Mucosal Immune System Flashcards
What is the only physical barrier against invasion of MO in mucosal surfaces?
Thin layer of mucosal epithelium
Innate defences of mucosal tissues?
Anti-micorbial peptides (defensins) Antimicrobial peptides- lysosomes Cilia Goblet cells- mucus Tight Epithelia junctions
What body surfaces are lined by mucus-secreting epithelium that is protected by the mucosal immune system?
- Gastrointestinal tract
- Respiratory tract
- Urogenital tract
Vast majority of infectious agents invade body thrpugh these routes
What diseases are associated with pathogen entering mucosal surfaces?
Diarrheal diseases Acute respiratory infections Tuberculosis HIV/AIDS Measles Whooping cough
Commensal micro-organsims/microbiota
Most found in colon of large intestine
Live in symbiosis with host
Do no harm
Beneficial to host
Inflammatory bowel disease (crohn’s), celiac disease
Happen when there is an immune response against commensal bacteria
Where are commensal micro-organisms found?
Colon Mouth Skin Oesophagus Stomach Vagina
Mucosal immune system
Largest part of body’s immune tissues
Produces most of immunoglobulins
Contains 3/4 of all lymphocytes
Anatomical features of mucosal immune system
Mucosal epithelia Lymphoid tissue Peyer's patches Lymphoid follicles Tonsils
Effector mechanisms of mucosal immune system
Activated/memory T cells
T regulatory cells
IgA
microbiota
Immunoregulatory environment of mucosal immune system
Inhibitory macrophages
Tolerance inducing dendritic cells
Where are lymphocytes, macrophages, dendritic cells and other immune cells found?
Throughout mucosal tissues
Surface epithelium of mucosa
Lamina propia
What are the secondary lymphoid tissues in the gut?
Group of organs called GALT
with draining mesenteric lymph nodes
What happens at secondary lymphoid organs?
immune response is initiated
What does GALT include?
Peyer’s patches in submucosa of small intestine= large collection of lymphoid tissue
Isolated lymphoid follicles throughout intestine
Appendix
Palatine and lingual tonsils and adenoids
What are palatine, adenoid and lingual tonsils?
Large aggregates of lymphoid tissue
Covered by a layer of squamous epithelium
Form a ring= Waldeyer’s ring at back of mouth- entrance of gut and airways
Why do tonsils become enlarged in childhood?
Recurrent infections
In the past- had to be removed by surgery
What happens in people with tonsils and adenoids removed?
Reduced IgA response
Where are the peyer’s patches, isolated lymphoid follicles and lymphoid tissue of the appendix located?
Intestinal wall (GALT)
What happens in the peyer’s patches?
Initiation of immune response in gut
Structure of peyer’s patches
Dome like aggregates of lymphoid cells
Project into intestinal lumen
What are found in peyer’s patches?
Richer in B cells then lymph nodes and spleen
Large number of B cell follicles
With germinal centres
Small areas of T cells
Subepithelial dome= layer between epithelium and follicles- rich in dendritic, T, B cells
What is the surface epithelium of peyer’s patches?
Follicle associated epithelium
Single layer of columnar epithelial cells
What cells are found in the follicle associated epithelium of peyer’s patches?
M cells (microfold)
How are peyer’s patches and isolated lymphoid follicles connected to lymphatics?
Mesenteric lymph node (largest lymph nodes in the body)
Why is the immune response og GALT different to that in spleen and lymph nodes?
Microenvironment of GALT has its own lymphoid cells and hormones
M cells structure
Massive pockets filled with B and T cells and dendritic cells
How do M cells directly take up antigen?
- M cell takes up antigen by endocytosis/phagocytosis
- Antigen transported across M cells in vesicles and released at basal surface
- Antigen presented by dendritic cell
- Dendritic cell activates T cells
- Dendritic cell moves to T cell area of peyer’s patches and meet naive antigen specific T cells= activated T helper cell
- They activate B cells- induce class switching to IgA (when T helper cell releases cytokines IL-4/IL-10/IFN-Gamma)
In the intestine where are effector lymphocytes mainly found?
Epithelium
Lamina propia
What does the epithelium of intestine mainly consist of?
Lymphocytes - especially CD8
What does the lamina propia mainly consist of ?
CD4 and CD8 T cells
and some macrophages, plasma cells, dendritic cells and sometimes eosinophils and mast cells
What is the circulation of lymphocytes in the mucosal immune system controlled by?
Adhesion molecules
Chemokines
Circulation of lymphocytes in mucosal immune system
Naive lymphocytes enter peyer’s patches and mesenteric lymph nodes through high endothelial venules
If lymphocyte encounters antigen in GALT= it is activated
Activated lymphocyte enters lymphatics via mesenteric LN
end up in thoracic duct
circulate in bloodstream
re-enter lamina propia
Lymphocytes differentiate into effector cells
What must happen before activated lymphocytes differentiate into effector cells?
Leave via lymphatics into bloodstream then back into lamina propia
What do activated B cells do in the peyer’s patch once they have recirculated and reentered lamina propia?
In secondary lymphoid follicle-germinal centre
Class switch= IgA producing plasma cells
Plasma cells and effector T cells rarely found in peyer’s patches
What antibody class is associated with mucosal immune system?
IgA (produced by plasma cells)
What do IgA do?
Prevent bacteria adhering to host cell
Neutralise toxins made by pathogen
What do broad-spectrum drugs do regarding commensal micro-organisms?
Antibiotics kill large numbers of commensal MOs
Creates niche- commensal can’t compete with entering pathogens
e.g Clostridium difficile grows in an antibiotic treated gut
causes bloody diarrhea
What do commensal bacteria do?
Stimulate IgA production
Inhibit inflammation
Immune response to commensal bacteria
T cells can respond to commensal bacteria
But T cells= regulated to prevent this
What is caused when regulatory mechanism of preventing immune response to commensal bacteria?
Inflammatory bowel disease e.g Crohn’s
Systemic immune response against flagellin of commensal bacteria
What prevents immune response to commensal bacteria?
They lack virulence factors
So they are taken up by phagocytic cells and rapidly killed
Endotoxin made by commensal bacteria is sensitive to neutralisation
What are germinal centres?
Lots of lymphoid follicles found in secondary lymphoid follicle
What do germinal centres consist of?
B cells, macrophages, follicular dendritic cells
What happens in germinal centres?
B cell proliferation
Proliferating B cells found in centre
Inactive B cells are pushed towards edge= mantle zone
B cells surrounded by their associated T helper cells
Somatic hypermutation
What happens in the dark zone of the germinal centre? (near left)
Naive B cell undergoes clonal expansion
Somatic hypermutation- in V region of BCR gene- nucleotides are added/delete
What happens in the light zone of germinal centre?
Clonal expansion- B cell differentiates into plasma and memory cells,differentiation, class switching- induced by cytokines: IL-4, IL-10,IFN-Gamma BCR are checked by follicular dendritic cells B cells with non-functional BCR or crap BCR are killed by apoptosis a=by follicular dendritic cells
What is somatic hypermutation?
Induces point mutations in variable region of DNA of BCR
at a very high rate
Mutant BCRs= selected for survival and move to light zone
What happens when somatic hypermutation causes a bad mutation in B cell?
Decreased affinity of antibody for antigen
Can recognise self -proteins
Causes apoptosis of B cell (by dendritic follicular cell)
Favourable mutations made by somatic hypermutation leads to?
Increased affinity of antibody for antigen
Selection of B cells with highest affinity- these cells are given survival signals
What happens after somatic hypermutation is done?
High affinity B cells selected to move to light zone Receive second survival signal by T helper cell Causes B cells to differentiate into plasma/memory cells Inducing class switching= different isotypes made- induced by IL-4, IL-10, IFN-gamma
mesenteric lymph node?
Contains naive T and B cells(IgM)
Connected to areas of GI tract
What is the lamina propia?
Connective tissue
Contains activated immune cells (CD4 and CD8 T cells and plasma cells- activated B cells)
How do naive lymphocytes (T and B) enter peyer’s patches?
via High endothelial venules
Where are naive B and T cells found in peyer’s patches?
Naive T cell= outside follicle
Naive B cell= within follicle
What happens if there are no antigens or dendritic APCs present in peyer’s patches?
Lymphocytes recirculate through bloodstream or go to spleen
In mucosal immunity what must happen to naive B cells?
Naive B cells igM is converted to igA
IgA is major in mucosal immunity
What happens once dendritic APC has activated T and B cells?
T and B cells leave peyer’s patches and travel through body then end up in lamina propria
in mucosal immunity once B cells are class switched to igA how are the actually activated?
IgA B cells are activated when in tissues by T helper 2 cells that make IL-4 IL-4= allows class switching of B cell
Route of antigen in lymph node?
- Antigen and APC from tissue fluid travel into lymph node in lymphatic fluid
- In paracortex of lymph node dendritic cell presents antigen= MHC II APC
- Dendritic cells and B cells activate T helper cell
- B cells are activated by T helper cell or by antigen directly
- Activated B and T helper cells form foci with many proliferating B cells
- A few B cells and T helper cells migrate to primary follicle of cortex and interact with follicular dendritic cells
- Causes a production of a secondary lymphoid follicle with a germinal centre causing B cells to differentiate and proliferate into plasma cells= creating antibodies
Tonsils function
Adenoids, palatine, lingual
- Tonsils= macrophages, neutrophils, granulocytes and mast cells
- Discrete follicles and germinal centres= B cells
- Germinal centres and discrete follicles= surrounded by T cells
- Tonsils= meshwork of connective tissue= traps pathogen
- Contain primary and secondary lymphoid follicles= but NON-CAPSULATED (luminal surface covered in squamous epithelium)
Protect against pathogen entering nose/mouth (nasal and oral epithelia)
