Lecture 14 - Coeliac Disease Flashcards
Describe the main features of Coeliac disease
- inflammatory mediated
- genetically susceptible individuals
- intolerance to gluten
What is the treatment of Coeliac disease?
Gluten free diet
What is the genetic basis of Coeliac?
There is a strong genetic correlation: Individuals with: • HLA-DQ2 • HLA-DQ8 are highly susceptible
What compounds are absorbed across the small intestine?
- glucose
- amino acids
- fats
- fat soluble vitamins
- iron
- water soluble vitamins
What are the subdivisions of the small intestine?
- Duodenum
- Jejunum
- Ileum
Describe the tissue structure of the small bowel
- Mucosal epithelium
- Submucosa
- Muscularis propria
Describe the structures that increase SA in the small bowel
- Valves of Kerkring
- Villi
- Microvilli
Describe the structure of a villus, including the various cell types
- made up of many enterocytes
- flanked by crypts
- in the centre is the lamina propria
- capillary bed & lacteal
- IELs
- Paneth cells
- Goblet cells
What is the function of Paneth & Goblet cells?
Paneth: secrete defensins
Goblet: mucous production
Describe the structure of an enterocyte
- Microvilli on apical border (luminal side)
* many mitochondria in cytoplasm
What is the normal proportion of IELs to enterocytes?
around 5 IELs per 100 enterocytes
What cellular changes are seen in coeliac disease?
• Marked increase in n° of IELs in the mucosal epithelium
(> 30 IELs per 100 enterocytes)
• stunting of enterocytes
Outline the stages in villous atrophy
Phase I:
• > 30 IELs per 100 enterocytes
Phase II:
• lengthening & branching of crypts
• further intraepithelial lymphocytosis
• lengthening of villous (compensation)
Phase III:
• total villous atrophy
• crypt hyperplasia
What is hyperplasia?
Increase in cell number
What is gluten found in?
Wheat
Rye
Barley
How long is the small intestine?
7 meters
Where are most nutrients absorbed in the gut?
Duodenum & jejunum
Describe cell turnover in the GIT
How long do the cells last?
- 1400 cells lost per day from the tip of the villous
- new cells produced from stem cells in the crypt
- new cells travel up to the top of the villous
• Each cell lives 2-3 days
What is the crypt:villous ratio?
1:4
What is in the lamina propria?
Lymphocytes & plasma cells
Where are Paneth cells?
In the base of the crypts
What are defensins?
Antimicrobial proteins
What are the names of the three phases of villous atrophy?
1: Infiltrative
2: Hyperplastic
3: Destructive
What is the significance of villous atrophy?
What are the clinical presentations?
Markedly reduced surface area of the small bowel Food can not be absorbed Clinical presentation: • diarrhoea, bloating, cramps, flatulence • anaemia • vitamin deficiencies • osteoporosis (due to Ca2+ deficiency) • Failure to Thrive etc.
When is coeliac normally diagnosed?
Late 30’s, early 40’s
What are the four elements in the pathogenesis of coeliac disease?
- Genetics
- Environment
- T-cells
- Gluten
Which two alleles must be present for coeliac disease?
What else can we say about these genes?
HLA-DQ2
HLA-DQ8
NB not all people with the genes have coeliac disease
What is the effect of breast feeding in development of Coeliac disease?
It is protective
How does early gluten exposure effect development of coeliac disease?
Too much gluten, too soon increases the risk
What factors of the early infant environment play a role in development of the disease?
- Gluten exposure
- Infection
- Breast feeding
What is the role of IFN-γ in coeliac disease?
Released by auto reactive CD8+ IELs in the villi
Damages the enterocytes, leading to villous atrophy
What is the composition of gluten?
- Gliadins
* Glutenins
What is significant about the CD4+ T cells in the gut mucosa of people with coeliac disease?
They are reactive to gluten epitopes
Which amino acid is present in high numbers in Gliadins and Glutenins?
Which amino acid is rare?
High in proline
Low in glutamine
Describe the digestion and absorption of gluten
- Proline confers resistance to digestion by proteases
- Gluten peptides pass through the intestinal epithelium intact
- Intact peptides are deaminated
Glutamine –> Glutamate
What converts glutamine to glutamate?
tTG
Tissue Transglutaminase
What is significant about the negatively charged glutamate in the gluten peptides?
Binds to the groove of the MHC II in antigen presenting cells
What is special about glutamate?
It is negatively charged
Describe what happens after the gluten peptide is presented on MHC II
- MHC II molecule + peptide recognised by CD4+
- CD4+ T cell activated
- Activation of plasma cells by CD4+ T cells
- Plasma cells produce Ab against Gliadin and tTG
- Activated T cells produce IFN-γ
- IFN-γ damages enterocytes
What is the specificity of the Ab produced by the plasma cells in coeliac disease?
What is the effect of these Abs?
Anti-tTG
Anti-AGA (gliadin)
- NB These Abs do not cause the disease
- These circulate in the blood stream, and are thus good diagnostic markers
Describe the role of MIC-A and MIC-B in response to bacterial infection
- Bacterial infection,
phagocytosis by enterocyte of the bacterium - Expression of stress-induced proteins in enterocyte:
• MIC-A
• MIC-B
(basolateral side) - γδ-T cells recognise MIC-A and MIC-B with the NK receptor
- γδ-T cells induces apoptosis of the infected cell
What is NKR?
Where is it found?
Natural Killer receptor
• NK cells
• γδ-T cells
• Autoreactive CD8+ IELs in coeliac disease
Describe the cellular pathogenesis when gliadin peptides are taken up by enterocytes
- Enterocytes have take up gluten peptides
- Enterocytes become damaged, release IL-15 and express MIC-A and MIC-B on the basolateral side
- IL-15 causes CD8+
T cells to upregulate NKR - IELs have a lower
activation
threshold, and recognise
self antigen - CD8+ IEL induce cytotoxicity in GIT epithelium
(6. Malignant transformation of CD8+ IELs)
How is coeliac disease diagnosed?
- Serological testing
Looking for:
• Anti-tTG Ab
• Deamidated gliadin peptide - HLA-DQ haplotyping
• absence of the allele rules out coeliac disease - Small bowel biopsy during gluten exposure
What is the gold standard for coeliac diagnosis?
Small bowel biopsy during gluten exposure
Why is early diagnosis important?
Long term risks:
• osteoporosis
• autoimmune diseases
• increased risk of malignancy
Sufferers diagnosed as children have much better prognosis than those diagnosed later as adults
Which malignancies are associated with coeliac disease?
20-30 x risk for small bowel cancers:
• Small bowel lymphoma; Enteropathy associated T-cell lymphoma
• Small bowel adenocarcinoma
2x risk of
• Oesophageal cancer
What is EATL?
Enteropathy associated T-cell lymphoma
small bowel lymphoma
What are MIC-A and MIC-B?
Non-classical MHC I
Expressed as a stress signal on the cell surface
Recognised by NK receptors on NK cells and γδ T cells, which induce apoptosis of the stressed cell
