Lecture 8: Coeliac Disease

Question 1

What is coeliac disease?

Answer 1

It is an immunological disease driven by an environmental antigen (gluten) found in wheat, rye, and barley/ It results in the chronic inflammation of the small bowel mucosa. The main treatment is the removal of gluten from the diet.

Question 2

How is coeliac disease diagnosed?

Answer 2

• Blood test: antibodies to transglutaminase and gliadin
• Gastroscopy: small intestinal villous atrophy, crypt hyperplasia, raised intraepithelial lymphocytes (IELs)
  
  • Marsh type 1: villous to crypt length ratio is normal (4:1), but there are more than 30 IELs per 100 enterocytes
  • Marsh type 2: in addition to IELs, there is elongation and branching of crypts
  • Marsh type 3: villi are shortened and blunted and villous to crypt ratio is less than 1:4

Question 3

Recall the appearance of coeliac disease in gastroscopy and bowel biopsy.

Answer 3

Question 4

What is gluten?

Answer 4

Question 5

How does gluten affect coeliac patients?

Answer 5

• Acute
  
  • Symptoms (typically within hours) such as vomiting, abdominal pain, diarrhoea, headache, lethargy
• Chronic
  
  • Symptoms such as nausea, bloating, pain, diarrhoea, or constipation; chronic fatigue, anaemia, nutrient deficiencies,
  • Other co-morbidities and increased mortality
    
    • Auto-immune disease, sepsis, infertility, liver disease
  • Impaired quality of life

Question 6

Recall some of the complications of coeliac disease.

Answer 6

Goitre, osteoporosis, alopecia, dermatitis, mouth ulcers, dental enamel defects

Question 7

Mention the features shared between coeliac disease and other autoimmune diseases.

Answer 7

• breakdown of self-tolerance leading to self-directed inflammation
• genetic and environmental factors important
• adaptive immune response plays a predominant role in the eventual clinical expression of disease
• autoantibodies predate clinical disease expression and can manifest before target organ damage is discernible
• Polygenic inheritance
  
  • most risk associated with MHC genes
  • coeliac disease is highly heritable

Question 8

Recall the main features of coeliac disease pathogenesis.

Answer 8

Question 9

Immunotoxic gluten peptides survive __________________.

Answer 9

gastrointestinal digestion

Note: proline confers resistance to gastric and pancreatic proteases - immunogenic regions cluster in areas of high proline

Question 10

Mention the key susceptibility genes in coeliac disease.

Answer 10

Most coeliac patients express HLA-DQ2 and/or DQ8

Question 11

Recall the diagram in regard to gluten peptide presentation.

Answer 11

HLA haplotcyte (APC cells) will dictate the repertoire of gluten peptides presented to T cells.

Question 12

Absence of HLA-DQ2/8 in patients means they won’t be susceptible to coeliac disease. True or False?

Answer 12

False

Question 13

People with mutations in HLA-DQ2/8 would have the coeliac disease. True or False?

Answer 13

False.

Question 14

Describe the mechanism of post-transcriptional modification of gluten.

Answer 14

The mechanism is essential for efficient antigen binding to HLA. Tissue transglutaminase (TG2) introduces site-specific glutamate (E) residues (‘deamidation’ from glutamic acid residues).

Targeted: QXP or QXX

Not targeted: QP or QXXP

Question 15

Deamidation of gluten peptides significantly increases the ________________.

Answer 15

Question 16

Describe the immune cell that is responsible for promoting intestinal damage.

Answer 16

Gluten-specific CD4+ T cells are pro-inflammatory and promote intestinal damage.

HLA-DQ restricted CD4+ T cells are CD-specific and express α4ß7+ (gut homing) and have a pro-inflammatory phenotype (IFN-g and IL-21). It can be found in the intestine of coeliac patients and can also be induced. in peripheral blood by oral gluten consumption. T cells specific for these dominant epitopes are long-lives in the blood intestinal tissue of coeliac patients.

Question 17

Intraepithelial CD4+ T cells are believed to drive intestinal epithelial cell destruction from interaction from pro-inflammatory cytokines release by other helper cells. True or False?

Answer 17

False

CD8+ T cells are responsible for the blunting of the epithelial cell through interaction with IFN-gamma as well as IL-21 released by CD4+ T cells.

Question 18

B cells may amplify the adaptive immune cascade through their role as _______________.

Answer 18

Antigen-presenting cells

Question 19

Describe how B to T cell presentation may act as an “amplification” loop sustaining the autoimmune process.

Answer 19

Through the production of antibodies to transglutaminase (tTG) and deamidated gliadin peptides (DGP).

tTG-IgA has an angiogenic effect - which may affect placental development leading to miscarriage. It deposits in the intestine predicting disease onset. tTG- specific plasma cells are also greatly expanded in the intestinal lesion (5-25%).

Gluten-specific T cells may help tTG- and DGP- specific B cells produce antibodies

Question 20

How is CD diagnosed?

Answer 20

Question 21

Recall an integrated model of coeliac disease pathogenesis.

Answer 21

Question 22

Why do some people lose gluten tolerance?

Answer 22

Geographic distribution of coeliac disease correlates with wheat (gluten) consumption and HLA susceptibility (not always true). Other factors include:

• infections
• medications
• seasonality
• higher economic status
• maternal iron overload
• altered microbe-host interactions

Question 23

Describe several therapeutic opportunities for CD.

Answer 23