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lecture 14 Flashcards

Coeliac Disease - gluten-sensitive enteropathy

1
Q

What is coeliac disease?

A
  • immunologically mediated disease in genetically susceptible individuals, driven by an environmental antigen, gluten, found in wheat, rye and barley, which results in chronic inflammation of the small bowel mucosa
  • remission on a gluten free diet is the hallmark of the disease
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2
Q

What is the prevalence of coeliac disease?

A
  • ~1:100
  • likely to be ~ 50,000 victorians with coeliac disease
  • most races affect: europeans, middle eastern, north indians. Rare in SE asians, japanese, indigenous australians
  • very strong genetic association (HLA-DQ2, -DQ8) –> MHC class II (only found in caucasians) and VIII
  • may manifest anytime from infancy (after introduction of gluten to diet) to late adulthood
  • only treatment is gluten free diet
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3
Q

What is the gross anatomy of the GIT?

A
  • oesaphagus
  • stomach
  • small intestine, 7m long, 9cm in circumference, endowed with semicircular valves (Valves of Kerkring) (most affected): duodenum (most affected), jejunum, ileum, each with own functions
  • colon
  • rectum
  • anus
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4
Q

Where are the sites of absorption in the small intestine?

A
  • most fats, protein, fat soluble vitamins are absorbed in the duodenum through to the jejunum
  • same for glucose, iron, water soluble vitamins (B,C, Folic acid)
  • vitamin B12 and bile acids absorbed in the ileum
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5
Q

What are the consequences of coeliac disease based on sites of absorption?

A
  • often anaemia

- foul, smelly stool

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6
Q

What are villi? Desribe their structure etc

A
  • cover the surface of the gut to increase surface area for absorption
  • covered in epithelial cells (enterocytes) which absorb and digest foods
  • about 1400 cells per day are lost from each villus
  • in total we lose a few kilos of these cells a day
  • cells replaced from crypt epithelium (about 200-300)
  • the only way to increase that number is to increase the number of cells available for proliferation - can’t proliferate faster
  • it’s like an escalator of cells from birth to death
  • each villus is supplied from four or five crypts
  • size ratio 1:4 (crypt to villi)
  • goblet cells that produce mucus
  • in between are the intra-epithelium lymphocytes which play a major role in coeliac disease.
  • paneth cells at base of crypts: secrete defensins, protect us against viruses, microbes, bacteria, other antigens
  • brush border: microvilli
  • like 5 lymphocytes/100 enterocytes
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7
Q

What is in the lamina propria?

A
  • lymphatics that absorb fat and carry it to the liver
  • veins that carry blood away from the gut ) and obviously arteries
  • whole lot of cells in this meshwork which are mesenchymal cells that provide support
  • defence system
  • lymphocytes and plasma cells that produce antibodies
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8
Q

What adaptations does the small intestine have to increase its surface area?

A
  • amplification of absorptive surface of the small intestine resulting from structural adaptations
    (increase in surface area relative to cylinder)
  • cylinder (1) + folds of kerkring (3) + villi (30) + microvilli (60)
  • SA = doubles tennis court
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9
Q

What kinds of lymphocytes are the IELs?

A
  • CD8+ T cells
  • <25/100 enterocytes
  • CD4+ T cells are only in the lamina propria, not in the epithelium
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10
Q

What happens to the number of IELs in coeliac disease?

A
  • marked excess in surface epithelium
  • massive increase
  • brush border hardly visible
  • electron micrograph of apical half of stunted enterocytes in coeliac disease showing loss, distortion and stunting of residual microvilli
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11
Q

What are the stages in the development of villous atrophy with crypt hyperplasia?

A

Infiltrative (type I)
- in Marsh type 1, the villous to crypt length ratio is normal (4:1), but there are more than 30 IELs per 100 erythrocytes

Hyperplastic (type II)
- in Marsh type 2, in addition to intraepithelial lymphocytes there is elongation and branching of crypts

Destructive (type III)
- villi are shortened and blunted and the villus to crypt ratio is less than 1:4

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12
Q

What are the clinical presentations of coeliac disease?

A
  • gastrointestinal: diarrhoea, bloating, abdominal cramps, flatulence
  • anaemia (iron deficiency), vitamin deficiencies
  • malabsorption of nutrients
  • failure to thrive as an infant
  • osteoporosis
  • lethargy (chronic fatigue), migraines, infertility, mouth ulcers
  • increased prevalence of autoimmune diseases - e.g. Type I diabetes, autoimmune thyroiditis
  • can be completely asymptomatic
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13
Q

At what age does the disease present?

A
  • many
  • first peak at 0-9 years old
  • increases progressively to about 30 - 50
  • less over time
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14
Q

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

A
  • genetics
  • environment
  • T-cells
  • gluten
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15
Q

How do genetics contribute to coeliac disease?

A
  • HLA-DQ2 or HLA-DQ8 present in 99.6% of all patients with coeliac disease
  • 20-30% of those without coeliac disease (in populations at risk) also have HLA-DQ2 or HLA-DQ8
  • these HLA genes are involved in antigen presentation to T cells
  • other unidentified genes are involved
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16
Q

How does the early infant environment play a critical role in development of coeliac disease?

A
  • breast feeding is protective
  • timing/amount of gluten introduced to infant diet (too much gluten, too soon - increases risk)
  • infections e.g. gastroenteritis
17
Q

What is the role of T cells in the development of coeliac disease?

A
  • in coeliac disease, CD4+ HLA-DQ2 or HLA-DQ8 restricted T-cells, reactive to gluten specific epitopes reside in the small bowel mucosa
  • these cause damage by producing harmful cytokines e.g. IFN-gamma
  • CD8+ T-cells accumulate in the epithelium and are involved in the innate immune response
18
Q

What are the epitopes on gluten that are recognised?

A
  • gliadins
  • glutenins
  • these proteins are very rich in proline, this interferes with successful digestion by gastric/pancreatic/intestinal enzymes
19
Q

How is gluten effective an antigen?

A
  • gluten proteins are high in the amino acids proline (P) and glutamine (Q) (35% and 20% respectively) whereas glutamate (E) is rare
  • this confers resistance to gastric/pancreatic/intestinal proteases and certain gluten peptides pass through the intestinal epithelium intact
  • intact peptides are deaminated by tissue transglutaminase (tTG) converting glutamine residues to negatively charged glutamate (binds to the groove in APCs)
20
Q

How are gluten peptides presented to CD4+ T-cells?

A
  • these negatively charged peptides bind more efficiently to HLA-DQ2 and -DQ8 molecules on antigen presenting cells (APCs)
  • CD4+ T cells recognise the deaminated peptides bound to MHC-II molecules and elaborate cytokines
21
Q

What happens following CD4+ T cell recognition of gluten peptides?

A
  • they are activated and stimulate plasma cells to secrete Anti-tTG and anti-AGA
  • these are not responsible for the disease
  • they are useful markers that circulate in the blood stream and provide a diagnostic clue
  • activated T cells start produced IL-4, gamma-IFN, TNF-alpha –> these damage the enterocytes
22
Q

What is the injury or infection induced response of enterocytes and IEL T-cells, as part of innate immunity?

A
  • infection of an epithelial cell signals the synthesis of a series of stress-induced proteins
  • the infected epithelial cell expresses two atypical class I molecules known as MIC-A and MIC-B
  • gamma:delta T cells bearing the NK receptor NKG2D bind to MIC:A and MIC:B
  • the infected epithelial cell is killed by induction of apoptosis and replaced by adjacent healthy cells
23
Q

What is the role of innate immunity and intraepithelial lymphocytes (IEL) in the pathogenesis of coeliac disease?

A
  • epithelial cells react to other gliadin peptides (31-49, 31-49)
  • induce stress –> causes cell to start secreting IL15 and also to express atypical MHC class I molecules (MIC-A and MIC-B)
  • IL-15 causes CD8+ cells to upregulate TCR and by so doing they cause these cells to recognise self antigens (lower threshold)
  • become cytotoxic to own epithelial cells
  • this shouldn’t happen
  • at the same time these cells start multiplying, occasionally becoming cancerous
24
Q

How do we diagnose coeliac disease?

A
  • serological testing
    • tissue transglutaminase antibody (tTG) ~90% sensitivity, good specificity
    • deamidated gliadin peptide (DGP-IgG), 80-90% sensitivity
  • HLA-DQ haplotyping – the absence of HLA-DQ2 or DQ8 effectively rules out a diagnosis of coeliac disease (present in 99.6% of coeliac patients, 30% of non-coeliac)
  • a small bowel biopsy during gluten exposure is the gold standard for diagnosis
25
Q

Why is early diagnosis important?

A
  • over 80% of cases are not currently diagnosed due to minor or no symptoms, or doctor’s failure to test for the disease (Coeliac iceberg)
  • long term risks if left untreated include osteoporosis, autoimmune diseases, increased risk of cancer
    • 20x relative risk for small bowel lymphoma (EATL)
    • 30x RR for small bowel adenocarcinoma
    • 2-4x RR for oesophageal cancer
    • 2x increased mortality
  • treatment with gluten free diet abolishes symptoms and reduces long term risks
    • children diagnosed and placed on a gluten free diet have a better outcome than adults with a late diagnosis
26
Q

What is EATL?

A
  • enteropathy associated T-cell lymphoma
  • ulcers
  • wall replaced by white tissue
  • black necrotic tissue
  • highly metastatic tissue
  • highly abnormal looking T cells
  • cancerous T cells - elongated

PATH30001 (34 decks)

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