MCM 2-23 Gut Immunity Flashcards
lamina propria
directly underneath mucousal layer of intestinal tissue. “thin plate” where most effector responses of mucosal immunity occur
skin vs mucosa immunity
SKIN
- pro inflammatory macrophages and dendrites present
- infection results in recruitment of inflammatory cells (granulocytes/monocytes)
- Collateral (immune mediated) damage to tissue. scarring.
- environment where invading organisms are either destroyed or sealed off (Granuloma)
Muscoca
- Many immnune cells (lymphocytes, anti-inflammatory macrophages, dendrites) along with immunoglobulin
- infection results in highly localized inflammation with much less recruitment
- little to no tissue disruption
- environment of evolving adaptive immunity where host and microbe co-exist.
describe mucus
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
describe goblet cells
specialized epithelial cells that produce mucous and sit in epithelium
describe the mucus current
deep crevace between villi are a dead pocket, as goblet cells excrete mucus, the mucus flows out and washes these crypts out
describe membrane bound mucus
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
membrane bound vs secreted mucus
membrane bound - thick, dense, protects absorptive epithelium
secreted - excreted by goblet cells, carries bacteria away
paneth cells
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.
describe how epithelial cells defect infection and respond
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
special features of intestinal macrophages
still eat and kill microbes
limits collateral damage by not performing respiratory bursts, dont produce cytokines, dont activate T cells
important mucus points
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
intestinal epithelial cells recognize…
microbial invasion and can initiate localized inflammation
epithelial cells are turned over…
rapidly, abour every 48 hours, ending inflammatory signaling
mucosal macrophages are ________ but not ___________
phagocytotic but not inflammatory signalign
2 macroscopic anatomical structures that contribute to mucosal immunity
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
microscopic structures that contribute to immune response
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.
what do M cells do?
specialize in transporting “transcytosis” microbes and antigens through the epithelium and into underlying lymphoid tissues
establishment of pro-active adaptive immunity in mucous tissues
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
mucosal immunity is ________
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.
lymphocytes activated in one mucousal tissue will..
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.
where are gut antibodies produced?
- produced in lamina propria, shuttled to lumen.
- Polymeric secretory Ig’s (IgA and IgM) move through basement membrane and are bound by poly-IG-receptors on epithelial cells
- this complex moves into the epithelial cell via RME
- trancytosis moves complex to lumenal face of cell (apical)
- 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.
M cells
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.
CD103+ Dendritic Cells
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.
Intraepithelial Lymphocytes
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.
CD4+ Effector Cells
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.
tregs
Reduce responses to harmless antigens (e.g. food components).
what are the two forms of IgA?
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.
what allows guides lymphocytes from one mucus to defend all mucus surfaces?
cell receptors and adhesion molecules guide lymphocytes to the correct anatomical locations
Effects of invading pathogens vs harmless food particles?
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.
appropriate T-cell differentiation is important for helminth clearance
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
TH1 activity for helminth
excretes IFN-gamma
- macrophages activated, causing tissue damage
- b-cells produce IgG, not protective against worms
- decreased epithelial turnover
parasite survives
TH2 activity for helminth
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
small parasite, like mycobacteria….
good to have TH1 response, macrophages can engufl
which cytokine is produced by TH1 cells and DOES NOT help to mount an effective anti-helminth response?
IFN-y
M-cells
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.
CD103+ Dendritic Cells
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.
Intraepithelial Lymphocytes
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.
TH1
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.
TH2
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.
