Mucosal Immunity-Hudig Flashcards
Mucosa has what?
igA
What are the diseases mediated by mucosal immunity?
Celiac Disease
Crohn’s disease
Ulcerative Colitis
What are th17 cells?
these secrets IL-17
create inflammation in autoimmune disease
found at mucosal borders
What are T regs?
regulatory cells that maintain tolerance to self antigen
What are neutrophils?
phagocytes, a part of the innate immune system, respond to bacteria
What is the key to the GI system?
that food antigens are tolerated by the immune system
What is GALT?
gut associated lymphoid system
starts with tonsils, includes the stomach, the SI, colon
peyer’s patches only in the gut are immune!
Talk about the villus & the crypts in the intestines.
Villus-this is where food absorption takes place, includes goblet cells and absorptive cells/enterocytes.
Crypts have endocrine cells (paneth cells) that produce defensins that kill & keep bacteria in the gut.
Talk about the path of food in the intestines.
absorption via enterocytes of villus
food peptides & lipid micelles absorbed
carried via hepatic portal vein to the liver.
Usu food antigens aren’t treated as foreign.
What do goblet cells do? Paneth cells?
Goblet cells–secrete mucus
Paneth cells–endocrine cells in crypts that produce defensins to keep & retain bacteria in the gut.
WHat is commensal bacteria?
bacteria that is “permanent” in the gut & is an individual’s fingerprint & protects from bad bacteria.
pathogenic if systemic
not found in eyes, breast, lungs
What do the following cell types secrete? How does this all come together to help kill bacteria?
goblet cells–mucus; binds defensins
enterocytes–secretes beta defensins
paneth cells–secretes alpha defensins
defensins kill bacteria
What is another name for alpha defensins?
cryptidins
How does mucus & defensins work together?
mucus is anionic
defensins are cationic
neg. phosphate head of lipid membranes of bacteria bind to defensins
they bind together & when a critical conc’n is reached–kill bacteria.
Why is mucus so important in killing bacteria?
it gathers the bacteria & defensins together so that they can reach the critical conc’n for killing
Describe the structure of alpha & beta defensins.
amphipathic
How are antigens from food in the gut lumen introduced into the body?
by M cells in Peyer’s patches (immune)
they are then presented to dendritic cells that activate CD4 cells (based on which cytokines they secrete) & maybe you get B cells making IgA or IgM
Aside from Peyer’s patches, where else do you find DCs, T & B cells?
in lymphoid follicles
You must have a balance in the gut of DCs/T/B cells & what other cell type?
T reg
A healthy Gi tract doesn’t have a bunch of which 2 things?
neutrophils
Th17
Mucins & defensins are a part of which type of immunity?
innate
Memory cells of the gut circulate but return to ______.
the mucosa
What are intraepithelial lymphocytes?
IELs are found in the villi
these are a type of CD8 cells that kill infected enterocytes
**can kill in antigen-specific way or like NK cells can respond to stress proteins
What’s the deal with mucosal antibodies?
secreted by B cells
only IgA or IgM
they aggregate pathogens & protect the epithelial cells.
spit out 3-4 grams of these a day
T/F Mucosa is half the immune system.
T
What’s the deal with the lymphatics near villi & peyer’s patches of the intestines?
draining lymphatics to the mesenteric lymph nodes
Explain what the deal is with M cells.
micro fold cells.
bring in whole bacteria or whole proteins by endocytosis or phagocytosis
have pockets that include DC, T, B cells
Which MHC do DC cells use for antigen presentation in the gut?
MHCII b/c we are talking extracellular antigen
What regulatory cells respond in the mucosal system to dendritic cell antigens?
T regulatory cells.
If DC cells tell Th0 cells to differentiate into T follicular helpers what do you get?
IgA from B cells
IF DC secrete a lot of IL-4, what do you get?
TH2 dominant
IgE secreted from B cells
What do T regs (the normal kind that responds to self) do?
produce IL-10 & TGF-beta to shut down all T & B responses to an antigen
What types of antigens do induced T regs respond to? Secretion of ____ by DC prompts these cells.
non-self
food & bacteria etc. different from normal T regs.
secretion of TGFbeta
What are 2 places that secrete TGFbeta? IT is rich in the mucosal environment.
enterocytes
CD103+ DCs
WHat is the deal with lymphocyte homing?
how you get CD8 IELs to the mucosa of the gut (SI or LI)
they up regulate integrins that bind to MADCAM1 (addressin in blood vessels)
they up regulate their CCR9 receptors that bind to CCL25 chemokines in the gut
alpha4beta7 is expressed on lymphocytes that home to the mucosa. WHat do they bind to?
it binds to MADCAM1 in blood vessels near gut
it binds to E-cadherin in the epithelium of the gut.
What are the immune cells of the epithelium of the gut?
IEL bound by E-cadherin to the the enterocytes
What are the immune cells of the lamina propria of the gut?
CD4 T cells macrophages mast cells--filled with IgE DC plasma cells--IgM, IgE, IgA
What do CD8 IELs do?
they kill either via antigen-specific mode or NK mechanism where they sense stress proteins.
- *virus infects epithelium & displays a viral peptide to IEL via MHC class 1.
- *kills the cell via granzyme or FAS-ligand
What are some cytokines produced by dendritic cells?
TGFbeta
IL6
IL12
TGFbeta from DC–>get:
TGFbeta & IL6 from DC–>get:
IL12 from DC–>get:
T follicular helper cells–>make:
TGFbeta from DC–>get: Treg cells
TGFbeta & IL6 from DC–>get: Th17cells
IL12 from DC–>get: Th1 cells that favor the production of CTL
T follicular helper cells–>make: IgA
Class switch to IGA is driven by ____.
Which 2 immunoglobulins can be transported into the gut via __ chain & ___ receptor?
driven by TGFbeta
IgA & IgM via J chain & plgR
What is the mucosa helps with a viral infection? bacterial infection? What are the sentinel cells? What helps stop the nonsense when it is just food?
viral–>CD8 IEL killers
bacterial–>memory th17 that w/ fibroblasts (w/ IL17 receptors) call in the neutrophils
sentinel cells–>IgE mast cells
memory T reg recognize–it’s just food!
What are some things that fibroblasts secrete?
CXCL2 & CXCL8 chemokines
What might some people want to block IL-17 receptors on fibroblasts?
for rheumatoid arthritis or something where neutrophils are called into battle unnecessarily & just end up committing frustrated phagocytosis & releasing elastase etc.
T/F Celiac disease is the same as wheat intolerance or wheat allergies.
False. autoimmune issue w/ antibodies against self.
enteropathy to villi
treatable w/ gluten free diet
10-30% mortality rate.
What % of celiac cases are classic? What are the features that are present in non-classic cases?
50% classic
in non-classic cases see malabsorption & anemia
What are the classical symptoms of celiac disease?
diarrhea
abdominal pain
abdominal distention
failure to thrive (b/c of malabsorption of nutrients)
megaloblastic anemia (malabsorption of VB12 intrinsic factor)
weight loss
damaged villi in SI
What are the nonclassical symptoms of celiac disease?
delayed puberty
reduced growth
anemia
damaged villi in SI
Describe the villi in patients with Celiac.
shorter
cryptic hyperplasia
a lot of IELs
**can only see if clinical symptoms are also present when you take the biopsy.
Describe some of the antibodies & autoantibodies seen in Celiac disease.
IgA autoantibodies to tissue transglutaminase 2
IgA autoantibodies to endomysium antigens
IgA antibody against de-amidated gliadin (gluten peptide)
Tell me more about IgA autoantibodies to tissue transglutaminase 2.
sensitive & specific
- *only if exposed to gluten for 2 weeks prior
- *small subset of patients lack IgA
Which HLA alleles are common in patients with Celiac?
90%: DQ2 +
5%: DQ8+
How long does it take for children to heal after adopting a gluten free diet? Adults?
Children: 3-6 mo
Adults: years
Celiac patients show_______ of the mucosa.
scalloping
How many grams of gluten are normally ingested per day? How much to trigger issues in celiac pt?
10-20 grams gluten consumed per day
micrograms can trigger rxn in celiac pt.
Gluten is digested to produce ______.
______ modified enzymatically so glutamine AAs become glutamic acid AA residues, acquire negative charge
Gliadin-modifying enzyme is _____________.
Gluten is digested to produce gliadin.
Gliadin modified enzymatically so glutamine AAs become glutamic acid AA residues, acquire negative charge
Gliadin-modifying enzyme is tissue transglutaminase 2 (tTG2)
What is gliadin?
33AA long peptide from gluten
What do responding CD4 Th1 helper cells do in celiac patients?
proliferate to modify gliadin
Responding B cells to gliadin make antibodies to what? Which of these are productive/make sense? Which don’t?
Ab’s to gliadin makes sense IgA auto-ab’s to tTG2, no sense IgA auto-ab’s to EMA, no sense Autoantibodies lack role in pathogenesis Then IEL CTLs do their thang.
> ___ IELs/100 enterocytes in celiac patients.
> 25/100
So with celiac you get a bunch of IELs that kill enterocytes…what happens next?
As the enterocytes die, the villi shrink and become dysfunctional.
Remember, that in celiac IEL CD8s can also kill enterocytes via NK cell mode of “stress”. Explain how this happens.
BIo-stress causes enterocytes to express MIC-A&B. Then this binds the NKG2D receptors on IELs & they kill the poor fellows.
Note: CD4 anti-modified gliadin T helpers potentiate IEL CD8s to acquire NK receptors.
What are some potential therapies for celiac disease?
monoclonal antibodies to block T cell mucosal integrins or MALT chemokine receptors.
What is Crohn’s disease?
affects both ileum and colon
associated with defects of defensins
perhaps lower neutrophil recruitment
What is Ulcerative Colitis?
affects only colon
associated with defects of mucus
How does Crohn’s usu present? Endoscopically?
abdominal pain
perianal disease
**Cobblestoning mucosa and aphthous or linear ulcers. Thickened wall.
How does ulcerative colitis present? Endoscopically?
GI bleeding
**diffuse continuous involvement of the mucosa.
Radiographically? Crohn’s
Pathologically?
fistulae, asymmetry, and ileal involvement
Path:mucosal discontinuity, transmural involvement, and granulomas, crypt abscesses
Radiographically? UC
Pathologically?
show continuous disease without fistulizing or ileal disease
*Path: doesn’t show the things present in Crohn’s
see some pseudo polyps & crypt distortion & loss of hausfrau
What is aphthous?
a small, white spot or pustule, caused by either viral or fungal infections, that appears in the mouth, on the lips, or in the gastrointestinal tract in certain diseases, as thrush
Once again, what is the path of Crohn’s disease?
Thickening, obstruction and fissures throughout GI,
small intestine involvement
Frequently transmural lesions
see granulomatous lesions
T/F Crohn’s disease has an association w/ the same HLA types as in Celiac disease.
False. No HLA association at all w/ Crohn’s.
What are the genetic associations that have been found w/ Crohn’s?
Genetic association with variant intracellular NOD2 sensors
Genetic association with autophagy gene variants
Ileal Crohn’s is b/c of lack of ____.
Colonic Crohn’s is b/c of lack of ____.
Ileal–>lack of paneth cells producing alpha defensins.
colonic crohn’s–>lack of enterocytes producing beta defensins.
CD4 cells become ____ & ____ in Crohn’s.
Th1 & Th17
What are some treatments for crohn’s?
increasing Tregs
rifaximin
anti-TNFalpha biological (monoclonal antibodies)
What are some future therapies for Crohn’s?
oral recombinant defensins
mAB anti-IL17 receptors
what are some of the immune imbalances in Crohn’s disease?
low defensins normal mucus neutrophilic infiltrate less T regs More Th1s more live bacterial activated phagocytic cells
Let’s talk pathology of UC again.
limited to colon
mucosa & submucosa affected
but no deeper
normal defensins, low mucus
What might be the cause of low mucus in UC?
low secretory MUC2 or transmembrane MUC3 & MUC4
What is the future for immunotherapies for UC?
th2 cells make IL-13.These up regulate goblet cells to secrete more mucin.
