l11- mucosal immunity

Question 1

what does MALT, GALT and BALT stand for

Answer 1

Mucosal-associated lymphatic tissue

which is divided into the other 2 :
Bronchial associated lymphatic tissue
&
gut associated lymphatic tissue

Question 2

3 important features of mucosal sites

Answer 2

• 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
• with an estimated surface area of 400 m2 it harbours 60% of all effector cells

Question 3

what are mucosal sites the prime site of entry of

Answer 3

Infectious pathogens

Question 4

What are the 3 sites of mucosal HIV transmission routes

Answer 4

• genitourinary
• Rectal
• Oral mucosa

Question 5

what are The main defence strategies of intestinal mucosa & oropharynx
(1)

Answer 5

1- Endogenous flora
-10^14 bacteria, hundreds of different species

2)Epithelium and Mucus :
a-Mechanical Barriers (cells, tight junctions)

b-Specialised epithelial cells (goblet cells, absorptive epithelial cells, M cells, Paneth cells)

c- Antimicrobial substances (defensins, lysozymes, lactoferrin, phospholipases )

d-Mucins (extensively glycosylated proteins) form a viscous barrier

3) Regionalised’ Immune System & gut homing of B and T cells:

a- Waldeyer’s ring (lingual and palatine tonsils, nasopharyngeal tonsils)

b- Peyer´s patches

c- Mesenteric lymph nodes

d- Intraepithelial immune cells

e- Lamina propria immune cells, including sampling DCs

Question 6

what is lactoferrin

Answer 6

Lactoferrin’s primary role is to sequester free iron, and in doing so remove essential substrate required for bacterial growth.[37] Antibacterial action of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to lipopolysaccharide of bacterial walls, and the oxidized iron part of the lactoferrin oxidizes bacteria via formation of peroxides. This affects the membrane permeability and results in the cell breakdown

Question 7

describe the Lymphoid complexes along the gastrointestinal tract

Answer 7

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.

Question 8

differences between primary and secondary lymphoid tissue

Answer 8

1) The lymphoid tissues can be divided into primary and secondary lymphoid organs. Primary lymphoid tissues are sites where lymphocytes develop from progenitor cells into functional and mature lymphocytes.
2) Secondary lymphoid tissues are sites where lymphocytes interact with each other and nonlymphoid cells to generate immune responses to antigens.

Question 9

what is the structure of waldeyer’s wring

Answer 9

1 pharyngeal tonsil (or “adenoids”), are located on the roof of the nasopharynx, under the sphenoid bone.
2 tubal tonsils on each side, where each auditory tube opens into the nasopharynx
2 palatine tonsils (commonly called “the tonsils”), are located in the oropharynx
1 group of lingual tonsil are located on the back part of the tongue

consists of MALT

Question 10

what is the function of Mcells

Answer 10

M cells transport antigens to subepithelial lymphoid structures

Question 11

function of epithelial cells

Answer 11

Epithelial cells express TLRs (TLR2,4,5,6,7,9 depending on region of gut). TLR5 is expressed on the basolateral surface (activated by invading bacteria) and intracytoplasmic NLR for bacterial flagellins are activated only upon access of bacteria to the cytosol (invasion)

Question 12

function of Paneth cells

Answer 12

produce human defensin 5 (HD5) precursor, HD6 precursor, trypsin (activates HD5 and HD6 by proteolytic cleavage)

Question 13

what does TLR ligation cause

Answer 13

Surface TLR ligation will cause tightening of epithelial junctions, increase proliferation, epithelial motility, enhancing barrier function but not inflammation

Question 14

Describe PPs

Answer 14

PPs contain germinal centres for B- and T cells
They are located in the distal ileum in areas of follicle associated epithelium (FAE)
The foetal human 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

Inductive site for immune response

Question 15

what are the 3 domains of PPs

Answer 15

The follicular area

The interfollicular area

Follicle-associated epithelium (FAE)

Question 16

describe the follicular and interfollicular areas of PPs

Answer 16

: lymphoid follicles with a germinal center (GC) containing proliferating B-lymphocytes, follicular dendritic cells (FDCs) and macrophages. The follicle is surrounded by the corona, or subepithelial dome (SED) containing mixed-cells including B-cells, T-cells, macrophages and dendritic cells (DCs).

Question 17

how does FAE differ from normal epithelium

Answer 17

-The FAE differs from normal epithelium in regards to microvilli regularity and length, and the presence of infiltrating immune cells

-

Question 18

how are PPs connected to the circulation

Answer 18

by endothelial venules (from blood to PP) and lymphatic vessels (from PP to mesenteric LN).

Question 19

what are actions naïve lymphocytes

Answer 19

lymphocytes immigrate into the PP via specialized high endothelial venules. Naıve or activated lymphocytes leave the PP via efferent lymphatic vessels at the serosal side of the PPs.

Question 20

PPs:describe M cells

Answer 20

Small microvilli (microfolds)

Large cell membrane fenestrations
these features enhance antigen uptake from epithelum (phagocytosis, fluid-phase endocytosis)

Trans-cellular transport of antigen

Exocytosis at the basolateral membrane and

Question 21

Learn anatomy of slide 23

Answer 21

how was it

Question 22

What are the mesenteric lymph nodes

Answer 22

These lymph nodes are located at the base of the mesentery and collect lymph, cells and antigens from the intestinal mucosa. They are the main site for oral tolerance induction.

MLN drain lymph from intestinal mucosa

Many food antigens will bypass lymphatic tissue, however, and reach the liver through the portal vein

Immune cells in liver sinuses have an important function in protecting us from microbes/microbial products in the portal vein (e.g. LPS)

Whereas the main ‘program’ is tolerance induction, in some instances, protective immune responses need to be raised.

Question 23

what are the lamina propria and intraepithelial lymphocyte compartments

Answer 23

IEL are situated in the basolateral part of epithelium
Have an Irregular shape
Have long extensions in close contact with neighboring epithelial cells
Occur in variable numbers along the gut
There are up to 12% Eosinophils in IEL preparations

Question 24

what is the consistency of IEL

Answer 24

In the small intestine, the great majority of IEL is comprised of TCRab+CD8aa+ cells, followed by TCRab+CD8ab+ cells, with just a small fraction of TCRab+CD4ab+. The proportion TCRab+CD4ab+ increases in the distal region of the small intestine and may reach as much as 30%of the total IEL population in that area of the colon, suggesting a compartmentalization of the different IEL subsets along the intestines in order to accomplish specific immunological functions

Question 25

what are the 3 main groups that Intraepithelial T-cells can be subdivided into three main groups:

Answer 25

TCRab+CD8ab+
TCRab+CD4ab+
TCRab+ CD8aa+

Question 26

Describe intra-epithelial T cell immunity

Answer 26

• virus infects mucosal epithelium cell
• Infected cell displays viral peptides to CD8 IEL via MHC class 1
• Activated IEL kills infected epithelial cell by perforin and Fas-dependent pathways
• Epithelial cells undergo stress as a result of infection, damage, or toxic peptides and express MIC-A and MIC-B
• NKG2D on IEL binds to MIC-A,B and activates the IEL, CD8aia homodimers also bind to TL
• Activated IEL kills the stressed cell via the perforin/granzyme pathway

Question 27

describe function of DC in intraepithelial T cells

Answer 27

(DC) sit in the lamina propria and have long extensions reaching through the epithelium to ‘sample’ contents of the intestinal tube. Such antigens are presented to T-cells.

Question 28

describe the roles of different T cells after infection

Answer 28

T cell differentiation is influenced by epithelial cells and DCs

T regulatory (Treg) cells produce for example IL-10 and are crucial in establishing and maintaining food tolerance and class switch, including TGF-β and others.

Th1 cells produce IFN-g and are important in killing virally infected epithelial cells for example.

Th2 T cells may be induced by worm infection. IL-4 and IL-13 will increase fluid secretion, mucus secretion, bowel motility and smooth muscle contraction.

Th17 cells produce IL-17 and IL-22. These cytokines and interact with receptors on epithelial cells to regulate the production of mucins or defensins (antimicrobial peptides).

Question 29

describe the physiochemical role of IgA

Answer 29

The ‘secretory component’ (Poly-Ig-receptor) binds to the J-chain and enables the trans-endothelial transport of dimeric IgA. It may have a role in localising secreted IgA in mucus.

IgA is the main antibody in secretions

IgA against food antigens provides immune exclusion

IgA activates the complement system only weakly

Secretion of IgA (coupled to J chain) depends on a trans-cellular transport mechanism

Question 30

describe the intraepithelial sequence of IGA release

Answer 30

• SigA exerts both cross-reactive, innate-like and infection or vaccine-induced specific protection against epithelial invasion; also hard protection
• pIgA and pIgM exert non-inflammatory effects inside and below the epithelium
• SIgA antibodies play no protective role following invasion of infectious agents

Question 31

explain vitamin A induced gut homing

Answer 31

• The gut-homing properties of effector lymphocytes are imprinted in the lymphoid tissues where they have undergone differentiation from naive precursors.
• DCs in gut-associated lymphoid tissues (including Peyer’s patches and mesenteric lymph nodes) are induced by thymic stromal lymphopoietin (TSLP) and other factors to express retinaldehyde dehydrogenase (RALDH). This enzyme converts dietary vitamin A into retinoic acid.
• When naive B or T cells are activated by antigen in gut associated lymphatic tissue, they are exposed to retinoic acid produced by dendritic cells, and this induces the expression of the chemokine receptor CCR9 and the integrin α4β7 on the plasma cells and effector T cells that arise from the naive lymphocytes.
• The effector lymphocytes enter the circulation and home back into the gut lamina propria because the chemokine CCL25 (the ligand for CCR9) and the adhesion molecule MadCAM (the ligand for α4β7) are displayed on lamina propria venular endothelial cells.

Question 32

study slide 31

Answer 32

how did it go