Mucosal immune system - Block D lecture one Flashcards
what is mucosal immunity
Mucosal immunity is the immune system present in the mucosa, including gut, lungs and urogenital tract
what is the disease with the highest deaths per year ?
diarrhoea
what does the mucosal immune system make up percentage of the body ?
Mucosal immune system makes up 70% of the body, more important than thymus and spleen.
why do we need to know the mechanisms of mucosal immunity ?
Most pathogens enter via mucosal route
Is it better to immunise via mucosal route?
You need to understand mechanisms so that you can devise strategies against inflammatory bowel disease, asthma and COPD
Could you use oral tolerance to stop responding to food we eat but could this be used to prevent autoimmune diseases?
what are the most important cells im mucosal immunty ?
Dendritic cells
Epithelial cells
T cells
B cells
describe the GI tract ?
GI tract has large surface area of 400m2 - about the floor area of a 65 x 65 ft room. This is 200 times the area of your skin covered by single layer of epithelial cells to allow efficient nutrient absorption.
microbiome ?
Inside the gut there are 100 million million (10^14) commensal organisms of 400 species, the microbiome. This is 2,500 kg food antigens (proteins) in a lifetime. Mucosal immune system has to be able to discriminate between antigens with no pathogenic potential (dietary proteins and commensal organisms) and antigens associated with potentially harmful microbes.
mechanical immune response?
Mechanical immune responses to prevent infection include the single cell layer epithelial barrier which contains tight junctions to prevent the microbes entering between them.
Peristalsis moves the infection out of the gut and diarrhoea is an increase in fluid secretion in the gut is good to get rid of worms which and large this is called the weep and sweep action. This is non specific
humoral defences ?
Humoral defences are secreted and nonspecific this
Gastric acid - pH 1
Lysozyme - break down bacteria
Peroxidase - break down bacteria
Mucin - part of mucus which impeded interaction of pathogen and mucous surface
Anti-microbial peptides - prevent growth
Defensins - prevent growth
Trefoil proteins – prevent growth
mucosal assocaiyed lymphoid tissue (MALT) ?
Mucosal associated lymphoid tissue (MALT) is the mucosal immune system including the lung , gut and urogenital tract.
gastrointestinal associated lymphoid tissue (GALT) ?
gastrointestinal associated lymphoid tissue (GALT) is just the gastrointestinal tract. It has features including Mesenteric lymph nodes, Peyer’s patches, Lamina propria and Cryptopatches (in mice) which are collections of immune cells to help to prevent infection and controlling cancer.70 % of ALL lymphocytes are found in the gut
villi ?
In the small intestine, there are long finger like projections called villi, which are there to allow an increase in absorptive surface area
crypt of lieberkuhn ?
Crypt of Lieberkühn is where the epithelial cells proliferate and pan F cells such as trefoil proteins and defenisns
proliferation of epithelial cells ?
The epithelial cells proliferate then move up the epithelial escalator until it reaches the top where it undergoes apoptosis before reabsorption. This process takes 2 to 3 days, continually renewing the epithelial cells, this is beneficial because if a pathogen has entered it doesn’t have time to replicate before the cell is removed by apoptosis. If infection has occurred, then the rate of epithelial renewal increases, and the depths of crypts increase
IEL ?
IEL are intracellular epithelial lymphocytes which control their patch for infection or transformed epithelial cells, then apoptosis occurs.
lamina propria ?
In the lamina propria this underlies the crypts in germinal centres (aggregation of T, B and dendritic cells)
dendritic cells ?
The dendritic cells circulate in the lymphatic system and can receive signals from IEL, if the dendritic cell identifies a pathogen or antigen then they recruit T cells and alert B cells to produce antibodies
peyers patch ?
The peyers patch is an area of interaction between B, T, macrophages and dendritic cells. This are contains a special M cell which is a microfold cell. This M cell is lacking the brush border present in the other cells, the role of the cell is to present antigen from the gut lumen to the cells underneath in the Peyer’s patch. The cells in the peyers patch, lymphatic system then leave and enter the mesenteric lymph node, and this is a passive circulation of cells.
FAE ?
FAE is the follicular associated epithelial which overlays the peyers patch
goblet cell ?
produces mucus
endocrine cell ?
produces hormone
tuft cell ?
controls immune responses
Pan F cells ?
produces Trefoil factors
stem cells ?
at the bottom is where the stem cells are that produce the epithelial cells
what are the mucosal surfaces protected by ?
MALT
B cells ?
B cells produce antibodies, this can occur in the germinal centre of the lamina propria
what makes up the IEL ?
alpha, beta and gamma T cells make up the intracellular epithelial lymphocytes (IEL)
what immunoglobulins are present in the gut lumen ?
IgM, IgG and IgE and IgA are all present in the gut lumen
Secreted or leakage from the systemic gut.
IgA ?
IgA is the major class of antibody actively secreted into the gut lumen and lungs; it contains a protective element that prevents it from being degraded from pathogens. A normal adult secretes ~ 3g IgA/day, about 70% of total Ab output. It prevents attachment of bacteria, toxins, viruses, absorption of foreign substances to epithelial cells. Most recent Ig to evolve, only found in mammals and birds, not reptiles or fish. Some bacteria produce proteases against the hinge region of IgA eliminating secondary effector function
gamma delta T cells in the intestine
All T cells have a receptor made up of 2 chains part of CD3 molecule. Most are alpha and beta chains but gamma and delta T cells are found in the intestine.
gd cells make up about 50% of IEL in mice, about 20% in man, up to 70% in cows. Only 5% are present in other lymphoid tissues. But as 70% of all lymphocytes are in the gut they make up about 35% of T cells in mice and 15% in man
Role is that they are the first line of defence, also regulatory cells (mucosal homeostasis) and bridge between innate and adaptive responses
gd cells and antigen processing ?
γδ T cells are peculiar - do not seem to require antigen processing and MHC presentation of peptide epitopes. γδ T cells may have important role in recognition of lipid antigens. This contrasts with alpha and beta T cells which are about proteins and peptides.They are of an invariant nature and may be triggered by alarm signals, such as heat shock proteins (HSP).
what do gd cells interact with ?
The delta gamma T cells can interact with NK cells and other cells in adaptive and innate immunity. They act as a bridge, like NK cells as they have mechanisms of adaptive immunity and innate.
alpha , beta T cells compared to gd T cells ?
ab T cells are tightly regulated within the thymus, gd T cells can develop extrathymically in liver and gut.gd T cells express RAG-1 so they can undergo recombination for diversity.
gd T cells are homodimeric for CD8 i.e. aa CD8
FceR1g chain acts as a component of the gd T cell CD3 complex , this is the receptor for mast cells (IgE)
gd T cells are oligoclonal i.e. not diverse, TCR gd repertoire is polyclonal in newborns
gd T cells may be important in mucosal defence early in life before ab T cell and IgA responses are developed.
what has more variation gd or ab T cells ?
Gamma delta only has 840 variations while alpha beta has 3 million.
function of gd IEL ?
Surveillance of intestinal epithelial layer against microbial invasion (20-100 epithelial cells/gamma delta T cell).
Have cytotoxic activity against microbial pathogens via lysis of infected epithelial cells. Furthermore, they are involved in providing B cell help through the production of cytokines and chemokines (e.g., IL-1, IL-2, IL-4, IL-5, IL-10, IFN-g, TNF-a, TGF-b, lymphotactin).
Also support of epithelial cell growth and the maintenance of epithelial barrier integrity. This occurs by production of growth factors (e.g. keratinocyte growth factor (KGF). Also involved in the removal of damaged or transformed epithelial cells.
Immunoregulatory by abrogating/promoting oral tolerance by production of cytokines (e.g. IL-4, IL-10, IFN- g, TGF-b ).
description in depth of peyers patch ?
Described by de Peyer in 1667, it is an organised lymphoid aggregate. Comprised of specialised follicle-associated epithelium (FAE) overlying a sub epithelial dome (SED) , within the dome there are multiple B cell follicles that contain germinal centres (GC),
Within the germinal centres there are Interfollicular regions (IFR) contain T cells, high endothelial venules (HEV) and efferent lymphatics. All lymphoid migration occurs from the blood across HEV as there are no afferent lymphatics in the gut
M microfold Cell ?
This is the primary site of antigen handling in the gut, they are specialised epithelial cells. They have a poorly developed brush border, so aren’t there to absorb nutrients. No microvilli and Thin glycocalyx so easy for antigen to cross membrane. Absence of hydrolytic enzymes so don’t break down protein passing membrane. Express MHC class II on basolateral surface, the inside and can present antigen to B and T cells in the SED layer. Rich in pinocytotic vesicles, they can engulf and take up antigen present in the gut
what happens to antigen in the gut ?
2% of dietary protein is found in portal venous of liver after a meal
Lumenal pre-processing
gastric acid,
gastric enzymes - digest
pancreatic proteases - digest
Antigen is absorbed but does not evoke an immune response
what needs to occur for an immune response ?
For an immune response is the APC could be macrophage or dendritic cell which patrols around for antigens. When it encounters an antigen, it will process it and present it via it’s MHC II by peptide. It presents it to an effector CD4+ T cell. If the cell has encountered a danger signal it will be upregulated it’s co stimulatory molecules. These co stimulatory molecules then activate the T cell to produce cytokines.
On the antigen presenting cell, there must be peptide TCR and the costimulatory molecules CD28 CD80/86.
antigen sampling in the gut dendritic cell route ?
Dendritic cells can push their cell extensions (arm) through the gaps of the epithelial cells and grab antigens, the antigen can then come into the area be processed and enter the lymphatic system, arrive at lymph nodes where the antigen is presented to T cells.
If there is a danger signal , then the gap junctions between the epithelial cells will open up , so that the dendritic cells can pass to process the antigens.
epithelial cell route of antigen presenting ?
Antigens can be absorbed by the epithelial cells, it can then either enter the high endothelial venules and traffic into the blood, presented to T cells as epithelial cells contain MHC class II , or presented to macrophages. These are the 3 basic routes
M cell route ?
This is the most important route; antigen is taken up by M cell and processed where it can be taken up by dendritic cells. It can also directly activate T cells, then once active these can help B cells in the germinal centre to produce IgA. Or they can exit via the high endothelial venules, to the mesenteric lymph nodes and enter the lymphatic system to activate immune cells.
lymphocyte homing in the intestine ?
To enter the gut there is lymphocyte homing with tissue selective trafficking, they will try to enter where they came from. Initial exposure to antigen in mucosal inductive sites gut at
Peyer’s patches. Once in the Peyers patch it leaves via the efferent lymphatics and enter the mesenteric lymph node (MLN) then leaves here and enters the thoracic duct to the thymus , then enters the blood to be reintroduced in the gut tissue. This occurs by Mucosal homing with the expression of integrin (sticky molecule) a4b7 , this integrin will bind to an addresin at sites with the expression of MAdCAM , the muscosal effector site is the lamina propria.
lymphocyte homing in the intestine ?
Everything leaves the gut via the high endothelial venules, into the mesenteric lymph node. The cells at the top of the villi are expressing a4b7 and will only bind to MAdCAM , which is only expressed on the high endothelial venules in the lamina propria of the gut in the body.
vascular adhesion molecules ?
MAdCAM-1 is a mucosal addressin cell adhesion molecule – selectively expressed on postcapillary venules in the lamina propria and gut associated lymphoid tissue such as PP and MLN.
MAdCAM binds to cells expressing Intestinal homing receptor a4b7 , not naive cells they have to be activated.Heterodimeric integrin adhesion receptor family expressed in high levels on intestinal memory and effector cells. Binds MAdCAM-1
why is this important ?
Vaccine development
How can you direct lymphocytes immunised in the gut systemically as they won’t leave the gut?
How can you direct systemically immunised cells to the gut?
Therapeutic implications
Block MAdCAM-a4b7 interactions and block lymphocytes inducing inflammation in the gut
what can antigen be proccessed by ?
Antigen can be processed by:
M cells
Epithelial cells
Dendritic cells
lymphocyes primed to antigen in the gut will return to the gut how ?
MAdCAM-1
Mucosal adhesion molecule – selectively expressed in gut associated lymphoid tissue such as PP and MLN.
Intestinal homing receptor a4b7
Integrin expressed by intestinal memory and effector cells. Binds MAdCAM-1
