Lecture 14 - Coeliac Disease Flashcards by Eleanor Nicklason

Describe the main features of Coeliac disease

inflammatory mediated
genetically susceptible individuals
intolerance to gluten

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What is the treatment of Coeliac disease?

Gluten free diet

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What is the genetic basis of Coeliac?

There is a strong genetic correlation:
Individuals with:
 • HLA-DQ2
 • HLA-DQ8
are highly susceptible

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What compounds are absorbed across the small intestine?

glucose
amino acids
fats
fat soluble vitamins
iron
water soluble vitamins

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What are the subdivisions of the small intestine?

Duodenum
Jejunum
Ileum

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Describe the tissue structure of the small bowel

Mucosal epithelium
Submucosa
Muscularis propria

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Describe the structures that increase SA in the small bowel

Valves of Kerkring
Villi
Microvilli

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Describe the structure of a villus, including the various cell types

made up of many enterocytes
flanked by crypts
in the centre is the lamina propria
capillary bed & lacteal
IELs
Paneth cells
Goblet cells

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What is the function of Paneth & Goblet cells?

Paneth: secrete defensins
Goblet: mucous production

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Describe the structure of an enterocyte

Microvilli on apical border (luminal side)

* many mitochondria in cytoplasm

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What is the normal proportion of IELs to enterocytes?

around 5 IELs per 100 enterocytes

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What cellular changes are seen in coeliac disease?

• Marked increase in n° of IELs in the mucosal epithelium
(> 30 IELs per 100 enterocytes)
• stunting of enterocytes

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Outline the stages in villous atrophy

Phase I:
• > 30 IELs per 100 enterocytes

Phase II:
• lengthening & branching of crypts
• further intraepithelial lymphocytosis
• lengthening of villous (compensation)

Phase III:
• total villous atrophy
• crypt hyperplasia

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What is hyperplasia?

Increase in cell number

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What is gluten found in?

Wheat
Rye
Barley

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How long is the small intestine?

7 meters

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Where are most nutrients absorbed in the gut?

Duodenum & jejunum

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Describe cell turnover in the GIT

How long do the cells last?

1400 cells lost per day from the tip of the villous
new cells produced from stem cells in the crypt
new cells travel up to the top of the villous

• Each cell lives 2-3 days

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What is the crypt:villous ratio?

1:4

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What is in the lamina propria?

Lymphocytes & plasma cells

Where are Paneth cells?

In the base of the crypts

What are defensins?

Antimicrobial proteins

What are the names of the three phases of villous atrophy?

1: Infiltrative
2: Hyperplastic
3: Destructive

What is the significance of villous atrophy?

What are the clinical presentations?

Markedly reduced surface area of the small bowel 
Food can not be absorbed
Clinical presentation:
 • diarrhoea, bloating, cramps, flatulence
 • anaemia
 • vitamin deficiencies
 • osteoporosis (due to Ca2+ deficiency)
 • Failure to Thrive
etc.

When is coeliac normally diagnosed?

Late 30's, early 40's

What are the four elements in the pathogenesis of coeliac disease?

* Genetics * Environment * T-cells * Gluten

Which two alleles must be present for coeliac disease? | What else can we say about these genes?

HLA-DQ2 HLA-DQ8 NB not all people with the genes have coeliac disease

What is the effect of breast feeding in development of Coeliac disease?

It is protective

How does early gluten exposure effect development of coeliac disease?

Too much gluten, too soon increases the risk

What factors of the early infant environment play a role in development of the disease?

* Gluten exposure * Infection * Breast feeding

What is the role of IFN-γ in coeliac disease?

Released by auto reactive CD8+ IELs in the villi | Damages the enterocytes, leading to villous atrophy

What is the composition of gluten?

* Gliadins | * Glutenins

What is significant about the CD4+ T cells in the gut mucosa of people with coeliac disease?

They are reactive to gluten epitopes

Which amino acid is present in high numbers in Gliadins and Glutenins? Which amino acid is rare?

High in proline | Low in glutamine

Describe the digestion and absorption of gluten

1. Proline confers resistance to digestion by proteases 2. Gluten peptides pass through the intestinal epithelium intact 3. Intact peptides are deaminated Glutamine --> Glutamate

What converts glutamine to glutamate?

tTG | Tissue Transglutaminase

What is significant about the negatively charged glutamate in the gluten peptides?

Binds to the groove of the MHC II in antigen presenting cells

What is special about glutamate?

It is negatively charged

Describe what happens after the gluten peptide is presented on MHC II

1. MHC II molecule + peptide recognised by CD4+ 2. CD4+ T cell activated 3. Activation of plasma cells by CD4+ T cells 4. Plasma cells produce Ab against Gliadin and tTG 5. Activated T cells produce IFN-γ 6. IFN-γ damages enterocytes

What is the specificity of the Ab produced by the plasma cells in coeliac disease? What is the effect of these Abs?

Anti-tTG Anti-AGA (gliadin) * NB These Abs do not cause the disease * These circulate in the blood stream, and are thus good diagnostic markers

Describe the role of MIC-A and MIC-B in response to bacterial infection

1. Bacterial infection, phagocytosis by enterocyte of the bacterium 2. Expression of stress-induced proteins in enterocyte: • MIC-A • MIC-B (basolateral side) 3. γδ-T cells recognise MIC-A and MIC-B with the NK receptor 5. γδ-T cells induces apoptosis of the infected cell

What is NKR? | Where is it found?

Natural Killer receptor • NK cells • γδ-T cells • Autoreactive CD8+ IELs in coeliac disease

Describe the cellular pathogenesis when gliadin peptides are taken up by enterocytes

1. Enterocytes have take up gluten peptides 2. Enterocytes become damaged, release IL-15 and express MIC-A and MIC-B on the basolateral side 3. IL-15 causes CD8+ T cells to upregulate NKR 4. IELs have a lower activation threshold, and recognise self antigen 5. CD8+ IEL induce cytotoxicity in GIT epithelium (6. Malignant transformation of CD8+ IELs)

How is coeliac disease diagnosed?

1. Serological testing Looking for: • Anti-tTG Ab • Deamidated gliadin peptide 2. HLA-DQ haplotyping • absence of the allele rules out coeliac disease 3. Small bowel biopsy during gluten exposure

What is the gold standard for coeliac diagnosis?

Small bowel biopsy during gluten exposure

Why is early diagnosis important?

Long term risks: • osteoporosis • autoimmune diseases • increased risk of malignancy Sufferers diagnosed as children have much better prognosis than those diagnosed later as adults

Which malignancies are associated with coeliac disease?

20-30 x risk for small bowel cancers: • Small bowel lymphoma; Enteropathy associated T-cell lymphoma • Small bowel adenocarcinoma 2x risk of • Oesophageal cancer

What is EATL?

Enteropathy associated T-cell lymphoma | small bowel lymphoma

What are MIC-A and MIC-B?

Non-classical MHC I Expressed as a stress signal on the cell surface Recognised by NK receptors on NK cells and γδ T cells, which induce apoptosis of the stressed cell