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“ Sprue ” is a somewhat antiquated term referring generally to intestinal malabsorption

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“ Sprue ” is a somewhat antiquated term referring generally to intestinal malabsorption. Celiac Disease. One of the most common immune-mediated disorders Prevalence in U.S./Europe  1 % Implies that approx. 3M afflicted in U.S. alone Causes destruction of villous structure in the intestine

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Presentation Transcript
slide1

“Sprue” is a somewhat antiquated term referring generally to intestinal malabsorption

celiac disease
Celiac Disease
  • One of the most common immune-mediated disorders
  • Prevalence in U.S./Europe  1 %
    • Implies that approx. 3M afflicted in U.S. alone
  • Causes destruction of villous structure in the intestine
    • Symptoms: diarrhea, fatigue, abdominal pain, malabsorption, neurological abnormalities
celiac disease3
Celiac Disease

Celiac Sprue is a lifelong

disease, and if untreated it is associated

with increased mortality

celiac disease4
Celiac Disease
  • Triggered by ingestion of wheat gluten.
gluten
Gluten
  • “Gluten” is a general term for a composite of the storage proteins gliadin and glutenin.
    • These proteins (conjoined with starch) comprise ~80% of the total protein in wheat/rye/barley seed.
how does gluten cause negative effects
How does gluten cause negative effects?
  • Certain Pro- and Gln-rich gliadin peptide fragments survive the digestion process & make it to the gut
  • These peptides are deamidated by tissue transglutaminase (tTGase)
  • APCs in HLA-DQ2 or –DQ8 positive individuals express these deamidated peptide fragments on class II MHC molecules
  • The resulting CD4+ T-cell mediated immune response can eventually result in the development of celiac disease
slide8
Therefore, the only currently recognized treatment for celiac disease is complete abstinence from food grains containing gluten proteins
    • Bread, beer, cereals, many sauces…

I tried a gluten-free diet for a month this year… Let’s just say that I wasn’t the nicest guy to be around during that month. It’s difficult!

aims of this study
Aims of this study
  • Determine the physiologically stable regions of gliadin
  • Investigate the biochemical basis of this stability
  • Shed light on possible future treatments for celiac disease
slide11

Fig 1. gliadin digested with gastric + pancreatic proteases (pepsin, trypsin, chymotrypsin, elastase, caboxypeptidase) followed by LC-ESIMS

“33-mer” = LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF

significance of 33 mer
Significance of 33-mer
  • Even after prolonged exposure to proteases, the 33-mer reamains intact
  • Three previously identified epitopes (PFPQPQLPY, PQPQLPYPQ, and PYPQPQLPY) are found within this 33-mer

“33-mer” = LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF

slide14

Fig. 2. BBM digestions

(A) 33-mer

(B) Epitope within 33-mer

BBM: brush border intestinal membrane enzymes  essential for breaking down any remaining peptides after gastric and pancreatic digestion

slide15

Fig. 2.

33-mer

LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF

Epitope within 33-mer

QLQPFPQPQLPY

slide16

Implication  there’s something about the 33-mer which makes it highly resistant to physiological enzymatic degradation

slide17

Fig 3. Stimulation of 3 HLA DQ2-restricted T cell clones, derived from patients with celiac disease. Each of these T cell clones recognizes a class II MHC molecule presenting a distinct deamidated gluten epitope.

Implication  the 33-mer is a very potent stimulator of these HLA DQ2 restricted T cell clones, even more so than the epitopes by themselves… Why??

EC50 ~ 80 nM

(EC50 median effective concentration)

slide18

Table 2. Respose of polyclonal T cell lines derived from patients with celiac disease to gluten epitopes (peptide X) and the 33-mer (bottom row)

“… we interpret the combination of metabolic

stability and multivalency of the 33-mer to

endow it with exceptional toxic potency…”

why is the 33 mer so resistant to gastrointestinal breakdown
Why is the 33-mer so resistant to gastrointestinal breakdown?
  • This is likely due to the abundance and location of proline residues
  • This gave the authors the bright idea to investigate the activity of a prolyl endopeptidase (PEP) on breakdown of the 33-mer…
    • (prolyl endopeptidases cleave peptides after proline residues)
slide20

Fig 4.

  • 33-mer incubated in vitro with PEP
  • 33-mer digested in vivo in rat intestine with and without PEP
  • Stimulation of HLA DQ2 restricted T cell clone by 33-mer after PEP and BBM treatment, followed by tTGase treatment

PEP seems to effectively catalyze breakdown of the 33-mer

overall implications of this study
Overall implications of this study
  • The 33-mer peptide, derived from gliadin, shows several characteristics suggesting that it is the primary initiator of the autoimmune response to gluten in patients with celiac disease.
    • Potential for much further study… vaccine??
  • Prolyl endopeptidase therapy may have the potential to detoxify gluten in celiac disease patients.
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