Download Role of Gluten Peptides

Coeliac Disease
Jaide Brown
Breea Buckley
Krissy Rowe
What is Coeliac Disease (CD)?
• An immune-mediated disease triggered by glutencontaining grains
• Presents in 2 forms
– Typical CD
– Atypical CD
What is Gluten?
• A protein found in the endosperm of seeds
– Wheat’s gliadin and glutenin
– Barley’s hordeins
– Rye’s secalins
• Responsible for the elastic texture of bread
http://www.jci.org/articles/view/30253/figure/2
What are the Forms and Associated
Symptoms of CD?
• Typical CD
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Chronic Diarrhea/Constipation
Abdominal pain, gas and distension
Anemia
Weight loss/malnutrition
http://www.nature.com/nrgastro/journal/v6/n1/full/ncpgasthep1298.htm
What are the Forms and Associated
Symptoms of CD?
• Atypical CD
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Bone/Joint Pain
Delayed Puberty or Infertility
Fatigue
Tingling/Numbness in Extremities
These cases are very rare
What are the Forms and Associated
Symptoms of CD?
CD may be asymptomatic
• If untreated can lead to;
– Vitamin and iron deficiencies, osteoporosis, pancreatic
insufficiencies, intestinal lymphomas or other GI
Cancers
Epidemiology
• Affects ~1% of US population
– Potentially affects a higher percentage
– Many individuals go undiagnosed
• RISK FACTORS
– Genetic
• Intestinal permeability, MHC
– TGase enzyme
– Enteric Infection
– Co-morbidity with other autoimmune disease
CD OVERVIEW
http://www.jci.org/articles/view/30253/figure/2
What is the Immunological
Mechanism of CD?
Role of Gluten Peptides:
•
Gluten peptides are not easily digest by gastric, pancreatic or brush border
enzymes
– High concentration of proline and glutamine amino acids
•
Accumulation of large gluten peptide fragments
– Some may be involved in the immune response
Associated Risk Factors/Triggers
•
•
Consumption of Gluten
Intestinal Permeability (Genetics)
Accumulation is not enough to develop CD
Healthy vs. afflicted individuals show no difference in ability to digest these large
peptides
What is MHC’s Role in Developing CD?
MHC-II alleles
– HLA-DQ locus
• HLA-DQ2 = 90-95% of CD cases
• HLA-DQ8 = 5-10% of CD cases
What is it about these alleles that increases the risk
for CD?
– APCs with HLA-DQ2 and HLA-DQ8 MHC-II can bind “gluten” peptides
Associated Risk Factors/Triggers
MHC-II Genetics
HLA-DQ and HLA-DQ8 haplotypes can bind gluten
These binding grooves favor negatively charged residues
Not naturally found within lumen
What is the Role of TGase in
Development of CD?
What is TGase?
• Transglutaminase enzyme
• Involved in tissue repair by crosslinking peptides
Its Role?
• Under certain conditions (low pH) TGase will deaminate glutamine to
form negatively charged glutamic acid
DEAMINATION
L-Glutamine
Glutamic Acid
Associated Risk Factors/Triggers
Release of TGase into the mucosal layer when
gluten peptides are present
Activation of CD4+ T cells
• HLA-DQ2 and HLA-DQ8 restricted T cells interact
with APCs and become activated
• Activated CD4+ T cells secrete cytokines
– IFN-γ (Interferon-gamma)
• Associated with a TH1 immune response
• Intracellular pathogen/autoimmunity
– Associated with initiation of mucosal damage
– Neutralization shown to prevent gluten-induced damage
Why so rare?
• 40% of population has HLA-DQ2 and HLA-DQ8 antigens
Enteric Infection Role:
– DQ2 and DQ8 MHC is poorly expressed in normal mucosa
– TGase enzyme is poorly expressed in normal mucosa
– Enteric viral infection up-regulates production of HLA antigens
and cytokine production
• Cytokines cause inflammation/tissue damage
• Release of TGase enzyme leads to deamination
The Big Picture:
Who Should Be Tested?
• 1st and 2nd degree relatives of CD patients
• Relatives of patients and patients with Type-I
diabetes
• Individuals with Sjögren/Down/Turner Syndrome
• People with immune, thyroid, and liver disorders
How to Diagnose?
• Serology
– IgA
• Endoscopy/Biopsy
– Small Intestine
• HLA
– Absence of HLA-DQ2 or HLA-DQ8
Treatment
• Gluten-free diet
• Current research
focuses on:
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Genetically detoxified grains
Celiac vaccines (oral or intranasal)
Inhibitors of TGase
Inhibitors of effects of zoulin on
intestinal permeability
References
Ahn R, Ding YC, Fasano A, Green PHR, Murray J, Neuhausen S, Garner C. 2012. Association
Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple
Independent Susceptibility Loci. PLoS One 7(5): e36926.
Carlo C, Fasano A. 2001. Current Approaches to Diagnosis and Treatment of Celiac Disease:
An Evolving Spectrum. Gastroenterology 120: 636-651.
Evans KE, Sanders DS. 2012. Celiac Disease. Gastroenterology clinics of North America. 41(3):
639-650.
Kagnoff MF. 2007. Celiac Disease: Pathogenesis of a Model Immunogenetic Disease. The
Journal of Clinical Investigation. 117(1): 41-49.
Pietzak MM. 2005. Follow-up of Patients with Celiac Disease: Achieving Compliance with
Treatment. Gastroenterology 128: S135-S141.
Walker MM, Murray JA. 2011. An update in the diagnosis of coeliac disease. Histopathology. 59:
166-179.
Questions For You!
1.Celiac disease is caused by...
A.A specific allele that is present in all cases of Celiac Disease.
B.Increased intestinal permeability.
C.A viral infection that leads to inflammation.
D.A variety of factors contribute to the onset of Celiac Disease including
specific genotypes of MHC, genes involved in permeability of mucosa,
and other genetic factors.
Questions For You!
2. A woman is suspected of having coeliac disease; she undergoes
an HLA test and an endoscopy. Which scenario most points to a
diagnosis of coeliac disease?
A)
B)
C)
D)
E)
Negative HLA test, positive for villous atrophy
Positive HLA test, negative for villous atrophy
Positive HLA test, positive for villous atrophy
Negative HLA test, negative for villous atrophy
Both A and D
Questions For You!
3.What is “gluten”
A.A brush-border enzyme responsible for digesting cereal grains within
the small intestine
B.B)A generic term referring to proteins found in the endosperm of
wheat, barley, and rye grains
C.C)An enzyme responsible for deaminating glutamine to produce
glutamic acid
D.D)None of the above
Questions For You!
4. An enteric infection leads to an increased risk of
developing CD by…
A.Upregulating MHC expression and cytokine production which results
in inflammation and intestinal damage
B.Overwhelming the immune system so it cannot combat both the viral
infection and accumulation of gluten peptides
C.Forming complexes of pathogenic toxins and gluten peptide
fragments which cause intestinal inflammation and damage
D.All of the above
Questions For You!
5. Name 2 risk factors/triggers and give a
brief explanation of how they contribute to
the development of CD