Give the basic details on mucosal surfaces
- Exposed to the environment
- 1 ton of nutrients pass through the adult gut each year
- Large surface area specialised for absorption
- Resistant micro flora at most mucosal epithelia
- Main route of entry for a pathogen
Give some differences between systemic and mucosal environments
Systemic:
- Contained
- Sterile
- Encounters undefined antigens rarely
Mucosal:
- Exposed
- Non-sterile
- Encounters undefined antigens continuously
What is the importance of mucosal immunity?
- Protection against pathogens
- Prevention of hypersensitivity to foods / commensal organisms / microflora
- Preventing self immune diseases
- Vaccine development
What are mucosal tissues defined as?
Tissues exposed to the environment.
Give some features of the non-immunological and immunological mucosal barrier
Non-immunological:
- Natural barriers e..g stomach acid
- Mucin - forming gels
- Peristalsis - movement to pass mircobes away
- Proteolysis - enzymes produced
- Microvillus membrane - harder for microbes to adhere to
Immunological:
- Secretory IgA/IgM
- IELs (intra epithelial lymphocytes)
- Phagocytes
What are regionalised secondary mucosal immune tissues?
- Specific inductive or effector sites at mucosal surfaces (Inductive - inducing immune response
Effector - site where immune response is having its effect - Sites are called Mucosal Associated Lymphoid Tissue
- Each mucosal surface has its own
- The regionalised areas feed into each other
What is the common mucosal immune system?
It is a connected series of tissues.
All mucosal surfaces of the body are part of this.
The lymphatic and the vascular system allows the movement of immune cells that can go to other mucosal sites.
Get a trickle down effect where induction at one site will induce a weaker response elsewhere.
Give some information on the GALT organisation
Consists of the epithelial layer and the lamina propria underneath.
It has 2 secondary inductive sites (peyers patches and isolated lymphoid follicles).
Give details on the structure and function of Peyers patches
- Sub-epithelial follicles
- Located throughout the small intestine (200 here)
- Patches contain 50% B cells, 30% T cells and 8% macrophages
- They are inductive sites of GALT
- They connect to the lymphatic system only by efferent lymph vessels, they have no afferent vessels
- B lymphocytes from the Peyer’s patch give rise to IgA producing plasma cells which home to all mucosal sites
(They contain lymphocytes that are ready to be activated when they come in contact with an antigen and then they will move elsewhere to give their response.
Most of the plasma cells here are pre-differentiated.
Only draining lymphatics out, no lymphatics are led in.)
Give the details of the well organised Peyer patch structure
Can see the patches sit under the epithelial layer and then drains to the mesenteric lymph node which is also fed by lymphatics coming from the lamina propria. From there it drops into the systemic distribution to be fed back into the required site.
Give the details on the structure and function of the isolated lymphoid follicles
They are induced by products of commensal gut microorganisms.
No communal organisms means you will not have these things. More exposed to commensals, the more the organism will have.
They are mainly B cells, some T cells and dendritic cells.
They are more numerous than Peyers patches (15x more).
Found in organised tissues where immune responses are induced.
They are smaller than Peyers patches.
What are M cells and where are they present?
They are microfold cells.
Unique epithelial cell subset.
They are specialised in uptake and transepithelial transport of particulate antigens.
No brush border / microvilli. Instead they have a folded membrane which means they are great for endocytosis.
Located in the epithelial layer above Peyer’s patches and isolated lymphoid follicles.
They have a big invagination to allow for B and T cells to engage within the M cell to become rapidly in contact with any antigens moved across the M cell.
The M cells take up particulate matter and transport it into the invagination to be sample by the dendritic and T cells or passed further into the structure.
(Each of the secondary sites have a unique epithelial cell which sit in the epithelial cap on the top of both isolated lymphoid follicles and Peyer’s patches. These are microfold cells).
What happens inside the Peyers patch?
- T and B cells become fully activated (also in the mesenteric lymph nodes)
- T and B cells switch expression from L-selectin and CCR7 to A4B7 integrin and CCR9 (switch from naive to mature cells)
- B cells class switch to IgA
Why do we need Peyers patches when we have lymph nodes?
- T and B cell get rapid activation here and continuous sampling of the surrounding environment to the patch can occur.
- T and B cells switch from naive cells to mature cells to express integrins rather than selectins.
- Get class switching for B cells for antibody expression.
- Cells produced here will go into the circulation and to their place of response.
Give some conventional cells and some specific cells of the mucosal immune system
Conventional Cells:
- Dendritic cells
- Macrophages
- Neutrophils
- Mast cells
- Eosinophils
- Basophils
- T cells
- B cells
Specific cells:
- Epithelial cells
- M cells
- Intraepithelial Lymphocytes
- Gamma/delta T cells
(Eosinophils and Basophils are present here to be involved in parasitic infections.
Have specific cells found only in mucosal immunity also.
Intra epithelial lymphocytes - embedded within the epithelium.
Gamma-delta T cells - associated with mucosal sites and skin sites)
What are the 2 effector sites of mucosal compartments?
There are 2 effector sites which are the lamina propria and the epithelial layer.
Each has its own immune cells. Lamina propria has T cells have other lymphocytes, plasma cells, dendritic cells, mast cells and macrophages and neutrophils. There is a surface of IgA.
Epithelial layer - have the epithelial cells which can provide immune responses (purely innate). Intra epithelial T cells present here which tend to be CD8 in origin. Dendritic cells present that goes through the surface to sample it. IgA is secreted across the boundary. Many less immune cells.
Give details on the T cells of the lamina propria
Give details on the lamina propria T cells subsets
- Found underlying the epithelial layer
- Majority are CD4+ (helper cells)
- Most express alpha 4 beta 7 integrin
- They produce cytokines dependant on their subset
- Tregs act to regulate / suppress other immune cells via IL-10 and TGF beta
- Th1 act to activate macrophages via IFN gamma
- Th2 act to induce B cell class - switching to IgA via IL-5
- Th17 act to maintain epithelial barrier function cia IL-22 and activate neutrophils via IL-17
What are Intra Epithelial Lymphocytes?
- All are T cells, majority are CD8+
- delta/gamma T cells may be frequent >70% on certain species
- express specific integrins
- unresponsive to TCR stimulation
- these cells express E-cadherin which is a protein that is expressed that helps them to bind to the epithelial cells rather than the lamina propria.
- mature outside the thymus
What is lymphocyte homing?
Lymphocyte homing refers to adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs.
Response that has been generated in the mesenteric lymph node or the peyers patches or the isolated follicles.
It gets the activated cells to the site of infection.
What are the steps involved in migration of the immune cells to the epithelial cell suface?
- The first step in homing is chemoattraction (moving up a concentration gradient).
Chemokines recruit lymphocytes and induce expression of adhesion molecules.
Have a conc of the chemotaxis agent (could be a chemokine) and you go up the conc gradient.
The chemokine is attracting things in but is also activating the cell and causing it to produce certain factors.
In a naive cell, it will produce Lectins. This lectin interacts with the MADCAM. This is a molecule expressed on epithelial and lamina propriety cells.
- Second step is rolling adhesion. The lymphocyte binds loosely to the endothelial cell and rolls along.
The lymphocyte is attracted to an area and then bind loosely with the endothelial cells.
The interaction being the seletins and MADCAM is not particularly strong which means that although it sticks, you have a flow of blood over the top so it ends up rolling.
In sticking, a signal transmits thats induces changes in the lymphocyte and the epithelial cell.
- Tight adhesion:
Increase in the signal of alpha 4, beta 7 integrin which interacts with MADCAM tightly.
Lymphocyte is no longer rolled along, it is attached tightly to the endothelial cell.
Further integrins are made e.g. ICAM 1 and ICAM 2 on the endothelial cell.
LFA-1 expressed on the lymphocyte to give further tighter adhesion of the lymphocyte to the endothelial cell.
Further integrins are made e.g. ICAM 1 and ICAM 2 on the endothelial cell. This is due to the integration molcule signalling in both directions (through MADCAM 1 into endothelial cell and also through integrin into lymphocyte)
LFA-1 expressed on the lymphocyte to give further tighter adhesion of the lymphocyte to the endothelial cell.
- Diapedesis:
It then causes a further change in the cell which allows the final process of diapedesis.
This is the endothelial cell allowing the lymphocyte to move between different cells or through the middle of the cell.
This causes the lymphocyte to move out of the blood flow and into the surrounding tissue. From there it will continue moving up the conc gradient of the chemotaxic gradient until it gets to its final site (where the chemokine are being produced at the site of infection).
What is the mucosal cell function of B cells?
Primary function is to produce IgA.
Under the influence of TGF beta and IL-5, they switch production from IgM to IgA.
Secretory IgA:
- where is it produced?
- where is it secreted across?
Produced IgA is constantly being produced at the epithelial cells at mucosal sites.
It gets secreted across the epithelial surfaces.
Do lymphoid organs or mucosal tissues have more:
- IgA
- IgG
IgA is more in mucosal.
IgG is more in lymphoid tissues.
What does a secretory antibody have compared to a normal antibody?
It has 2 more chains, a joining and a secretory chain.
Joining chain makes IgA a dimeric structure.
Monomeric IgA is joined to the joining chain with amount IgA.
The polymeric IgA is then secreted by the plasma cell.
Pro = This means we have 4 antigen binding sites and 2 regions to interact with other molecules instead of 1
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Micro-organism, structure and function25
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Introduction to Host Defence22
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Innate Immunity19
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Adaptive Immunity T Cells 116
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Adaptive Immunity T Cells 212
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Adaptive Immunity T Cells 37
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The human and oral microbes20
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The human and oral microbiome 220
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Mucosal Immunity35
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Immunodeficiency and HIV19
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Adaptive Immunity B cell32
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Cellular response to injury15
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Mechanisms of Autoimmunity and Hypersensitivity24
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Pathogenicity: colonisation and evasion28
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Pathogenicity: Virulence Determinants19
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Fungal Infections23
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Acute Inflammation19
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Chronic Inflammation 115
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Chronic Inflammation 221
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Pathology of Pulpitis16
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Pathology of periapical periodontitis18
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Microbiology of dental caries35
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Biofilm and polymicrobial infections26
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Anti-Inflam Drugs28
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Introduction to Viruse29
