Mucosal Immunity Flashcards
What are mucosal surfaces?
-Surfaces exposed to the environment
-large surfaces specialised for absorption
What are the surface areas of the gut and skin
Skin ~2m^2
Gut ~400m^2
What do most mucosal epithelia have?
Resident microflora
So mucosal surfaces are the main route of entry for infectious microorganisms
What is the difference between the systemic & mucosal environemnt?
Systemic environment:
-contained
- sterile
-Encounters undefined antigens
rarely
Mucosal environment
-exposed
-non-sterile
-Encounters undefined antigens
continuously
What is the importance of mucosal immunity?
-Protection against pathogens
-Prevention of hypersensitivity to foods, commensal organisms, microbiota, etc.
-Immunopathology - Crohn’s disease, Coeliac disease, lung inflammation.
-Vaccine development
-Lymphocyte development
What are the mucosal tissues of the body?
- Lachrymal gland
-Salivary gland
-Mammary gland
-Uro-genital tract
-Kidney
-Conjuctiva
-Oral cavity
-Esophagus
-Stomach
-Intestine
-Sinus
-Trachea
-Lungs
What are the non-immunological & immunological aspects of the mucosal barrier?
Non-immunological:
Natural barriers (e.g. stomach acid)
Mucin
Peristalsis
Proteolysis
Microvillus membrane
Immunological:
Secretory IgA/IgM (IgG)
Mucin
IELs - Intraepithelial lymphocytes
Phagocytes
What 2 types can we divide secondary mucosal immune tissues into?
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
What is MALT?
Mucosal associated lymphatic tissue
Each mucosal surface has its own e.g. NALT (nasal), GALT (gut)
What is it meant by a ‘common mucosal immune system’?
-Mucosal immune system is a connected series of tissues
-All the different mucosal surfaces of the body are part of a ‘common’ mucosal system.
What are the 2 main inductive sites in GALT?
Peyer’s patches
Isolated lymphoid follicle
What are Peyer’s patches?
-Sub-epithelial follicles located throughout the SI and there are ~200 in man
What do Peyer’s patches contain?
50% B cells, 30% T cells, 8% macrophages
There are very few plasma cells
How do Peyer’s patches connect to the lymphatic system?
Only by efferent lymph vessels, they have no afferent vessels.
What do the B lymphocytes from the Peyer’s patches give rise to?
They give rise to IgA producing plasma cells which home to all mucosal sites in the body
How do Peyer’s patches differ from ILFs?
-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
What are ILFs?
-Isolated lymphoid follicles
-Are induced products of commensal microorganisms
How are ILFs similar to Peyer’s patches?
Their composition: ILFs are also mainly B cells, some T cells & some dendritic cells.
What are one of the key cells associated with both Peyer’s patches & ILFs?
M cells (microfold cells)
What are M cells?
They’re a unique epithelial subset which exist within the main epithelial barrier & they specialise in the uptake & transepithelial transport of particulate antigens.
Do M cells have a brush border or microvilli?
no
What is the main M cell function?
-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
Where are M cells located?
Located in the epithelial layer above Peyer’s patches & ILFs
What is the function of a Peyer’s patch?
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
What is the lamina propria?
Tissue which underlies the epithelial layer.
What are the 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
What are the T cells you find in the lamina propria?
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
What are the lamina propria T cell subsets?
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
What is the second type of lymphocytes associated with the mucosal tissue?
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)
How do we get these cells to their site of action?
Chemoattraction
Rolling adhesion
Tight adhesion
Arrest of rolling lymphocyte
Diapedesis
What happens in chemoattraction?
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
What happens in rolling adhesion?
Lymphocyte binds loosely to endothelial cells & rolls along
What happens in tight adhesion?
Chemokine-mediated activation of alpha4beta7 integrin which binds to MadCAM-1
What happens once you have arrest of the rolling lymphocyte?
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
What happens in diapedesis?
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
What is the primary function of mucosal B cells?
To produce IgA
Under the influence of TGFBeta and IL-5, they switch production from IgM to IgA
What is secretory IgA & where is it produced?
-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
What is a further function of IELs?
IEL protect & maintain the epithelial barrier layer, protecting against infection
Compare the structure of serum IgG and IgA antibodies
IgG on top, IgA on bottom
IgA = dimeric joined by J chain. 4 antigen binding sites instead of 2
slide 36
What are features of oral tolerance?
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
What is oral tolerance?
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
What are the mechanisms of IgA & IgG on antibodies?
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
What do some proposed mechanisms regarding oral tolerance involve?
Activity of Tregs (TGFB + retinoic acid = centric cells drive the differentiation of Niave CD4 to iTreg)
Induction of anergy
What are some general properties of oral tolerance?
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.
What happens if oral tolerance breaks down?
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
What are the functions of mucosal T cells?
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
Describe how induction of anergy could be a potential mechanism.
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
What are some key points in this lecture.
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.
