lecture 7 Flashcards
(25 cards)
the mucosal system
The mucosal system is an important compartment of the immune system which protects internal surfaces
Up till now we have discussed adaptive immunity in the lymph nodes which is stimulated following infection
via the skin
in internal organs
or systemic in the blood stream
The mucosal system is an even larger immunological compartment and protects surfaces where most pathogens invade
organs inovlved in the mucosal system
The mucosal immune system includes lymphoid organs associated with intestine, respiratory tract and urogenital tract and associated glands
how is the mucosal surfaces protected by the organs around it?
The mucosal system is protected by commensal microorganisms (microbiota) which are beneficial to their host- the colon is most heavily colonised
vaginal births - combination of fluids will seed the gut flora of that individual. children through cesarian could be more susceptible to alergies or diseases. because they dont get into contact with microflora
distinctive features of the mucosal immune system
anatomical features that distinguish it from the systemic immune system
effector mechanisms that are unique to the gut
immunoregulatory environment with unique characteristics
TABLE IN L7 S5
what is GALT
The organised tissues which make up GALT are the sites of T and B cell antigen presentation facilitated by M cells
how is an immune response triggered
Antigens at intestinal surfaces must be transported across an epithelial cell layer to stimulate the mucosal immune response- the M cells do this
- M cells take up antigen by endocytosis and phagocytosis
- antigen is transported across the M cells in vesicles and released at the basal surface
- antigen is bound by dendritic cells which activate T cells
mucosal immune system compartments and cells
The mucosal immune system contains large numbers of immune cells even in the absence of disease and forms two distinct compartments –> the epithelium and the lamina propria.
Cellular composition of the two compartments of the mucosal immune system
The lamina propria contains a mixture of IgA secreting plasma cells, memory T cells, conventional CD4+ and CD8+ cells, dendritic cells, macrophages and mast cells.
The major cell type in the epithelium is a CD8+ T cell which expresses an integrin which is able to bind E-cadherin, an epithelial adhesion molecule.
How do naïve T cells become effector T cells in the intestinal immune system?
DIAGRAM IN L7 S10
how do pathogens get across the membrane?
Unique populations of dendritic cells in the mucosal immune system capture antigen transported across the epithelium by a variety of mechanisms
- non sepcific transport across epithelium
- FcRn dependent transport
- apoptosis dependent transfer
- antigen capture
Immune response in the lamina propria and the antigen experienced T cells
The lamina propria contains antigen-experienced T cells which have been activated by dendritic cells.
- The T cell population is in the proportion CD4:CD8 3:1
- CD4+ T cells secrete large amounts of cytokines including IL-17, the colon is the only place in the healthy body, where TH17 cells are found, but TH1 and TH2 also found
- These T cells would in other places cause inflammation- but balanced by Treg cells which secrete IL-10
- During infection effector activity increases owing to either more effector cells recruited or diminished activity of Treg cells
It also contains unusual populations of innate-type lymphocytes producing IL-22 which are somewhat like NK cells
unique cells in the epithelium
The epithelium is a unique compartment of the immune system which contains intraepithelial lymphocytes
they are CD8+ T cells
they lie within the epithelial layer between epithelial cells
Properties of intraepithelial lymphocytes
The intraepithelial lymphocytes have an activated phenotype in the absence of infection- there are two types (a) and (b).
The intraepithelial lymphocytes express CD8 and contain perforin and granzymes (a).
The TCRs on the intraepithelial lymphocytes display restricted VDJ usage (b).
The intraepithelial lymphocytes express an endothelium binding integrin.
Their importance is to recognise changes in gut epithelial cells as a result of damage or stress of infection.
how can Effector T cells (type a) kill virus infected targets?
Effector T cells (type a) can kill virus infected targets by typical Class I MHC recognition
- virus infects mucosal epithelium cell
- infected cell displays viral peptide to CD8 IEL via MHC class I
- activated IEL kills infected epithelial cell by perforin/granzyme and Fas-dependent pathways
stressed intestinal cells
Stressed intestinal cells express the non classical MHC molecules MIC-A and B and produce IL-15. Type b IELs are activated by IL-15 and recognise MIC-A,B with a specific receptor NKG2D
DIAGRAM IN L7 S17
what is the secretory IgA release?
Secretory IgA is the antibody response associated with mucous membranes and is trancytosed with the help of Polymeric Ig R
DIAGRAM IN L7 S18
The 3 functions of IgA on epithelial surfaces
- secreted IgA on the gut surface can bind and neutralise pathogens and toxins
- IgA is able to bind and neutralise antigens internalised in endosomes
- IgA can export toxins and pathogens from the lamina propria while being secreted
The mucosal response to infection and regulation of mucosal immune responses
The major role of mucosal immunity is to protect against a huge variety of enteric pathogens
The response must be able to recognise and respond to any pathogen, but must not produce the same response to harmless antigens (eg food) or commensal organisms
The mucosal immune response has to balance these competing demands
Enteric pathogens cause a local inflammatory response
The innate immune system is usually sufficient to eliminate the variety of gut infections that can take place
Pattern recognition receptors (PRRs) like the toll-like receptors (TLR) present on epithelial cells are important in this process
Ligation of TLR stimulates release of cytokines & chemokines which attract monocytes eosinophils and T cells out of the blood and the release of antimicrobial peptides
Tissue resident dendritic cells are also attracted
– Stimulation of costimulatory molecules on the dendritic cells overcomes their normally relatively unresponsive state in the gut
pathogens can harness what processes?
The inflammatory response and M cell transport can be harnessed by pathogens to aid their entry into gut epithelia-eg Salmonella enterica
salmonellae enter and kill M cells, and then infect macrophages and epithelial cells
The GIT is a major source of antigen
The majority of antigens in the intestinal tract come either from food or commensal bacteria not from pathogenic organisms.
These do not raise an immune response even though they should be considered as non-self since not in the thymus when T cells are educated.
This phenomenon is known as oral tolerance and attempts have been made to harness it for the treatment of autoimmune disease.
how is the mucosal immune system is balanced
protective immunity and mucosal tolerance
BY: antigens primary Ig production primary T cell response response to antigen reexposure
how is the balance of microorganisms in the gut?
and the role of dendritic cells?
Peaceful coexistance of commensal organisms in the gut
Mucosal dendritic cells regulate the balance between the induction of tolerance or immunity in the intestine
Reasons for a lack of response to food and commensals
The commensal organisms and food antigens do not carry the danger signals recognised by the TLRs on the surface of macrophages and dendritic cells (PAMPs).
Hence they do not stimulate an inflammatory response which is necessary to generate an immune response.
Commensal gut flora also inhibit the activation of dendritic cells, by production of molecules like prostaglandin- these cells give out weak co-stimulatory signals to CD4+ T cells making them differentiate into regulatory T cells and preventing them from activating to TH1 or TH2 cells.
Regulatory CD4+ T cells generate anti inflammatory cytokines and stimulate an anti inflammatory local IgA response by class switching.
