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PATH30001 - Mechanisms of Disease > Lecture 14 - Coeliac Disease > Flashcards

Lecture 14 - Coeliac Disease Flashcards

1
Q

Describe the main features of Coeliac disease

A
  • inflammatory mediated
  • genetically susceptible individuals
  • intolerance to gluten
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2
Q

What is the treatment of Coeliac disease?

A

Gluten free diet

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3
Q

What is the genetic basis of Coeliac?

A 
There is a strong genetic correlation:
Individuals with:
 • HLA-DQ2
 • HLA-DQ8
are highly susceptible
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4
Q

What compounds are absorbed across the small intestine?

A
  • glucose
  • amino acids
  • fats
  • fat soluble vitamins
  • iron
  • water soluble vitamins
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5
Q

What are the subdivisions of the small intestine?

A
  • Duodenum
  • Jejunum
  • Ileum
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6
Q

Describe the tissue structure of the small bowel

A
  1. Mucosal epithelium
  2. Submucosa
  3. Muscularis propria
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7
Q

Describe the structures that increase SA in the small bowel

A
  1. Valves of Kerkring
  2. Villi
  3. Microvilli
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8
Q

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

A
  • 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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9
Q

What is the function of Paneth & Goblet cells?

A

Paneth: secrete defensins
Goblet: mucous production

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10
Q

Describe the structure of an enterocyte

A
  • Microvilli on apical border (luminal side)

* many mitochondria in cytoplasm

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11
Q

What is the normal proportion of IELs to enterocytes?

A

around 5 IELs per 100 enterocytes

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12
Q

What cellular changes are seen in coeliac disease?

A

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

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13
Q

Outline the stages in villous atrophy

A

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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14
Q

What is hyperplasia?

A

Increase in cell number

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15
Q

What is gluten found in?

A

Wheat
Rye
Barley

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16
Q

How long is the small intestine?

A

7 meters

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17
Q

Where are most nutrients absorbed in the gut?

A

Duodenum & jejunum

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18
Q

Describe cell turnover in the GIT

How long do the cells last?

A
  • 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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19
Q

What is the crypt:villous ratio?

A

1:4

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20
Q

What is in the lamina propria?

A

Lymphocytes & plasma cells

21
Q

Where are Paneth cells?

A

In the base of the crypts

22
Q

What are defensins?

A

Antimicrobial proteins

23
Q

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

A

1: Infiltrative
2: Hyperplastic
3: Destructive

24
Q

What is the significance of villous atrophy?

What are the clinical presentations?

A 
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.
25
Q

When is coeliac normally diagnosed?

A

Late 30’s, early 40’s

26
Q

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

A
  • Genetics
  • Environment
  • T-cells
  • Gluten
27
Q

Which two alleles must be present for coeliac disease?

What else can we say about these genes?

A

HLA-DQ2
HLA-DQ8

NB not all people with the genes have coeliac disease

28
Q

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

A

It is protective

29
Q

How does early gluten exposure effect development of coeliac disease?

A

Too much gluten, too soon increases the risk

30
Q

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

A
  • Gluten exposure
  • Infection
  • Breast feeding
31
Q

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

A

Released by auto reactive CD8+ IELs in the villi

Damages the enterocytes, leading to villous atrophy

32
Q

What is the composition of gluten?

A
  • Gliadins

* Glutenins

33
Q

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

A

They are reactive to gluten epitopes

34
Q

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

Which amino acid is rare?

A

High in proline

Low in glutamine

35
Q

Describe the digestion and absorption of gluten

A
  1. Proline confers resistance to digestion by proteases
  2. Gluten peptides pass through the intestinal epithelium intact
  3. Intact peptides are deaminated
    Glutamine –> Glutamate
36
Q

What converts glutamine to glutamate?

A

tTG

Tissue Transglutaminase

37
Q

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

A

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

38
Q

What is special about glutamate?

A

It is negatively charged

39
Q

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

A
  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
40
Q

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

What is the effect of these Abs?

A

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
41
Q

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

A
  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
  4. γδ-T cells induces apoptosis of the infected cell
42
Q

What is NKR?

Where is it found?

A

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

43
Q

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

A
  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)
44
Q

How is coeliac disease diagnosed?

A
  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
45
Q

What is the gold standard for coeliac diagnosis?

A

Small bowel biopsy during gluten exposure

46
Q

Why is early diagnosis important?

A

Long term risks:
• osteoporosis
• autoimmune diseases
• increased risk of malignancy

Sufferers diagnosed as children have much better prognosis than those diagnosed later as adults

47
Q

Which malignancies are associated with coeliac disease?

A

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

2x risk of
• Oesophageal cancer

48
Q

What is EATL?

A

Enteropathy associated T-cell lymphoma

small bowel lymphoma

49
Q

What are MIC-A and MIC-B?

A

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

PATH30001 - Mechanisms of Disease (34 decks)

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