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Dentistry Year 2 - Pathology > Mucosal Immunity > Flashcards

Mucosal Immunity Flashcards

1
Q

Give the basic details on mucosal surfaces

A
  • 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
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2
Q

Give some differences between systemic and mucosal environments

A

Systemic:

  • Contained
  • Sterile
  • Encounters undefined antigens rarely

Mucosal:

  • Exposed
  • Non-sterile
  • Encounters undefined antigens continuously
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3
Q

What is the importance of mucosal immunity?

A
  • Protection against pathogens
  • Prevention of hypersensitivity to foods / commensal organisms / microflora
  • Preventing self immune diseases
  • Vaccine development
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4
Q

What are mucosal tissues defined as?

A

Tissues exposed to the environment.

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5
Q

Give some features of the non-immunological and immunological mucosal barrier

A

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
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6
Q

What are regionalised secondary mucosal immune tissues?

A
  • 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
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7
Q

What is the common mucosal immune system?

A

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.

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8
Q

Give some information on the GALT organisation

A

Consists of the epithelial layer and the lamina propria underneath.
It has 2 secondary inductive sites (peyers patches and isolated lymphoid follicles).

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9
Q

Give details on the structure and function of Peyers patches

A
  • 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.)

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10
Q

Give the details of the well organised Peyer patch structure

A

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.

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11
Q

Give the details on the structure and function of the isolated lymphoid follicles

A

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.

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12
Q

What are M cells and where are they present?

A

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).

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13
Q

What happens inside the Peyers patch?

A
  • 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
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14
Q

Why do we need Peyers patches when we have lymph nodes?

A
  • 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.
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15
Q

Give some conventional cells and some specific cells of the mucosal immune system

A

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)

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16
Q

What are the 2 effector sites of mucosal compartments?

A

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.

17
Q

Give details on the T cells of the lamina propria

Give details on the lamina propria T cells subsets

A
  • 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
18
Q

What are Intra Epithelial Lymphocytes?

A
  • 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
19
Q

What is lymphocyte homing?

A

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.

20
Q

What are the steps involved in migration of the immune cells to the epithelial cell suface?

A
  1. 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.

  1. 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.

  1. 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.

  1. 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).
21
Q

What is the mucosal cell function of B cells?

A

Primary function is to produce IgA.

Under the influence of TGF beta and IL-5, they switch production from IgM to IgA.

22
Q

Secretory IgA:

  • where is it produced?
  • where is it secreted across?
A

Produced IgA is constantly being produced at the epithelial cells at mucosal sites.
It gets secreted across the epithelial surfaces.

23
Q

Do lymphoid organs or mucosal tissues have more:

  • IgA
  • IgG
A

IgA is more in mucosal.

IgG is more in lymphoid tissues.

24
Q

What does a secretory antibody have compared to a normal antibody?

A

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

25
Q

How is secretory IgA transported?

A

It floats until it gets to the epithelial cell where on this cell there is a polymeric IgA receptor. This binds to the polymeric IgA, endocytoses it and moves it across the epithelial cell and then just before being released, there is protozoic cleavage event which cleaves the secretary chain from the polymeric IgA receptor which enables the IgA molecule to be released.

26
Q

What functions do IgG and IgA share?

A
  • Virus neutralisation
  • Enzyme and toxin neutralisation
  • Inhibition of adherence
  • Agglutination
27
Q

What functions do IgG and IgA not share?

A

IgG:

  • complement activation
  • opsonisation

IgA:

  • immune exclusion
  • intra-cellular neutralization
  • virus excretion
  • interactions with non-specific factors

(Because we are passing through an epithelial cell, when it comes to viruses infecting epithelial cells, IgA is better than IgG because you are at the site of the infection. IgG passes through the viral infected cell and can therefore target it faster than waiting for it to leave the cell.
IgG is much better at opsonisation for macrophages to then endocytose. However there is no complement in mucosal surfaces so this has no benefit.
IgA is great for immune exclusion (stopping things from getting in). Great at neutralising things inside the cell. Great at stopping viruses getting out the cell. It interactions with innate factors like enzymes to become stuck to the IgA to then specially target a microbe)

28
Q

What are the mucosal cell functions of T cells?

A

They maintain an environment that:

  • does not respond to commensal microbiota
  • doesnt respond to food / ingested antigens
  • does response to pathogenic microbes

They regulate responses in conjunction with epithelial cells to stop commensals being targeted.

Factors made by these cells are associated by controlling mucosal homing and controlling dendritic cell activation / induction of Treg.

29
Q

What is the role of intra epithelial lymphocytes?

A

Intra epithelial cells are all CD8 cells.
They can therefore target infected cells within the epithelial layer.
They release the performs and granzymes and by activating Fas ligand.
They protect and maintain the epithelial barrier layer, protecting against infection.

30
Q

What is oral tolerance?

A

A state of immune non-responsiveness to antigen induced by feeding.
It is a feature of the common immune system.
Can also be induced by immunisation at other mucosal sites.

31
Q

What are the features of oral tolerance?

A
  • Normal immune function
  • Tolerance can be local or systemic
  • It requires a functional immune system
  • Symbiosis : in the absence of commensals, a poor immune response develops and oral tolerance cannot be induced
32
Q

What are the general properties of oral tolerance?

A
  • Antigen specific
  • Often partial (e.g. antibodies inhibited, but T cell responses may remain)
  • Not complete (may be a quantitative reduction in antibody levels)
  • Wanes with time
  • Stop the feeding process, the tolerance effect will reduce and you will get a immune response
  • easier to stop a response in the first place than stop one thats already happening
  • The more immunogenic, the between changes of getting oral tolerance
  • dose and route dependant
33
Q

How does the breakdown of oral tolerance occur?

A
  • Immune responses to food leads to food intolerance

- Immune responses to commensal bacteria

34
Q

What is the likely mechanism for oral tolerance?

A

Treg

We have the antigen that comes in and is taken up but at the same time we are taking in vitamin A.

Epithelial cells secrete TGF beta and combines with vitamin A being processed to retinoic acid. Commensals produce retinoic acid in the gut.
Combined, they have an impact on dendritic cells to skew the development of any naive CD4 cells to instead of becoming a TH1 or Th2, they become a Treg.
These Tregs are called Iregs (induced Tregs).
The dendritic cells activate effector or memory Tregs to become Tregs themselves.
Large population of Tregs. Because the same dendritic cells that are presenting the antigen are being collected from the gut are also ones that are driving a Treg response rather than a Th1/Th2/Th17 response so the T cells that respond to a particular antigen become suppressive rather than activatory leading to suppression on any immune response.
Even if you get activation by other food antigens at the same time towards a TH1 or Th2 , they will be outweighed by the Tregs that will suppress in immune response.

35
Q

What is another method for oral tolerance?

A

Induction of anergy

  • some epithelial cells in the gut and lung normally express class 2 MHC
  • results is activation of TCR without the second signal leading to anergy of responsive T cells

(epithelial cells will not express CD28 meaning there is no second signal to the T cell that recognises any antigens which means those cells will become anergised and non-responsive)

Dentistry Year 2 - Pathology (25 decks)

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