Lecture 8: Coeliac Disease Flashcards
What is coeliac disease?
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.
How is coeliac disease diagnosed?
- 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
Recall the appearance of coeliac disease in gastroscopy and bowel biopsy.
What is gluten?
How does gluten affect coeliac patients?
- 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
Recall some of the complications of coeliac disease.
Goitre, osteoporosis, alopecia, dermatitis, mouth ulcers, dental enamel defects
Mention the features shared between coeliac disease and other autoimmune diseases.
- 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
Recall the main features of coeliac disease pathogenesis.
Immunotoxic gluten peptides survive __________________.
gastrointestinal digestion
Note: proline confers resistance to gastric and pancreatic proteases - immunogenic regions cluster in areas of high proline
Mention the key susceptibility genes in coeliac disease.
Most coeliac patients express HLA-DQ2 and/or DQ8
Recall the diagram in regard to gluten peptide presentation.
HLA haplotcyte (APC cells) will dictate the repertoire of gluten peptides presented to T cells.
Absence of HLA-DQ2/8 in patients means they won’t be susceptible to coeliac disease. True or False?
False
People with mutations in HLA-DQ2/8 would have the coeliac disease. True or False?
False.
Describe the mechanism of post-transcriptional modification of gluten.
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
Deamidation of gluten peptides significantly increases the ________________.
Describe the immune cell that is responsible for promoting intestinal damage.
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.
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?
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.
B cells may amplify the adaptive immune cascade through their role as _______________.
Antigen-presenting cells
Describe how B to T cell presentation may act as an “amplification” loop sustaining the autoimmune process.
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
How is CD diagnosed?
Recall an integrated model of coeliac disease pathogenesis.
Why do some people lose gluten tolerance?
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
Describe several therapeutic opportunities for CD.