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
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
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
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
5
Q
What are the consequences of coeliac disease based on sites of absorption?
A
- often anaemia
- foul, smelly stool
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
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
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
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
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
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
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
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
14
Q
What are the four elements in the pathogenesis of coeliac disease?
A
- genetics
- environment
- T-cells
- gluten
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
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
