Lecture 14 - Coeliac Disease Flashcards Preview

PATH30001 - Mechanisms of Disease > Lecture 14 - Coeliac Disease > Flashcards

Flashcards in Lecture 14 - Coeliac Disease Deck (49):
1

Describe the main features of Coeliac disease

• inflammatory mediated
• genetically susceptible individuals
• intolerance to gluten

2

What is the treatment of Coeliac disease?

Gluten free diet

3

What is the genetic basis of Coeliac?

There is a strong genetic correlation:
Individuals with:
• HLA-DQ2
• HLA-DQ8
are highly susceptible

4

What compounds are absorbed across the small intestine?

• glucose
• amino acids
• fats
• fat soluble vitamins
• iron
• water soluble vitamins

5

What are the subdivisions of the small intestine?

• Duodenum
• Jejunum
• Ileum

6

Describe the tissue structure of the small bowel

1. Mucosal epithelium
2. Submucosa
3. Muscularis propria

7

Describe the structures that increase SA in the small bowel

1. Valves of Kerkring
2. Villi
3. Microvilli

8

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

9

What is the function of Paneth & Goblet cells?

Paneth: secrete defensins
Goblet: mucous production

10

Describe the structure of an enterocyte

• Microvilli on apical border (luminal side)
• many mitochondria in cytoplasm

11

What is the normal proportion of IELs to enterocytes?

around 5 IELs per 100 enterocytes

12

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

13

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

14

What is hyperplasia?

Increase in cell number

15

What is gluten found in?

Wheat
Rye
Barley

16

How long is the small intestine?

7 meters

17

Where are most nutrients absorbed in the gut?

Duodenum & jejunum

18

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

19

What is the crypt:villous ratio?

1:4

20

What is in the lamina propria?

Lymphocytes & plasma cells

21

Where are Paneth cells?

In the base of the crypts

22

What are defensins?

Antimicrobial proteins

23

What are the names of the three phases of villous atrophy?

1: Infiltrative
2: Hyperplastic
3: Destructive

24

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.

25

When is coeliac normally diagnosed?

Late 30's, early 40's

26

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

• Genetics
• Environment
• T-cells
• Gluten

27

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

28

What is the effect of breast feeding in development of Coeliac disease?

It is protective

29

How does early gluten exposure effect development of coeliac disease?

Too much gluten, too soon increases the risk

30

What factors of the early infant environment play a role in development of the disease?

• Gluten exposure
• Infection
• Breast feeding

31

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

32

What is the composition of gluten?

• Gliadins
• Glutenins

33

What is significant about the CD4+ T cells in the gut mucosa of people with coeliac disease?

They are reactive to gluten epitopes

34

Which amino acid is present in high numbers in Gliadins and Glutenins?

Which amino acid is rare?

High in proline
Low in glutamine

35

Describe the digestion and absorption of gluten

1. Proline confers resistance to digestion by proteases
2. Gluten peptides pass through the intestinal epithelium intact
3. Intact peptides are deaminated
Glutamine --> Glutamate

36

What converts glutamine to glutamate?

tTG
Tissue Transglutaminase

37

What is significant about the negatively charged glutamate in the gluten peptides?

Binds to the groove of the MHC II in antigen presenting cells

38

What is special about glutamate?

It is negatively charged

39

Describe what happens after the gluten peptide is presented on MHC II

1. MHC II molecule + peptide recognised by CD4+
2. CD4+ T cell activated
3. Activation of plasma cells by CD4+ T cells
4. Plasma cells produce Ab against Gliadin and tTG
5. Activated T cells produce IFN-γ
6. IFN-γ damages enterocytes

40

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

41

Describe the role of MIC-A and MIC-B in response to bacterial infection

1. Bacterial infection,
phagocytosis by enterocyte of the bacterium

2. Expression of stress-induced proteins in enterocyte:
• MIC-A
• MIC-B
(basolateral side)

3. γδ-T cells recognise MIC-A and MIC-B with the NK receptor

5. γδ-T cells induces apoptosis of the infected cell

42

What is NKR?
Where is it found?

Natural Killer receptor
• NK cells
• γδ-T cells
• Autoreactive CD8+ IELs in coeliac disease

43

Describe the cellular pathogenesis when gliadin peptides are taken up by enterocytes

1. Enterocytes have take up gluten peptides

2. Enterocytes become damaged, release IL-15 and express MIC-A and MIC-B on the basolateral side

3. IL-15 causes CD8+
T cells to upregulate NKR

4. IELs have a lower
activation
threshold, and recognise
self antigen

5. CD8+ IEL induce cytotoxicity in GIT epithelium

(6. Malignant transformation of CD8+ IELs)

44

How is coeliac disease diagnosed?

1. Serological testing
Looking for:
• Anti-tTG Ab
• Deamidated gliadin peptide

2. HLA-DQ haplotyping
• absence of the allele rules out coeliac disease

3. Small bowel biopsy during gluten exposure

45

What is the gold standard for coeliac diagnosis?

Small bowel biopsy during gluten exposure

46

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

47

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

48

What is EATL?

Enteropathy associated T-cell lymphoma
(small bowel lymphoma)

49

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