Mucosal Immunity Flashcards
what do M cells do
capture and transport luminal Ag to DC, macrophages, FDC and B cells
how do naive B and T cells enter MALT
HEV
how are B cells activated in MALT
generate germinal center in MALT or Ag can traffic to lymph node and B cells undergo activation there
how are T cells activated in MALT
by Ag presenting DC in MALT or LN
what are inductor sites
sites of Ag capture, processing and immune activation
what cells predominate in mucosal immunity?
activated/memory T cells even in absence of infection
what are effector sites?
effector cells mount response to eliminate Ag source
what occurs once naive B and T cells have been primed to be effector and memory B and T cells?
migrate from MALT/LN to peripheral blood
what directs the process of extravasation of B and T effector cells in effector sites?
endothelia activation in lamina propria (adhesion molecules and chemokines)
where are B or T naive cells activated?
peyer’s patch follicles or mesenteric lymph node
describe process of immune response in mucosa
- pathogen enters via M cells or DC
- naive T and B cells enter peyer’s patches by HEV
- they are activated in Peyer’s patches or lymph node and undergo proliferation
- cells enter circulation
- activated PC and T cells enter mucosal tissue or lamina propria
- they produce cytokines and Ab and CTL lyse target cells
predominant Ig?
IgA
what is waldeyer’s ring?
the tonsils and adenoids that circle the pharynx, 1st site of exposure to many pathogens in children
what is the challenge of microbial commensals in the mucosa?
coexistence, bc mucosal immune system must maintain commensal numbers with a certain level of tolerance while having the capacity to eliminate non commensals
what kind of reaction is systemic immunity?
reactive (reacts to Ag)
what kind of reaction is mucosal immunity?
proactive (healthy tissue protected by mucosal immunity)
what is pathogen encounter like in mucosal immunity?
continuous exposure, so immune activation creates memory T and B cell responses
what is the benefit of creating mostly memory T and B cells in mucosal immunity?
they are all in the lamina propria so a rapid response occurs with minor damage in the tissue, and the inflammation that does occur is terminated by IL-10 producing TREG
what cell reduces inflammation in the mucosal immunity?
Treg cells that produce IL-10
what does IL-10 do?
suppresses promoters for inflammatory cytokines
what are mucins
glycoproteins in mucus
what is the purpose of mucus?
- coats surface of epithelial cells to prevent microbial contact
- protects against corrosive effects of Hcl in sm intestine
- matrix to capture and concentrate secreted antimicrobial agents like defensins
- prevent microbe and particle movement
what cytokines induce epithelial synthesis of mucin
- IL-1
- IL-6
- TNF alpha
- type I IFN
- elastase
what antimicrobial peptide (defensin) is made in small intestine
human alpha defensin (HAD) 5-6 made by paneth cells in crypts
what antimicrobial peptide is made in large intestine
human beta defensins (HBD 1-6) made by epithelial cells
what TLR are in the mucosa?
- TLR2
- TLR 3-7
- TLR9
what does TLR signaling do in mucosa?
increased tight junction expression and proliferation of enterocytes (NO INFLAMMATION)
where is TLR expression
basolateral surface to sense bacteria that actually invade the tissue
what cells are found in the lamina propria?
- CD4 t cells with CCR9 and alpha4beta7 integrin
- macrophages
- CD103+ DC
- CD103- CD11b+ DC
- mast cells/eosinophils
- plasma cells
where are CD103-CD11b+ DC found?
extends dendrites into lumen of gut to sample environment
where are CD103+ DC found
below surface of epithelia
what cells are found in the epithelial layer?
- IEL (CD8 T cells) intraepithelial lymphocytes
2. CD103-CD11b+ DC
what do CD4 cells in lamina propria display?
CCR9, alpha4beta7 integrin
what do CD8/IEL cells in epithelial layer display?
CCR9 and alphaEbeta7 integrin
what cells populate peyer’s patches
naive T cells directed by CCrR7 and L selectin
what receptor directs cells to peyers patches
CCR7 and L selectin
what do M cells do with Ag that they catch
they transfer Ag to CD103+ DC, which then activate T cells in the peyer’s patch
where do activated T cells go once they are activated
effector T cells recirculate to lamina propria (drain via LN to thoracic duct and then return via blood stream)
how are IEL activated?
enterocytes!!!!! not DC. Ag is presented directly by infected epithelial cells or MHC class I
what do IEL do once they are activated?
employ cytolytic granules (perforin) and upregulate Fas signaling to lyse infected epithelia
what does IEL do to stressed cells (MIC+)
IEL use activating receptors NKG2D to induce apoptosis of MIC+ epithelia
what is the main source of TFGbeta?
intestinal epithelial cells, because it promotes IgA isotype switching
why is mucosal T cell response dominated by Treg differentiation?
abundant TGFbeta promotes IgA isotype switching, and IL-4 and IL-10 promote B cell expansion and PC differentiation
describe the order of B cell activation in mucosa
naive B cells are activated in follicles of MALT, then undergo SHM then CSR under control of TGFbeta
main function of IgA
- neutralizes pathogen and toxins on surface or internalized in endosomes, and export toxins and pathogens from lamina propria
where can IgA also be released
from liver into the bile!!!!
how does salmonella bacteria exploit entry mechanisms for infectivity?
- enters and kills M cells, and infects macrophages and epithelial cells by invading basolateral membrane via TLR-5
- invade luminal surface of epithelial cells
- enter dendrites of DC that are sampling via CD103-
aka luminal entry to basolateral
how does shigella avoid IgA?
adjacent spreading!
- penetrate gut epithelium via M cells, then spread
- invade basal surface and spread to other epithelial cells
- LPS binds and oligomerizes NOD1 and activates NFkB pathway
- activated epithelium secretes CXCL8 to recruit a shit ton of neutrophils
what cells are important in process of tolerance?
mucosa DC
what do enterocytes always secrete?
thymic stromal lymphopoietin (TSLP) which can also be induced by NLR signaling
what does TSLP do
promotes CD103+ DC production of TFGbeta, IL-10 and retinoic acid (signal 3)
what occurs when CD103+ secretes TFGbeta, IL-10, retinoic acid?
Th2 and Treg cell differentiation
how are cytokine responses determined from DC103-?
ATP receptors detect increased levels of ATP from bacteria, which increases DC secretion of IL-1, IL-6, IL-12, TGFbeta.
what does IL-12 d
produces Th1 differentiation
what does IL-6/IL-1 and TGFbeta do?
produces Th17 differentiation
what occurs at mucosal steady state?
- low ATP in cell
- CD103- doesn’t signal for inflammation
- TSLP signals for CD103+
- this signals IL-10 and TGF beta
- Th2 and Treg cell differentiation
- tolerance!
what occurs if there is high ATP sensed in the cell?
- ATP receptors on CD103- triggers secretion of IL-12, iL-1, IL-6, TGFbeta
- differentiation of Th1 and Th17 to eliminate ALL microbes
