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HUMAN HEALTH AND DISEASE > Mucosal Immunity > Flashcards

Mucosal Immunity Flashcards

1
Q

What are mucosal surfaces?

A

-Surfaces exposed to the environment

-large surfaces specialised for absorption

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2
Q

What are the surface areas of the gut and skin

A

Skin ~2m^2
Gut ~400m^2

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3
Q

What do most mucosal epithelia have?

A

Resident microflora

So mucosal surfaces are the main route of entry for infectious microorganisms

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4
Q

What is the difference between the systemic & mucosal environemnt?

A

Systemic environment:
-contained
- sterile
-Encounters undefined antigens
rarely

Mucosal environment
-exposed
-non-sterile
-Encounters undefined antigens
continuously

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5
Q

What is the importance of mucosal immunity?

A

-Protection against pathogens

-Prevention of hypersensitivity to foods, commensal organisms, microbiota, etc.

-Immunopathology - Crohn’s disease, Coeliac disease, lung inflammation.

-Vaccine development

-Lymphocyte development

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6
Q

What are the mucosal tissues of the body?

A
  • Lachrymal gland
    -Salivary gland
    -Mammary gland
    -Uro-genital tract
    -Kidney
    -Conjuctiva
    -Oral cavity
    -Esophagus
    -Stomach
    -Intestine
    -Sinus
    -Trachea
    -Lungs
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7
Q

What are the non-immunological & immunological aspects of the mucosal barrier?

A

Non-immunological:
Natural barriers (e.g. stomach acid)
Mucin
Peristalsis
Proteolysis
Microvillus membrane

Immunological:
Secretory IgA/IgM (IgG)
Mucin
IELs - Intraepithelial lymphocytes
Phagocytes

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8
Q

What 2 types can we divide secondary mucosal immune tissues into?

A

Inductive sites- sites at which we induce an immune response

Effector sites- where the immune cells/immune response has its impact, much as for systemic immunity

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9
Q

What is MALT?

A

Mucosal associated lymphatic tissue

Each mucosal surface has its own e.g. NALT (nasal), GALT (gut)

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10
Q

What is it meant by a ‘common mucosal immune system’?

A

-Mucosal immune system is a connected series of tissues

-All the different mucosal surfaces of the body are part of a ‘common’ mucosal system.

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11
Q

What are the 2 main inductive sites in GALT?

A

Peyer’s patches

Isolated lymphoid follicle

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12
Q

What are Peyer’s patches?

A

-Sub-epithelial follicles located throughout the SI and there are ~200 in man

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13
Q

What do Peyer’s patches contain?

A

50% B cells, 30% T cells, 8% macrophages

There are very few plasma cells

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14
Q

How do Peyer’s patches connect to the lymphatic system?

A

Only by efferent lymph vessels, they have no afferent vessels.

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15
Q

What do the B lymphocytes from the Peyer’s patches give rise to?

A

They give rise to IgA producing plasma cells which home to all mucosal sites in the body

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16
Q

How do Peyer’s patches differ from ILFs?

A

-Unlike Peyer’s patches, which are preprogrammed genetically into an organism

-ILFs are a response to an immunological response activator such as a microbe

-Also ILFs are more numerous than Peyer’s patches

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17
Q

What are ILFs?

A

-Isolated lymphoid follicles

-Are induced products of commensal microorganisms

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18
Q

How are ILFs similar to Peyer’s patches?

A

Their composition: ILFs are also mainly B cells, some T cells & some dendritic cells.

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19
Q

What are one of the key cells associated with both Peyer’s patches & ILFs?

A

M cells (microfold cells)

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20
Q

What are M cells?

A

They’re a unique epithelial subset which exist within the main epithelial barrier & they specialise in the uptake & transepithelial transport of particulate antigens.

21
Q

Do M cells have a brush border or microvilli?

A

no

22
Q

What is the main M cell function?

A

-To take up antigen by endocytosis & phagocytosis & to then transport it across to the basal surface via vesicles

-Once at the basal surface, these are then released.

-whether it’s taken up by B cells, macrophages, dendritic cells etc. and presented to T cells to activate them

23
Q

Where are M cells located?

A

Located in the epithelial layer above Peyer’s patches & ILFs

24
Q

What is the function of a Peyer’s patch?

A

In peyer’s patch:

-T and B cells become fully activated

-T and B cells switch expression from L-selectin and CCR7 to a4B7 integrin and CCR9.

-B cells class switch to IgA

25
Q

What is the lamina propria?

A

Tissue which underlies the epithelial layer.

26
Q

What are the 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

27
Q

What are the T cells you find in the lamina propria?

A

Majority are CD4+ i.e. Treg cells

They outnumber the CD8+ cells by a factor of 2:1

Most of them express alpha4beta7 integrin which recognises the ligand MadCAM

They produce cytokines dependent on their subset

28
Q

What are the lamina propria T cell subsets?

A

Tregs act to regulate/supress other immune cells via IL-10 and TGFb

Th1 act to activate macrophages via IFNy

Th2 act to induce B cell class-switching to IgA via IL-5

Th17 act to maintain epithelial barrier function via IL-22 and activate neutrophils via IL-17

29
Q

What is the second type of lymphocytes associated with the mucosal tissue?

A

IELs (intraepithelial lymphocytes)

These are all T cells, majority is CD8+ (a large number are CD8alpha-alpha)

Gammadelta T cells may also be quite frequent in this population

Unlike the T cells in the lamina propria, these cells express alphaEbeta7 integrin which recognises the ligand E-cadherin, which is particularly associated with enterocytes & epithelial cells

Many of them are unresponsive to TCR stimulation & many are extrathymically derived ( not gone through regular T-cell production in the thymus)

30
Q

How do we get these cells to their site of action?

A

Chemoattraction
Rolling adhesion
Tight adhesion
Arrest of rolling lymphocyte
Diapedesis

31
Q

What happens in chemoattraction?

A

Chemokines recruit lymphocytes & induce expression of adhesion molecules on these lymphocytes & on surrounding endothelial cells

In a naive lymphocyte, they’ll induce the production of L-selectin on the surface of the lymphocyte

L-selectin will then come into contact with a MadCAM-1 on the surface of endothelial cells, which will be triggered to be highly expressed in areas where we have an infection by chemokines

32
Q

What happens in rolling adhesion?

A

Lymphocyte binds loosely to endothelial cells & rolls along

33
Q

What happens in tight adhesion?

A

Chemokine-mediated activation of alpha4beta7 integrin which binds to MadCAM-1

34
Q

What happens once you have arrest of the rolling lymphocyte?

A

You then start to see the production of other cell surface molecules both in the endothelial cell & in the lymphocytes themselves

LFA-1 binds ICAM-1 & ICAM-2

Further tighter binding

35
Q

What happens in diapedesis?

A

Junctions between endothelial cells become loose or the endothelial cell itself invaginates and allows the lymphocytes to penetrate through and into the surrounding tissues

Thus the lymphocyte extravasates & gains access to the supplied tissue from which it can move to the point of infection

36
Q

What is the primary function of mucosal B cells?

A

To produce IgA

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

37
Q

What is secretory IgA & where is it produced?

A

-produced at mucosal sites

-secreted across epithelial surfaces, found in all mucosal secretions (e.g. saliva)

-It has different functions/activities to IgG

-IgA is the most highly produced Ig

38
Q

What is a further function of IELs?

A

IEL protect & maintain the epithelial barrier layer, protecting against infection

39
Q

Compare the structure of serum IgG and IgA antibodies

A

IgG on top, IgA on bottom

IgA = dimeric joined by J chain. 4 antigen binding sites instead of 2

slide 36

40
Q

What are 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

41
Q

What is oral tolerance?

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 - i.e. Intranasal

42
Q

What are the mechanisms of IgA & IgG on antibodies?

A

IgG and IgA both have :
-Virus neutralisation
-Enzyme and toxin neutralisation
-Inhibition of adherence
-Agglutination

BUT IgG also has:
-Complement activation
-Opsonisation

But IgA has:
-Immune exclusion : preventing microbe getting into the body
-Inta-cellular neutralisation
-Virus excretion
-Interactions with non-specific factors : lysozyme, lactoferrin, peroxidase

43
Q

What do some proposed mechanisms regarding oral tolerance involve?

A

Activity of Tregs (TGFB + retinoic acid = centric cells drive the differentiation of Niave CD4 to iTreg)

Induction of anergy

44
Q

What are some general properties of oral tolerance?

A

Antigen specific

Often partial (eg. antibodies inhibited, but T cell responses may remain)

Not complete (eg. may be a quantitative reduction in antibody levels)

Wanes with time

Easier to abrogate a response than reduce an established response

Good immunogens are better at inducing tolerance

Dose and route dependent.

45
Q

What happens if oral tolerance breaks down?

A

immune responses to food:
Leads to food intolerance, e.g. coeliac disease

Immune responses to commensal bacteria:
Leads to inflammatory bowel disease (IBD)
E.g. Crohn’s disease, ulcerative colitis

46
Q

What are the functions of mucosal T cells?

A

Provide/maintain an environment that:

-Doesn’t respond to the commensal microbiota
-Doesn’t respond to food/ingested antigens
-Does respond to pathogenic microbes

They regulate responses in conjunction with epithelial cells:

-key in this process are the cytokine TGF-b and retinoic acid (a metabolite of vitamin A)

These factors control immune responses by:

-controlling mucosal homing
-controlling dendritic cell activation/induction of Treg

47
Q

Describe how induction of anergy could be a potential mechanism.

A

Some epithelial cells in the gut and lung normally express class II MHC, but not costimulatory molecules

Result is activation of TCR without the second (CD28) signal - leads to anergy of responsive T cells

48
Q

What are some key points in this lecture.

A

Mucosal surfaces: large, exposed to external environment, major route of entry of infectious microorganisms.

Mucosal (secretory) immune system is targeted by Lymphocyte homing and is the site of transport of sIgA.

Mucosal immunity involves a wide variety of cells.

Immunoregulation critical to avoid damaging inflammatory
responses to commensal flora or food antigens (both high load).

General unresponsiveness maintained by Treg.
TGF and Retinoic acid may be major factors.

Tolerance to an antigen can be induced by immunisation at a mucosal surface.

HUMAN HEALTH AND DISEASE (58 decks)

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