MCM 2-23 Gut Immunity

Question 1

lamina propria

Answer 1

directly underneath mucousal layer of intestinal tissue. “thin plate” where most effector responses of mucosal immunity occur

Question 2

skin vs mucosa immunity

Answer 2

SKIN

1. pro inflammatory macrophages and dendrites present
2. infection results in recruitment of inflammatory cells (granulocytes/monocytes)
3. Collateral (immune mediated) damage to tissue. scarring.
4. environment where invading organisms are either destroyed or sealed off (Granuloma)

Muscoca

1. Many immnune cells (lymphocytes, anti-inflammatory macrophages, dendrites) along with immunoglobulin
2. infection results in highly localized inflammation with much less recruitment
3. little to no tissue disruption
4. environment of evolving adaptive immunity where host and microbe co-exist.

Question 3

describe mucus

Answer 3

provides a molecular barrier. glycosylated chains that link end to end, glycosylated allows water to bind

mucus binds to antibodies that bind to corresponding antigens. Traps microorganisms inside, carried along tract and expelled from body

Question 4

describe goblet cells

Answer 4

specialized epithelial cells that produce mucous and sit in epithelium

Question 5

describe the mucus current

Answer 5

deep crevace between villi are a dead pocket, as goblet cells excrete mucus, the mucus flows out and washes these crypts out

Question 6

describe membrane bound mucus

Answer 6

membrane bound mucins expressed on surface of epithelial cells and bound to cells themselves.

• Non goblin epithelial cells
• forms dense layer of mucus, prevents microbes from getting to surface

resists penetration

Question 7

membrane bound vs secreted mucus

Answer 7

membrane bound - thick, dense, protects absorptive epithelium

secreted - excreted by goblet cells, carries bacteria away

Question 8

paneth cells

Answer 8

paneth cells are deep in the crypts of the duodenum (first segment of small intestine).

produces defensins - small peptides that form pores in microbial membranes. leasds to death if concentration high enough. concentration of defensins increases at the bottom of crypts.

Question 9

describe how epithelial cells defect infection and respond

Answer 9

intenstinal absorptive epithelial cells can sense inflammation/bacteria infection with Toll-Like receptors

TLR-5 detect bacteria that have penetrated lamina propria. triggers release of short lived inflammatory cyotkiines

Question 10

special features of intestinal macrophages

Answer 10

still eat and kill microbes

limits collateral damage by not performing respiratory bursts, dont produce cytokines, dont activate T cells

Question 11

important mucus points

Answer 11

functions as barrier to microbial invasion through physical properties and by binding to antibody

intestinal mucus secreted by goblet cells

membrane bound mucus is produced by enterocytes and forms a dense layer, preventing microbes from reaching epithelium

Question 12

intestinal epithelial cells recognize…

Answer 12

microbial invasion and can initiate localized inflammation

Question 13

epithelial cells are turned over…

Answer 13

rapidly, abour every 48 hours, ending inflammatory signaling

Question 14

mucosal macrophages are ________ but not ___________

Answer 14

phagocytotic but not inflammatory signalign

Question 15

2 macroscopic anatomical structures that contribute to mucosal immunity

Answer 15

Waldeyers ring - structures around mouth and throat form a ring of lymphatic tissue. all bacteria entering GI and respiratory can interact with IgA

appendix - collects antigen, has lots of lymphoid follicles, allows for surveillance of large intestine microbiota

Question 16

microscopic structures that contribute to immune response

Answer 16

in the intestine, areas of lymphoid tissue is called peyers patches. provide immune surveillance. Entrance to peyers patches are M cells which are folded to icnrease SA and enhance transcytosis of bacteria from lumen to peyers patch which is filled with dendrites, b cells, and t cells.

Question 17

what do M cells do?

Answer 17

specialize in transporting “transcytosis” microbes and antigens through the epithelium and into underlying lymphoid tissues

Question 18

establishment of pro-active adaptive immunity in mucous tissues

Answer 18

CD103+ dendritic cells found in peyers patches and mucousal lymphoid tissue

-microbes and food antigens get transcytosed through M cell.

Dendrite sees harmless food antigen (lacking danger molecules) and any t-cells that interact with the harmless food molecule are exposed to IL-10 with no co-stim = causes anergy. Antoher t-cell will be turned into a “food specific” tTreg cell by the dendrite which will express FOXP3

If it is a commensal, even then we want to form a T-cell activation. Dendrite WILL provide a costim.

T-cells actiavtd by dendritic or B cells will cooperate with B-cells, creating antibody excreting plasma cells excreting IgA

Question 19

mucosal immunity is ________

Answer 19

Mucosal immunity is proactive due to the constant presence of secreted Ig’s in the mucous layer as well as well as a greater variety of immune cells (lymphocytes, macrophages, dendritic cells, etc.) in the lamina propria.

Question 20

lymphocytes activated in one mucousal tissue will..

Answer 20

mature to defend all mucousal tissue. Subset of clones will go to other tissues and defend.

as mature lymphocytes leave tissue, roll along BV and come across adhesion molecules. come across moucsal tissue, enters area.

Question 21

where are gut antibodies produced?

Answer 21

1. produced in lamina propria, shuttled to lumen.
2. Polymeric secretory Ig’s (IgA and IgM) move through basement membrane and are bound by poly-IG-receptors on epithelial cells
3. this complex moves into the epithelial cell via RME
4. trancytosis moves complex to lumenal face of cell (apical)
5. receptor cleaves, Ig is released

can also be used for retrograde toxin transport
toxins beneath epithelial cells bind to antibodies specific to them, and the complex is moved via transcytosis to the gut lumen to be carried away.

Question 22

M cells

Answer 22

Act as the gatekeeper of the Peyer’s patches (aggregations of lymphoid tissue in the small intestine). They specialize in transporting microbes and antigens through the epithelium and into underlying lymphoid tissues.

Question 23

CD103+ Dendritic Cells

Answer 23

Orchestrate the response to antigens that pass through M cells via transcytosis. They help differentiate between pathogens and harmless antigens. They present antigens to naïve CD4 T cells leading to T cell activation (in response to microbial antigens), or T cell anergy and food antigen-specific Treg development (in response to food antigens). The latter (oral tolerance) is accomplished through IL-10 secretion.

Question 24

Intraepithelial Lymphocytes

Answer 24

Likely poised within the epithelium to respond to viral infection. Most are alpha-beta T cells, which respond to peptides in MHC’s. Fewer are gamma-delta T cells, which are less diverse in specificity and recognize chemical signs of cellular stress as well as peptides in MHC’s; they are generally cytotoxic, but also release growth factors and cytokines that promote rapid repair.

Question 25

CD4+ Effector Cells

Answer 25

Augment antibody production (by pairing with antigen-specific B cells) or activate macrophages in response to invasion. CD4 T cells activated in one Peyer’s patch will move to the other Peyer’s patches to spread the immune response.

Question 26

tregs

Answer 26

Reduce responses to harmless antigens (e.g. food components).

Question 27

what are the two forms of IgA?

Answer 27

IgA1 = 1 looks like L for long. more flexible long arms for better binding. many bacteria have enzymes that cleave Fc off. Found in areas of fewer bacteria (nasal passages) IgA2 = short hinge. S looks like a 2. Evolved form of IgA that has shorter arms, cannot be cleaved by bacteria proteolysis. Hindered arm movement so does not move as well, but does not get chewed up by bacterial enzymes. Found in areas with LOTS of bacteria, like colon.

Question 28

what allows guides lymphocytes from one mucus to defend all mucus surfaces?

Answer 28

cell receptors and adhesion molecules guide lymphocytes to the correct anatomical locations

Question 29

Effects of invading pathogens vs harmless food particles?

Answer 29

invading pathogens cause t-cell activation, leading to IgA production Harmless antigens lead naive T-cells to become T-regs and lead to oral tolerance.

Question 30

appropriate T-cell differentiation is important for helminth clearance

Answer 30

helminth - parasitic worm polarization of t-cells in response to parasitic worms is protective or detrimental TH2 = produce correct cytokines to give correct response. IgE causes water excretion, pushes parasitic worms off TH1 - interferon gamma, incorrect. but also activates macrophages which is fine for small paraistes

Question 31

TH1 activity for helminth

Answer 31

excretes IFN-gamma - macrophages activated, causing tissue damage - b-cells produce IgG, not protective against worms - decreased epithelial turnover parasite survives

Question 32

TH2 activity for helminth

Answer 32

IL3 = mast cells rectruited releasing histamine causing spasms and diarreah (to push out worms) IL-4 = b-cells produce IgE against parasitic antigens IL-5 = attracts helminth killing eosiniphils IL-13 = increase in goblet cells, increased epithelial turnover

Question 33

small parasite, like mycobacteria....

Answer 33

good to have TH1 response, macrophages can engufl

Question 34

which cytokine is produced by TH1 cells and DOES NOT help to mount an effective anti-helminth response?

Answer 34

IFN-y

Question 35

M-cells

Answer 35

Act as the gatekeeper of the Peyer’s patches (aggregations of lymphoid tissue in the small intestine). They specialize in transporting microbes and antigens through the epithelium and into underlying lymphoid tissues.

Question 36

CD103+ Dendritic Cells

Answer 36

Orchestrate the response to antigens that pass through M cells via transcytosis. They help differentiate between pathogens and harmless antigens. They present antigens to naïve CD4 T cells leading to T cell activation (in response to microbial antigens), or T cell anergy and food antigen-specific Treg development (in response to food antigens). The latter (oral tolerance) is accomplished through IL-10 secretion.

Question 37

Intraepithelial Lymphocytes

Answer 37

Likely poised within the epithelium to respond to viral infection. Most are alpha-beta T cells, which respond to peptides in MHC’s. Fewer are gamma-delta T cells, which are less diverse in specificity and recognize chemical signs of cellular stress as well as peptides in MHC’s; they are generally cytotoxic, but also release growth factors and cytokines that promote rapid repair.

Question 38

TH1

Answer 38

Secrete IFN-gamma, activating macrophages and causing tissue damage. B cells activated as a result of their action produce IgG, which is not effective against helminths. They also decrease epithelial turnover. Overall, TH1 cells promote helminth survival.

Question 39

TH2

Answer 39

Secrete IL-3 to recruit mast cells, which release histamine causing spasm and diarrhea. Secrete IL-4 causing B cells to produce IgE, which is effective against parasite antigens. Secrete IL-5, which attracts helminth-killing eosinophils. Also secrete IL-13, which increases the number of goblet cells (mucous-producing cells) and promotes epithelial turnover. Overall, TH2 cells promote helminth expulsion.