S2: Immunological Functions of the Alimentary Tract

Question 1

What is the immune system split into?

Answer 1

The immune system is split into innate (non-specific activity which blocks the ingress of new infections) and adaptive (where we respond to infection and prevent disease if necessary).

Question 2

Describe the innate immune system

Answer 2

• Prevents infection and avoids disease
• e.g. skin, epithelial barriers, secretions
• Non specific
• No memory
• Mediated by macrophages which hunt down foreign things

Question 3

Describe adaptive immune system

Answer 3

• 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.
• Highly specific to targeted microbe
• Memory - B cells turn into memory cells
• Adaptive is primarily mediated by the lymphocytes (B and T) and antibodies.

Question 4

Name structures in systemic immunity

Answer 4

Bone marrow, spleen, thymus lymph system, blood circulation

• Internal (embryology)

Question 5

Name structures in mucosal immunity

Answer 5

Mucous membranes – eyes, nose, mouth, lungs, gut, genitourinary tract

-External (embryology)

Question 6

Why do we get infections in our mucous membranes more commonly?

Answer 6

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 area represents are much larger surface area than the skin.

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.

Question 7

Why are secretions produced at mucosal membranes?

Answer 7

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.

Question 8

What are the innate mechanisms of protection in our gut?

Answer 8

• Mucin
• Peristalsis
• Antimicrobial peptides and proteins e.g. lysozyme, lactoferrin (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!)

Question 9

What are the adaptive mechanisms of protection in our gut?

Answer 9

• Mediated by antibodies

- Secretory IgA/IgM and IgG

Question 10

Sources of serum, saliva and local antibodies in the oral cavity

Answer 10

• Most of the secretions (containing enzymes and antibodies) will come out as saliva from salivary glands
• There is constant flow from serum derived fluid from blood

The serum and saliva protect the mouth and enter the gut.

• The epithelial layer of the gum, at gingival crevice contains immune cells.

Question 11

Describe lymphoid cells in the gut

Answer 11

• Covering the epithelial cells in a layer of thick sticky mucus that bacteria have to burrow through to get to cells
• Under epithelium is the sublamina (connective tissue)
• Monocytes are present scouting around under epithelium looking for pathogens
• There are langerhan cells. These cells have extensions that go out and can sample what is going on inside 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.
• However in the gut the main mechanism by which pathogens enter the gut and are recognised by the mucosal immune system is through Peyers patches. These are like lymph nodes across the gut (they are collection of lymphocytes). These peyers patches are actively sampling the contents of the gut lumen to see what is out there.

Question 12

What is the peyer’s patch linked with outside the lumen?

Answer 12

The Peyers patch is linked to the outside lumen by a specalised cell called an “M-cell” which is doing the sampling , the rest of the top is covered by epithelium.

Question 13

Describe the experiment with Peyer’s patches and mice

Answer 13

• One mouse had a gut injected with antigen without peyer’s patch and ligated sides and stitched up mouse
• Another mouse the same but with a peyer’s patch
• Some time later, in the area without the Peyers patch there was a weak antibody response and if you looked upstream or downstream also weak response.
• in the area with the Peyers patch there was a fantastic immune response and even further up and down the gut

Question 14

What is the easiest point of entry in the gut?

Answer 14

M cell

Question 15

Describe a M cell

Answer 15

• 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

Question 16

Describe mechanism of mucosal immune system

Answer 16

• Once pathogen gets to the lymphocyte, it triggers an immune response.
• B lymphocyte matures into B cell and it will migrate from Peyers patch and drain into local lymph node (where they continue to mature) and enter back into lymph circulation back into 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 go 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 are 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]

Question 17

What are mucosal antibodies predominantly?

Answer 17

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.

Question 18

Compare antibodies in secretion and blood

Answer 18

They are very different.

The serum IgA in blood is 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.

Question 19

Name an important adaptation that secretory antibodies have

Answer 19

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. Joining chain connects the two antibodies and secretory antibody made has adapted for harsher enviroment (doesn’t degrade as quickly).

However, the protease cleavage susceptibility is at the IgA1 hinge

Question 20

Describe mechanism of action of IgG and SIgA

Answer 20

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 SIgA, 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. which is useful in the gut so the innate epithelial barrier doesn’t open up preventing infection.

Question 21

Why is it beneficial to make vaccines for mucosal immunity?

Answer 21

• First port of call for bacteria

- Mucosal surfaces are so immunologic-ally active

Question 22

Benefits of oral immunisation

Answer 22

• Easy method - especially in less developed counteries

Question 23

List options for oral vaccines

Answer 23

They are 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

Question 24

Compare vaccine by injection and oral (primary and secondary response)

Answer 24

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.

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.
The secondary response is therefore poor and shortlived.

Question 25

What is oral tolerance?

Answer 25

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.

Question 26

Practical implications of oral tolerance

Answer 26

• 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)

Question 27

List factors that affect the induction of oral tolerance (compare with vaccination)

Answer 27

Induction of oral tolerance can depend on many factors such as the nature of the antigen, dose and frequency of delivery.

1. Tolerance - Soluble antigens - (i.e. if we give soluble antigens more likely person will develop tolerance to that antigen)
   Vaccination – Antigen/adjuvant or other (but if we give with adjuvant, more likely they will induce vaccination)
2. Tolerance – Repeated sustained doses
   Vaccination – Limited number of immunisations
3. Tolerance – High doses
   Vaccination – Low dose