entrance.
What is the characteristic lymphoid organ of the intestine?
Peyers patches down the length of the gut which are dome shaped structure containing B cell follicles with germina center, T cell area and dendritic cell. These are all the molecules needed for a response. These drain into lymphatic vessels towards mesentric lymph nodes.
The dome is overlaid by a specialized epithelial M cell
What is the function of M cells?
Microfold cells transport antigens/microorganisms from gut lumen to the lymphoid tissue in peyer’s patch beneath where an innate response begins.
they do not secrete mucus or enzymes
In the GI tract, how does immune response eliminate pathogens but not food?
there are large populations of commensal microorganisms which need to be limited.
To co-ordinate this response, GI has secondary lymphoid tissues throughout gut and other tissues, in epithelium and connective tissues.
Waldeyer’s ring: where the tonsils (palatine and adenolds, lingual) which form a ring of lymphoid tissue around gut entrance.
The Gut samples the content of its lumen via epithelial M cells and peyer’s patches and isolates lymphoid follicles
Describe the mechanism of M cell transport of antigens
- M cells take up antigen via phagocytosis: the dendritic cells lie in basal membrane pocket of the M cell which receive the pathogen
2) DC and B cell take up pathogen, process and present to naive T cells
3) cells stimulated inn M cell, or in the lymph node to proliferate and differentiate
In the GI tract, how does immune response eliminate pathogens but not food?
there are large populations of commensal microorganisms which need to be limited.
To co-ordinate this response, GI has secondary lymphoid tissues throughout gut and other tissues, in epithelium and connective tissues.
Waldeyer’s ring: where the tonsils (palatine and adenolds, lingual) which form a ring of lymphoid tissue around gut entrance.
The Gut samples the content of its lumen via epithelial M cells and peyer’s patches and isolates lymphoid follicles continuously.
T cells stimulated into effector T cells. helper T cells activate B cells to become plasma cells which make IgA against commensals, food antigens, pathogens.
What happens to DC when infection strikes in gut?
Lamina propria contianing DC cells; when infected, DC increase mobility, move epithelial wall and extend processes in order to capture antigens.
DC go to GALT or next lymph node to stimulate T cells.
What is lamina propria?
secondary lymphoid tissues underlying the connective tissues.
These are heavily populated with effector lymphocyes even in healthy tissue; these cells are active due to the changing contents of the gut needs sampling.
Describe the mechanism of M cell transport of antigens and resultant pathway
- M cells take up antigen via phagocytosis: the dendritic cells lie in basal membrane pocket of the M cell which receive the pathogen
2) DC and B cell take up pathogen, process and present to naive T cells
3) cells stimulated in M cell, or in the lymph node to proliferate and differentiate
4) home back to same/different mucosal tisssue from blood where IgA is secretes and T cells kill.
What is IEL (intraepithelial lymphocytes)
In the epithelial layer of small intestine, there is a IEL in between normal epithelial cells
They are CD8+ and contain granuloes. They are activated by antigen.
System protects mucosal site of infection but also distant mucosal sites. How do T cells home out of blood, into lamina propria and into epithelial?
This is coordinated by cytokines (integrin and adhesion molecules)
- alpha4-beta7 (a4b7) integrin on T cell binds to MadCAM-1 of endothelial gut wall cells.
- T cells squeeze through cell barrier into lamina propria.
- CCL25 from epithelium binds to CCR9 on T cell. In addition, T cell’s a4b7 binds to E-cadherin on epithelial cell.
What Ig do naive B cells switch to? What determines this switch?
They switch to IgA, the cytokine Beta(TGF-beta) determines this switch.
Describe IgA. What is unusual about IgA2 structure?
It is the major Ab in seromucous secretions like saliva, milk, colostrum milk, urogenital tract.
There are 2 subclasses: IgA1 AND IgA2.
IgA2 has 2/3 variants: IgA2m(1), IgA2m(2)
Structure of A1: long hinge enables FAB arms to bind to antigens great distance apart.
Structure of A2m1: No disulphide bridges between light and heavy chain, just between light-light chains and two heavy chains; the light and heavy chains associate NON COVALENTLY
What are effector functions of IgA? Describe Fc-a-R1 Funcions.
1) Manose-binding lectin Compement activation
2) IgA1/2 is specific for Fc-alpha-Receptor1 (CD89) in serum and secretory; it binds on Fc region.
This triggers:
i) phagocytosis
ii) enzyme release
iii) superoxide generation to attack cell.
What is the (ratio) differences of serum IgA and secretory IgA?
In serum it is monomeric with more A1 subclass (9:1)
In secretory it is more dimeric with more A2 (40:60). There is also 1 J(oining) chain and 1 secretory component (SC) in addition to H and L chains.
What is SC (secretory component)
It is a proteolytic fragment of the receptor which mediates transport of dimeric secretory IgA out into mucosal secretions.
What is the joining chain?
chain linked to Cys residues on IgA tail via disulphide bonds
Describe the process of IgA transcytosis
Dimeric IgA produced on basolateral surface of epithelium lining mucosal cell by activating plasma cells (interior)
It binds to polymeric immunoglobulin receptor (plgR) to form a complex, which is internalised into a vesicle and transported across epithelial cells via transcytosis.
When released, plgR is cleaved; part of receptor fragment stays attached via disulphide bridge which is the SC.
What is plgR (Polymeric immunoglobulin receptor)?
It has 5 Ig like domains which only binds to polymeric antibodies like dimeric IgA or dimeric IgM.
This mediates IgA transport into mucosal cell.
What are the functions of IgA once it reaches mucosal cell?
1) binds and neutralises at the gut surface and within endosomes of epithelial cell where pathogens have been underling the surface.
2 )moderates innate immune functions in the lamina propria including;
i) decreasing NK
ii) promoting opsonisation
iii) triggers eosinophil degranulation
How can pathogens compromise IgA?
IgA1 proteases secreted by bacteria which cleave the extended hinge of IgA1.
Bacteria can cause Gonorrhoea, meningitis, oral disease.
Different bacteria secrete different proteases which cleave at different points on IgA.
Describe IgA deficiency
This is fairly common and can be compensated for by increasing other isotype classes, such as dimeric IgM which can also bind to plgR and cross epithelium to mucosal lumen.
Also increase IgD, IgG
What is the function of M cells?
Microfold cells transport antigens/microorganisms from gut lumen to the lymphoid tissue in peyer’s patch beneath where an innate response begins. For sampling.
they do not secrete mucus or enzymes
What happens to DC when infection strikes in gut?
Lamina propria contianing DC cells; when infected, DC increase mobility, move epithelial wall and extend processes in order to capture antigens. (in addition to M cell capture)
DC go to GALT or next lymph node to stimulate T cells.
Which two cell types sample the gut lumen?
DC and M cells.
