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What is coeliac disease?

- 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


What is the prevalence of coeliac disease?

- ~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


What is the gross anatomy of the GIT?

- 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


Where are the sites of absorption in the small intestine?

- 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


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

- often anaemia
- foul, smelly stool


What are villi? Desribe their structure etc

- 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


What is in the lamina propria?

- 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


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

- 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


What kinds of lymphocytes are the IELs?

- CD8+ T cells
- <25/100 enterocytes
- CD4+ T cells are only in the lamina propria, not in the epithelium


What happens to the number of IELs in coeliac disease?

- 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


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

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


What are the clinical presentations of coeliac disease?

- 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


At what age does the disease present?

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


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

- genetics
- environment
- T-cells
- gluten


How do genetics contribute to coeliac disease?

- 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


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

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


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

- 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


What are the epitopes on gluten that are recognised?

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


How is gluten effective an antigen?

- 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)


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

- 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


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

- 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


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

- 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


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

- 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


How do we diagnose coeliac disease?

- 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


Why is early diagnosis important?

- 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


What is EATL?

- 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