Immunological Functions of the Alimentary Tract Flashcards
Human immune system
origin of immune cells?
area where they mature?
areas where they are active?
The human immune system is spread out throughout the body (not focused in one organ), the origins of cells of the immune system is generally the bone marrow.
There are areas where these cells will mature like the thymus and areas which are active in protecting us against infection e.g. lymph nodes.
Innate vs adaptive
specificity?
memory?
mediated by?
respond or prevent?
So innate immune system prevents infection and avoids disease, e.g. the skin. It is non-specific has no memory and is mediated by macrophages which hunt down foreign things, epithelial barriers, secretions.
Because it is non-specific it means it doesn’t recognise what is good or what is bad, nor do they have any memory for previous infections.
The adaptive system responds to infection and prevents disease, the critical difference is that innate system blocks infection in the first place whereas the adaptive immune system has to see an infection first before it can block it a second time.
The adaptive system is highly specific to a targeted microbe, it also has a memory so once the immune response has happened certain cells (some B-cells) become memory cells.
Adaptive is primarily mediated by the lymphocytes (B and T) and antibodies.
what is Mucosal immunity?
what is Systemic immunity?
Systemic immunity:
Bone marrow, spleen, thymus lymph system, blood circulation
Mucosal immunity:
Mucous membranes – eyes, nose, mouth, lungs, gut, genitourinary tract.
MUCOSAL IMMUNE SYSTEM
How do most infective agents enter out body?
what defence do we have at this locations? when do we have a problem? what is another issue with these areas?
What is the function of secretions at these areas? how do bacteria work around it?
what are the innate mechanism of protection in the gut? (4)
what mediates the adaptive mechanism?
what is one of the hardest things for mucosal immune system?
Most infective agents find it very hard to enter our skin, so most infections enter through the mucosal membranes which are easier to penetrate (we get lung, eye infections more commonly).
The mucosal membranes are also normally colonised by microbes in the first place, there are pathogens fighting with our commensal organisms for the right to stay there. So, we get a problem when an imbalance is struck between the two.
As well as this, the mucosal area represents are much larger surface area than the skin.
We produce secretions at our mucosal membranes and one of the functions of these secretions is to wash away anything that is there (e.g. saliva, cilia), so bacteria must be able to adapt to try adhere and not be washed away.
Innate mechanisms of protection (in gut) include:
• Mucin
• Peristalsis
• Antimicrobial peptides and proteins e.g. lysozyme, lactoferrin
o Accumulates iron and doesn’t allow it to become available for bacterial growth
• Phagocytes.
The same enzymes in stomach and gut that break down proteins will break down bacterial proteins, the acid as well does this.
Adaptive mechanisms are also present, these are largely mediated by antibodies (mucosal/secretory immune system).
One of the hardest things for the mucosal immune system is to differentiate between harmful pathogens and harmless antigens (e.g. foods and commensal bacteria, this is all good, so we have to have a way to discriminate between what is good and bad.
The mucosal barrier:
Innate • Natural barriers (e.g. stomach) • Mucin • Peristalsis • Proteolysis
Microvillus membrane or squamous cell
Immunological
• Secretory IgA/IgM and IgG
Sources of serum, saliva and local antibodies in the oral cavity
lymphoid tissue peripheral blood gingival focus of leucocytes crevicular fluid and leucocytes saliva
Lymphoid Cells in the Gut
What covers the mucosal epitheloum?
Outline 3 ways a pathogen can get into the body?
What is a langerhan cell and what do they do?
what are the 3 main lymphoid cells in the gut?
This is a cross-section of what our gut looks like, it can be seen on the bottom left there is a blood vessel and on the right lymphatics.
Covering the epithelium in blue is a layer of mucin. It is a thick sticky mucous surface, if you’re a bacteria you have to burrow through this to get to cells.
There are a couple of ways however pathogens can get across the gut surfaces.
One way would be a breach of the epithelium, in the picture we can see in the middle the epithelium has broken down (e.g. in an ulcer) and the pathogen is getting into the sub-lamina (connective tissue under epithelium).
Another way is related to the monocytes scouting around under the epithelium, looking for pathogens. In the picture we look at the top left in green is a Langerhans cell. These cells have extensions that go out and can sample what is going on in the lumen of the gut.
Some pathogens can enter into the cellular process and then be withdrawn back in with the macrophage, some pathogens may adhere to the extension and when the macrophage moves off it brings in the pathogen.
1) Intra-epithelial lymphocytes
2) Lymphocytes and macrophages scattered in the lamina propria
3) Peyer’s patches
Peyer’s Patches
what are they and what do they do?
How are they linked to the outside lumen/
what are the 3 types of lymphoid cells?
what happens if you don’t have peyer’s patch?
However, in the gut the main mechanism by which pathogens enter the gut and are recognised by the mucosal immune system is through Peyer’s patches. These are like lymph nodes across the gut (they are collection of lymphocytes). These Peyer’s patches are actively sampling the gut lumen to see what is out there.
The Peyer’s patch is linked to the outside lumen by a specialised cell called an “M-cell” which is doing the sampling, the rest of the top is covered by epithelium.
So, we have 3 types of lymphoid cell, intra-epithelial lymphocytes, lymphocytes and macrophages scattered in the lamina propria and Peyer’s patches.
Peyer’s patches are extremely important.
In an experiment, got a mouse gut and injected antigen into an area of gut without a Peyer’s patch and ligated the sides and stitched up the mouse, then in another mouse he did the same but injected antigen into an area with a Peyer’s patch.
When he came back some time later, in the area without the Peyer’s patch there was a weak antibody response and if you looked upstream or downstream also weak response.
In the Peyer’s patch one, there was a fantastic immune response and even further up and down the gut.
M - Cells
why are they called M-cells? where are thye and what do they do?
4 things than can gain entry via M cells?
why is M cell a weakness?
what happens once a pathogen gets through? where does this cell go and where from?
What is the very unique thing about immune response in the mucosal immune system?
How do they interact with other surfaces?
What is this response called?
What do they lymphocytes have to do before they can start producing antibodies?
Called an M-cell because of its microfold appearance. The M-cell sits on top and samples the gut fluid lumen and then sends it down to the lymphocyte underneath.
Various things can gain entry via these M-cells.
- Particles and macromolecules e.g. cholera toxin, latex particles
- Viruses e.g. poliovirus, HIV
- Parasites e.g. Cryptosporidium
- Bacteria e.g. Cholera, salmonella, campylobacter, shigella. E. coli, Yersinia
So, the M-cells are a strength of the gut and a weakness because it’s the easiest point of entry.
Once a pathogen gets through to the lymphocytes, it triggers an immune response. A B-lymphocyte will start to mature into a B-cell, as it does this it will migrate away from the Peyer’s patch and drain to the local lymph node (where they continue to mature) and enter back into the lymph circulation back into the blood circulation.
A very significant thing about the mucosal immune system is that, whereas in the systemic immune system these lymphocytes would stay in the blood circulation and produce antibodies, the mucosal lymphocytes home back to the mucosal immune system back to the gut they originally came from AND all the way up the gut, which is why in the experiment parts of the gut not directly exposed to antigen also showed immune responses.
As well as this they also home to other mucosal surfaces, e.g. immune response in gut, you will also get antibodies in your saliva, tears etc.
This is response, of encountering an antigen at one mucosal site leading to immunity across all mucosal sites is called the common mucosal response (immune system).
[The lymphocytes HAVE to home to a secretory gland before they can start producing antibody]
Mucosal Antibodies
what type of antibodies are predominantly secreted? where are they found? how does this help new born?
How is the serum/blood antibody different to mucosal/secretory antibody? why is this better for mucosal antibodies?
How is the antibody protected from break down in GI?
Mucosal antibodies are predominantly SIgA (secretory IgA), these are found in all secretions and breast milk. This provides passive immune protection in new-born infants.
The antibody you find in secretions is very different to the antibody you would find in the blood.
The Ig’s in the blood would look like the top, serum IgA composed of light chain and heavy chain.
In mucosal surfaces you have a more complex form of antibody, there are two of the structures and dimerize them with a joining protein which links the two together. This antibody has the capability to bind to 4 antigens, hence it makes it even more difficult for pathogens to burrow through the mucosal surface. In this way the mucosal IgA is much better at this surface than IgG would be.
Remember that the antibody is also a protein so just how bacterial proteins can be broken down; our own antibodies could potentially be broken down also.
So, one of the adaptations secretory antibodies have is that they are wrapped up by another protein called secretory component. This protects the antibody from being degraded by proteolytic enzymes we produce or produced by bacteria.
Mechanisms of Action of Antibodies
What two mechanisms does IgA do?
what 2 mechanisms does it not do that IgG would do?
One of the mechanisms of antibodies is they can bind to key functional sites on microbes and toxins. This blocks its functionality.
Antibodies can agglutinate (aggregate) bacteria.
Another important thing IgG does is it induces inflammation, by activating the complement pathway.
It also recruits immune cells.
With IgA, we want to block activity and agglutinate, but we don’t want to induce inflammation in the gut. So, IgA doesn’t induce inflammation or bind immune cells etc.
IgG: • Binding key functional sites on microbes and toxins • Agglutination • Induce inflammation • Recruit immune cells
SIgA:
• Binding key functional sites on microbes and toxins
• Better at agglutination (more binding sites)
• Intra-cellular neutralisation
• Immune exclusion
• Virus excretion
• Interactions with non-specific factors (i.e. lysozymes, lactoferrin, peroxidases)
Approaches to Oral Immunisation
why is oral immunisation such a good idea?
What options are there for oral immunisation?
It would seem that making vaccines for mucosal immunity would be very beneficial as mucosal surfaces are so immunologically active and the first port of call usually for bacteria.
Oral immunisation is an excellent and easy method for immunising individuals in less developed communities.
However, our options for oral vaccines is fairly limited.
- Attenuated virus (e.g. polio)
- Attenuated recombinant bacterial mutants
- Mucosal adjuvants (adjuvants make the vaccine work better)
- Liposomes, microspheres
- Capsules
- Transgenic edible plants
Systemic Immune Response to Primary and Secondary Challenge
What happens when you get an injection?
What happens when you get a booster shot?
How is this different to mucosal respsone? why?
How can we use GM plants?
This graph shows a typical response if given a vaccine by injection.
One injection would produce a small antibody response, taking one or two weeks to develop, then it would die down.
If you then gave a booster injection, it produces a massive response, mediated by IgG and this gives the immunity. It may take years for this antibody response to decline.
However, the same thing doesn’t happen with mucosal immunity unfortunately.
This is a response (plotted on log scale) for a mucosal vaccine, it can be seen that the second time around the response is very similar and the immunity takes a nosedive after the second response.
So, it is like having two primary responses. It appears that mucosal immunity doesn’t have a great memory
We can also use GM plants for Hepatitis B vaccine e.g. Hepatitis.
Oral Tolerance
what happens to systemic immune system if antigen is first encountered via mucosal system? why is this?
what are 3 pratical considerations of oral tolerance?
what does the induction of oral tolerance depend on?
oral tolerance vs vaccinations? (3 things)
If an antigen is first encountered through the mucosal immune system, the systemic immune system may become unresponsive (tolerised) to that antigen.
Orally delivered antigens can suppress systemic immunity, it is thought this may be a natural mechanism to prevent immune reactions to food and useful commensals.
Practical Considerations of Oral Tolerance
- Tolerance to dietary foods (we do need oral tolerance, so we can eat, in people with food allergies this oral tolerance has broken down)
- Oral vaccination and safety (we don’t want to cause oral tolerance)
- In treatment and prevention of autoimmune diseases (e.g. T1DM)
So, is oral intolerance a contraindication for oral immunisation?
o Well, induction of oral tolerance can depend on many factors such as the nature of the antigen, dose and frequency of delivery.
- Tolerance – soluble antigens (i.e. if we give soluble antigens more likely person will develop tolerance to that antigen)
o Vaccination – Antigen/adjuvant or other (but if we give with adjuvant, more likely they will induce vaccination) - Tolerance – Repeated sustained doses
o Vaccination – Limited number of immunisations - Tolerance – High doses
o Vaccination – Low dose
Mucosal Immune System Summary
The mucosal immune system can be stimulated by antigens independently of the systemic immune system. However, the two immune systems are not entirely isolated (e.g. in mouth, mucosal immune system effecting systemic).
The site of stimulation is usually at specialised sites e.g. GALT (Peyer’s patches), BALT (bronchial) and NALT (naso).
The major immunological factor is secretory IgA which is expressed at all mucosal sites and special (modified not to be degraded)
Most microbial infections start at mucosal sites, but most vaccines are administered systemically.
