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Summary - Class notes - Immunology and Disease
1580770800 Mucosal immunity and diseases (Paul de Vos)
What is the role of adipocytokines?Adipocytokines are regulated by adipose tissue, important for regulation of energy and glucose homeostasis, PLUS it is also an immunoregulatory cytokine.
What is the immuno-endo function of adiponectin?Adiponectin regulates insulin sensitivity
High adiponectin --> extra calories are stored in adipose tissue
Low adiponectin --> extra calories are stored in dangerous places such as liver, heart and muscles. Organs most sensitive for insulin resistance and diabetes.
Note: Obese mice with high adinopectin never develop diabetes.
The gut is the largest
immunologicalorgan. How many of the lymphocytesdoes the gut contain and which immunoglobulinesare produced here?The gut contains 3/4 of all lymphocytes (of which 90% are CD8+ T cells),
and 90% of all immunoglobulines are produced here (5 gr
Themucosal immune system consists of two distinct compartments, the epithelium and lamina propria. Whichcompartment contains which immune cells? Epithilium: CD8+ T cell, dendritic cells Laminapropria: CD4+ T cell, dendritic cells, B cells, macrophages, mast cells, plasma cells
Describe the unique collaberation between epithelial cells and dendritic cells in Peyer's patches when encountered by an antigen.1) M cells take up antigen by endocytosis and phagocytosis.
2) The antigen is then transported across the M cells in vesicles and released at the basal surface.
3) The antigen is then bound by dendritic cells, which activate T cells.
Which cytokines released from the dendritic cell, makes the T cell express IFN-y and IL-17?IL-6 and TGF-B
In what two ways can dendritic cells capture antigens from the lumen?- Dendritic cells can extend processes across the epithelial layer to capture antigen from the lumen of the gut
- Antigens can cross the epithelial layer.
Intraepithelial T-cells are always activated and ready to kill. Describe the process of how IELs get activated by a virus infecting a mucosal epithelium cell.1) The virus infects a mucosal epithelium cell.
2) Infected cell displays viral peptide to CD8 IEL via MHC class 1
3) Activated IEL kills the infected epithelial cell by perforin/granzyme and Fas-dependent pathways.
Intraepithelial T cells are always activated and ready to kill. Describe the process of how IELs get activated as a result of infection, damage, toxic peptides.1) Epithelial cells undergo stress as a result of infection, damage, or toxic peptides and as a result express MIC-A and MIC-B.
2) NKG2D on IELS bind to MIC-A,B and activate the IEL. CD8a:a homodimers bind to TL.
3) Activated IEL kills the stressed cell via the perforin/granzyme pathway.
What is the effect of disorders in intraepithelial T-cells?A disorder in IELs cause fast spread of pathogens in the epithelium (Listeria)
How does IgA cause the neutralizing and immunization of toxins?1) Secreted IgA (through endocytosis) on the gut surface can bind and neutralize pathogens and toxins.
2) IgA is able to bind and neutralize antigens internalized in endosomes.
3) IgA can export toxins and pathogens from the lamina propria while being secreted.
When it goes wrong and bacteria come in: describe the neutrophil extracellular trap (NETosis)Upon activation of the neutrophil receptors, neutrophil release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. The fibers trap the microorganims.
NET formation is associated with bacterial clearance, but also with thrombosis, sepsis and SLE.
We cannot live without commensals. What are the 4 uses of commensals?1) Stimulates mucosal and epithelial barrier function.
- produce small chain fatty acids (SCFA)
- stimulates mucus production.
2) Inhibit pathogenic bacteria
- by decreasing luminal pH, bacteriocidal proteins, blocking epithelial binding
- Stimulates anti-inflammatory cytokines (IL10 and TGF-b)
- Stimulates IgA production
4) Mandatory for our metabolism
- primary source vitamins
- digestion of complex diet components (cellulose)
- source for SCFA
Behind the epithelium lies GALT (Gut associated lymphoid tissue). What kind of receptor keep the balance between immunity versus tolerance?Pattern recognition receptors (PRRs) expressed by immune cells & epithelial cells.
What is the physiological role of zonulin?Zonulin increases permeability which changes the hydrostatic water pressure which bring water in intestinal lumen. Through this water the removal of pathogens from the human body can occur (diarrhea).
What is the pathophysiological role of zonulin in celiac disease?1) Gliadin (immunemodulating component of gluten) stimulates the CXCR3 chemokine receptor.
2) Release of zonulin.
3) Zonulin causes claudin modification in the tight junction and causes a increase of permeability, gliadin now passes the lamina propria.
4) After deamination gliadin binds to MHC or HLA on APC or on CXCR3 expressing cells such as APCs, NK cells and T cells.
5) Cytokines are released by APCs and gliadin is presented to T cells.
6) The final outcome entails a huge activation of both humoral and cellular nature.
How can leaky gut be related to type 1 diabetes?Intraluminal zonulin concentration is 35 fold higher in diabetec prone mice. There is a 70% reduction in diabetes incidence by blockade of zonulin receptor. Absense of formation of islet cell antigens.
Which molecule causes the blockage in tight junctions for molecules > 3.5 kDa?Claudin and occludin
Which receptors and cytokines differ in APC to differentiate a CD4/CD8 or Treg cell?Treg -> NLRs
Th# -> TLRs
What is the normal processing of macromolecules (< 3.5 kDa) through epithelial cells from intenstinal lumen?The macromolecules are broken down to nonimmunogenic molecules (tolerance induction)
Naive T cells that enter Peyer's patches from blood vessels directed by the homing receptor CCR7 and L-selectin. Describe how the homing progresses further, and how different chemokine receptors determine homing in the small and large intestines.1) T cells in the Peyer's patch encounter antigen transported accros M cells and become activated by dendritic cells.
2) Activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream.
3) Gut-homing effector T cells bind MAdCAM-1 on endothelium.
4) Activated T cells expressing alpha-4B7 integrin and CCR9 home into the small intestine.
T cells expressing CCR10 home into the large intestine.
In the lamina propria it is decided whether the mature T cells differentiate into intra-epithelial lymphocytes. How is this organized and what does this allow?The lymphocytes loose alpha4-B7 and express alphaE-B7.
This allows binding to E-cadherin on epithelium.
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