Mucosal Immunology Flashcards
(36 cards)
1
Q
What is MALT, BALT and GALT
A
- MALT is mucosa-associated lymphatic tissues that is divided into
- BALT: bronchus-associated lymphatic tissue
- GALT: gut-associated lymphatic tissue
2
Q
Why is the mucosal immune system important
A
- It is the biggest immune compartment of the organism
- With an estimated surface area of 400 m2 it harbours 60% of all effector cells
- It is in direct contact with the outside environment
- There is continuous antigen stimulation (food, endogenous flora, & pathogens)
- Mucosal sites are the ports of entry for many infections and an important target site for vaccine-induced protection
3
Q
What are the main defence strategies of Intestinal Mucosa & Oropharynx
(4)
A
- Endogenous flora
- Epithelium and Mucus
- Regionalised Immune System
- Gut homing of B and T cells
4
Q
How do the Epithelium and Mucus act as defence mechanism for the intestinal mucosal and oropharynx?
A
- Mechanical Barriers (cells, tight junctions)
- Mucins (extensively glycosylated proteins) form a viscous barrier
- Specialised epithelial cells (goblet cells, absorptive epithelial cells, M cells, Paneth cells)
- Antimicrobial substances (defensins, lysozyme, lactoferrin, phospholipases
5
Q
What makes up the Regionalised Immune System? (5)
A
- Waldeyer’s ring (lingual and palatine tonsils, nasopharyngeal tonsils)
- entrance of the digestive tract
- Peyer´s patches in the ileum
- Mesenteric Lymph nodes
- Intraepithelial immune system
- Lamina propria immune system
6
Q
How does the Gut homing of B and T cells act as a defence mechanism for the intestinal mucosal and oropharynx?
A
- Immune cells primed in the induction sites return to the relevant effector sites (homing) when there is damage or infection
7
Q
What is the best/ prudent diet and what is the impact on our gut and mucosa?
A
- Rich in fibre, supports healthy gut microbiota
- Short-Chain Fatty Acids produced by bacteria
- Increased mucus production, increased antimicrobial peptide production
- Increased expression of tight junction proteins
8
Q
How does your diet impact the composition of your microbiota?
A
9
Q
What is the typical ‘western’ diet and what is it’s impact on the mucosa?
A
- Low in fibre
- Diversity of bacteria reduced
- Low SCFA production
- More (chronic) inflammation
- leakiness
10
Q
How does your diet impact your mucosa and immune system function?
A
11
Q
What are the 4 key Intestinal Epithelial cells
- what is their action
A
- Epithelial cells
- Microvilli
- TLRs (TLR2,4,5,6,7,9 depending on region of gut).
- TLR5 on basolateral surface activated by bacteria.
- NLR in cytoplasm activated by flagellins (invading bacteria)
- Paneth cells
- produce human defensin 5 (HD5) precursor & HD6 precursor,
- Trypsin (activates HD5 and HD6 by proteolytic cleavage)
- Goblet cells
- Produce mucus as a physicochemical barrier
- Antibacterial peptides and antibodies of IgG secretory IgA type are dispersed in the mucus
- (-> transepithelial transport of IgA)
- M cells
- transport antigens from gut lumen to subepithelial lymphoid structures (-> Peyer’s patches)
12
Q
What is the action of Epithelial Cells
A
- regulation of tight junctions between cells through TLRs
- Microvilli
- TLRs (TLR2,4,5,6,7,9 depending on region of gut).
- TLR5 on basolateral surface activated by bacteria.
- NLR in cytoplasm activated by flagellins (invading bacteria)
13
Q
What is the action of Paneth cells
A
- produce human defensin 5 (HD5) precursor & HD6 precursor,
- __defensins prevent the bacteria from reaching the epithelium
- Trypsin (activates HD5 and HD6 by proteolytic cleavage)
14
Q
What is the action of Goblet cells?
A
- Produce mucus as a physicochemical barrier
- stops the gut bacteria from reaching the epithelium
- Antibacterial peptides and antibodies of IgG secretory IgA type are dispersed in the mucus
- (-> transepithelial transport of IgA)
15
Q
What is the action of M cells?
A
- transport antigens from gut lumen to subepithelial lymphoid structures (-> Peyer’s patches)
16
Q
What are the lymphoid complexes?
A
- Lymphoid complexes along the gastrointestinal tract. The volume of the rings indicates the relative amount of lymphoid tissue.
- The largest amount of lymphoid tissue is found in the oropharynx (Waldeyer’s ring) and terminal ileum.
17
Q
What are Peyer’s Patches?
- location
A
- PPs are located in the distal ileum in areas of follicle associated epithelium (FAE)
- PPs contain germinal centres for B- and T cells
- The foetal small intestine contains on average 60 PPs before week 30 of gestation and their number steadily increases reaching a maximum of about 240 at puberty
- they account for the large volume of lymphoid tissue in the terminal ileum
18
Q
Which cell(s) is contained within the Peters Patch Folliculare Associated Epithelium (FAE) dome/layer?
- what are their features
A
M- Cells
- Small microvilli (microfolds)
- Large cell membrane fenestrations
- enhances antigen uptake from the gut lumen (fluid-phase endocytosis)
- A trans-cellular transport mechanism for antigen
- Exocytosis at the basolateral membrane
- delivers antigen to dendritic cells (DCs) of underlying lymphatic structures
19
Q
What are the distinct areas within the Peyer’s Patches?
(4)
A
- Follicular-associated epithelium (FAE)
- Follicular area
- Interfollicular area
- Subepithelial dome
20
Q
Which cell(s) is contained within the Peyer’s Patch Follicular area?
A
- Lymphoid follicles with a germinal center (GC) containing proliferating B-lymphocytes
- Follicular dendritic cells (FDCs) fixing antigen on surface (not APCs, no class-II MHC)
- Macrophages (proper APCs, class-II MHC)
21
Q
Which cell(s) is contained within the Peyers Patch Interfollicular areas and subepithelial dome?
A
containing mixed-cells, including
- B-cells,
- T-cells,
- Macrophages
- Dendritic cells (DCs).
22
Q
How are Peyer’s Patches involved in Lymphocyte Homing?
- explain part 1 of the mechanism
A
- Naive B-cells enter the PP via specialized high endothelial venules (HEV).
- If they recognize antigen coming in from the M-cells at the top of the PP, they get activated and may start proliferating.
- Naive CD4 T-cells also enter the PP via specialized high endothelial venules (HEV)
- If they encounter a dendritic cell presenting antigen they recognize, they will begin proliferating and increasing in number.
- Some of the T-cells will then most likely encounter B-cells activated by the same antigen.
- T-cell/B-cell help takes place: they activate each other,
- T-cells move on to become fully fletched mature cells and B-cells undergo an Immunoglobulin class-switch to turn into Plasma cells.
- Most activated T-cells and B-cells both leave the PP via lymphatic drainage and reach their destination via the bloodstream.
- in PP B-cells are being programmed to produce IgA. This happens under the influence of nitric oxide and TGF-beta from dendritic cells.
23
Q
What is Mesentery?
A
a double fold of peritoneum that attaches the gut to the posterior abdominal wall.
24
Q
Where are Mesenteric Lymph nodes?
- what is their action?
A
- they are located at the base of the mesentery and collect lymph, cells and antigens from the intestinal mucosa.
- main site for oral tolerance induction
25
What is Oral tolerance?
- induction?
* avoidance of an immune response to foodstuffs and other matters
* Oral tolerance induction: could be used as a therapeutic option in allergy
26
Review the Mesenteric Lymph nodes of the SI
27
Review the Mesenteric Lymph nodes of the LI
28
How is the MLN involved in lymphocyte homing?
* MLN drain lymph from intestinal mucosa
* Naïve B-cells and T-cells arriving via high endothelial venules will travel from Peyer’s patches (induction sites) via MLN to the thoracic duct and bloodstream
* They will return to effector sites in the gut (‘homing’)
29
What is the role of Liver immune cells?
* Immune cells in liver sinuses maintain food tolerance and in protect from microbes/microbial products in the portal vein (e.g. LPS)
* can cause systemic inflammation if there is too much of it - HIV infection 'leaky gut'
* Whereas the main ‘program’ in the gut is tolerance induction, in some instances, protective immune responses are raised (along with inflammation)
30
Where are the Intraepithelial lymphocytes (IEL) located?
- what are the features of IEL?
* Irregular shape (adapt to the space around them)
* Long extensions in close contact with neighbouring epithelial cells
* Occurrence in variable numbers along the gut
* Mixed with Eosinophils (up to 12% in intraepithelial cell preparations)
31
What are the different groups of Intraepithelial Lymphocytes?
(2)
(8)
**_Tissue-resident memory T-cells_**
* TCRab+CD8ab+
* TCRab+ CD8aa+ (unconventional)
* TCRab+CD4
**_Innate-like and innate lymphocytes including_**
* mucosa-associated invariant T-cells cells (MAIT) ,
* invariant
* NK-T-cells,
* g/d T-cells,
* NK-cells
32
What is the role of NK cells in the gut?
* NK cells in the gut carry NK-cell receptors
* Apart from NK-cells some T-cells carry NK-cell receptors such as NKG2D, for example TCRab+ CD8aa+ (NKG2D=natural killer group 2D receptor).
* NKG2D can bind to stress receptors expressed on damaged gut epithelial cells,
* _MIC-A, or MIC-B_ (MHC class I polypeptide–related sequence A or B). Stress may be caused by toxins for example.
* IEL expressing NKG2D can kill damaged/stressed epithelial cells by inducing apoptosis (= programmed cell death)
* perforin
* _Intraepithelial CD8 T-cells produce IFN-g_ and are important in killing infected epithelial cells (for example those infected with viruses)
33
Explain T-helper-cell differentiation in the gut and the role of dendritic cells (DCs)
* T regulatory (Treg) cells are produced in response to harmless commensals in the presence of retinoic acid and TGF-b, a factor produced by dendritic cells for example.
* Tregs produce IL-10 among other cytokines and are crucial in establishing and maintaining tolerance to commensals and food.
* _Dendritic cells (DCs) sit in the lamina propria_. Some have extensions reaching through the epithelium to ‘sample’ contents of the intestinal tube.
34
Give an overview of IgA
- function
- transport
- associated molecules
* IgA is the main antibody in secretions
* IgA against food antigens provides immune exclusion
* not allowed in the organism but no inflammatory response is initiated which is important to allow proper digestion
* IgA activates the complement system only weakly
* Secretion of dimeric IgA (coupled by a J chain) depends on a trans-cellular transport mechanism
* _The poly-Ig receptor allows IgA binding to the basolateral surface of gut endothelial cells_ and a part of it remains attached to the IgA molecule throughout the transcellular transport.
* The Poly-Ig-receptor (pIgR) at the basal surface of epithelial cells can bind to the J-chain of IgA and to a lesser extent IgM
* It enables the trans-endothelial transport of dimeric IgA and also pentameric IgM (‘secretory component’).
* This mechanism helps enriching these Immunoglobulins in the mucus where they can exert their function of Immune exclusion
35
What nutrition and local factors affect B and T cell homing?
* Dendritic cells in gut-associated lymphoid tissues (including Peyer’s patches and mesenteric lymph nodes) are induced by local factors to express retinaldehyde dehydrogenase (RALDH). This enzyme converts dietary vitamin A into retinoic acid.
* Retinoic acid induces upregulation of adhesion molecules on lymphocytes in mesenterial lymph nodes or PP.
* Lymphocytes leaving these lymph nodes will express CCR9 and a4/b7, the ligands for CCL
36
Give a complete overview of T and B cell homing
* Lamina propria dendritic cells capture antigen (Ag) and Vitamin A from the gut lumen. They migrate to a mesenteric lymph node or a PP.
* When naive B or T-cells are activated by antigen in gut-associated lymphatic tissue, they are exposed to retinoic acid (RA) produced by the dendritic cells from Vitamin A .
* This induces the expression of the chemokine receptor CCR9 and increased expression of integrin α4β7 on primed T-cells. The same mechanisms works for B-cells.
* The effector lymphocytes then enter the circulation and travel via the lymphatic system, the thoracic duct, and the bloodstream back ‘home’ to the gut (‘homing’).
* The chemokine CCL25 (the ligand for CCR9) and the adhesion molecule MAdCAM (the ligand for α4β7) are displayed on lamina propria venular endothelial cells, allowing access to the homed cells (remember key & lock).
* This was the journey of a naïve T-cell from entering an induction sites in the gut lymphatic tissue via a HEV to re-entering the gut at an effector site as an antigen-primed effector T-cell. It has now become a lamina propria T-cell.
