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PATH30003- Frontiers in Human Disease > Lecture 21-Coeliac Disease > Flashcards

Lecture 21-Coeliac Disease Flashcards

1
Q

what is coeliac disease?

A

an immune illness caused by gluten in genetically susceptible people

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2
Q

3 major factors for development of coeliac disease?

A

dietary gluten
HLA-DQ2/8 and other genes
environmental factors

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3
Q

evolving view of coeliac disease from 1950s to 2018

A 
1950s
- gut malabsorption
- childhood illness
-prominent GI issues
-failure to thrive
-disease of the gut 
2018
- genetically based immune disease
- median age at diagnosis ~40
- multi organ disease
- range of clinical presentations
- disease of immune system
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4
Q

acute exposure to gluten- symptoms for patients

A

within hours

  • vomiting
  • abdominal pain
  • diarrhoea
  • headache
  • lethargy
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5
Q

chronic exposure to gluten- symptoms and implications for patients

A
  • nausea, bloating, pain, diarrhoea, chronic fatigue, anaemia, nutrient deficiences
  • other co morbidities and increased mortality if remain undiagnosed
  • autoimmune diseases
  • impaired quality of life
  • increased health related costs prior to diagnosis
  • high burden of treatment once diagnosed
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6
Q

coeliac disease- mouth

A

mouth ulcers, dental enamel defects

- unexplained- should get tested for Coeliac disease

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7
Q

other clinical symptoms of coeliac disease

A

goitre
osteoporosis
alopecia
dermatitis herpetiformis

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8
Q

high sensitivity antibodies to test for in diagnosis (85-90%)

A
  • tissue transglutaminase antibody (tTG-IgA)

- deamidated gliadin peptide (DGP-IgG)

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9
Q

is serology perfect?

A

no- false positives and false negatives

  • serology cannot diagnose coeliac disease on its own
  • small intestinal biopsies required
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10
Q

gastroscopy and bowel biopsies in coeliac disease shows?

A

from duodenum

  • flattened villi
  • inflammation in intestine
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11
Q

compare villus in normal and coeliac disease

A

normal- villi long, small number of IELs

Coeliac disease- increase in IELs, crypt hyperplasia, villous atrophy

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12
Q

stages of getting coeliac disease

A

stage 1- increased IELs
stage 2- increased IELs and crypt hyperplasia
stage 3- increased IELs, crypt hyperplasia, villous atrophy

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13
Q

potential pitfalls with gold standard of diagnosis

A
  • adequate gluten consumption necessary
  • some medications can mask changes
  • villous atrophy can be pathy- adequate sampling essential
  • skilled biopsy preparation and interpretation essential
  • other causes of small bowel inflammation exists (infective, immune, drugs)
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14
Q

describe gluten protein and where it is found

A

sticky, elasticky protein

found in wheat, barley, rye, (oats)

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15
Q

what does gluten contain that makes it toxic to patients with coeliac disease

A

gliadin and glutenin

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16
Q

why is the gluten free diet not an easy treatment?

A
  • lifelong, strict and complex (hidden sources of gluten)
  • safe threshold not well defined
  • non-adherence is comon
  • costly, less palatable
  • accidental gluten exposure
  • incomplete healing is comon (5 years strict diet, 50% full healing, 85% remission)
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17
Q

is the gluten free diet nutritionally superior? explain

what are the implications?

A

no it is not
can be higher in starch, sugar, fat and calories
- fewer grains, whole grains, more refined
-high GI
-lower in protein, iron, folate
-lower in fibre
implications
-weight gain problems; fatty liver disease, MetS
-low gluten intake = high cardiovascular events

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18
Q

what is essential for gluten to be toxic?

A

post translational modification

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19
Q

what does post translational modification of gluten allow?

A

efficient antigen binding to HLA

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20
Q

what happens in the post translational modification of gluten? what is this called?

A

DEAMIDATION- if certain motifs occur in the sequence, glutamine (Q) changes into glutamate (E)

  • significantly increases the stability of the gluten peptide
  • targeted : QXP or QXX (residues)
  • not targeted; QP or QXXP
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21
Q

role of tissue transglutaminase (TG2)

A

introduces site specific glutamate residues to HLA molecules

22
Q

HLA molecules favour?

A

negatively charged AAs in certain binding pockets

-different motifs for HLA DQ 2.5, 2.2, 8

23
Q

P3 anchor for DQ2.2 patients

A

prefers resides which are rare in gluten proteome, so fewer gluten peptides bind to DQ2.2

24
Q

what does proline in gliadin and glutenin do?

A

it confers resistance to gastric (pepsin) and pancreatic (trypsin, chymotrypsin) proteases which are normally involved in gastrointestinal digestion

25
Q

what clusters in areas of high proline?

A

immunogenic regions (immunodominant T cell epitopes)

26
Q

what is the key genetic link in coeliac disease?

A

strong HLA association implicates T cells

- CD4+ T cell recognition of gluten peptides

27
Q

what does DQ2.5 form?

A

heterodimer

28
Q

which HLA molecule has the highest risk for coeliac disease?

A

HLA-DQ2.5

  • homozygous has higher risk compared to heterozygous
  • homozygous more severe phenotype (T cells are induced much easier due to presentation of more peptides)
29
Q

percentage of patients with HLA-DQ2.5/8/2.2?

A

99.6%

30
Q

why cant the HLA types be solely used for diagnosis?

A

40-50% of people in community express these genes as well

31
Q

reasons for use of HLA types for diagnosis?

A
  • result does not depend on gluten intake

- absence of HLA-DQ2/8 excludes coeliac disease (strong negative predictive value)

32
Q

HLA binding focuses on?

A

short linear peptides

gluten T cell epitopes

33
Q

CD4+ gluten specific T cells express?

A

a4B7

IFN-gamma, IL-21 (pro inflammatory phenotype)

34
Q

how can CD4+ gluten specific T cells be induced?

A

in peripheral blood by oral gluten challenge

- already present in intestine of people with active CD (untreated)

35
Q

coeliac disease pathogenesis

A
  • CD8+ IELs target and destroy stressed epithelium
  • CD4+ T cells help B cells produce Abs to gliadin, gluten peptides & transglutaminase
  • Treg cells dont work properly
36
Q

what features does coeliac disease share with autoimmune diseases?

A
  • breakdown of self tolerance leading to self directed inflammation
  • genetic and env factors important
  • adaptive immune response plays predominant role in eventual clinical expression of disease
  • autoAbs can manifest before target organ damage is discernible
  • polygenic inheritance (non mendelian)
37
Q

feature unique to coeliac, not in autoimmune diseases

A

the trigger is an environmental allergen

- gluten can be removed from diet to treat disease- can be re introduced to study the resulting immune response

38
Q

coeliac disease has tight overlap with what?

A 
inflammatory diseases (CD, UC) 
autoimmune diseases (RA, SLE, T1D, MS)
39
Q

geographic distribution of coeliac disease correlates with?

A

wheat (gluten) consumption and HLA susceptibility

  • yet doesnt hold true that the higher frequency of these correlates with high prevalence
  • therefore env factors
40
Q

env factors that increase risk of coeliac disease

A
  • higher socioeconomic status and better hygiene
  • perinatal and childhood infections
  • medications e.g. antibiotics, proton pump inhibitors
  • elective C section
41
Q

env factors that have unclear risk of coeliac disease

A
  • breast feeding
  • timing of gluten introduction
  • quantity of gluten exposure at young age
42
Q

what happens to microbiome in Coeliac disease?

A

dysbiosis due to many factors

  • host genetics
  • delivery mode
  • feeding type
  • treatment
  • env exposures
43
Q

how does dysbiosis trigger coeliac disease?

A

pseudonomas cleaves at different residues to increase immunotoxicity of gluten
- promote pro inflammatory responses to gluten in vivo

44
Q

lactobacilli

A

cleave gluten to reduce immunotoxicity

45
Q

reovirus and coeliac disease

A

coeliac disease patients have higher anti-reovirus titres

- mouse models- reovirus promotes Th1 biased immunity to dietary antigen and suppresses T reg generation

46
Q

function of larazotide

A

zonulin antagonist

- reduce uptake of gluten by decreasing permeability of tight junctions

47
Q

function of glutenases

A

oral enzyme therapy- digest gluten peptides so they dont make it down to lamina propria

48
Q

function of binding agents

A

digest gluten- sequesters gluten in gut and wont make it to T cells

49
Q

quantitative method of therapy

A

reducing amount of gluten entering body

  • assist the gluten free diet
  • may allow safe ingestion of small amounts of gluten
  • may be useful for intermittent use e.g. social events
  • may help people with poor healing despite strict GFD
50
Q

qualitative method of therapy?

A

induce/restore tolerance to gluten

51
Q

Nexvax2 function

A

vaccine that has been tested

  • contains 3 immunogenic peptides
  • T regs will be decreased, cause deletion, anergy of antigen specific T cells for gluten
  • promising results shown, into trials
52
Q

hookworm therapy use

A

based on hygiene hypothesis

  • modulate immune response in Coeliac disease patients
  • results promising, in trials now

PATH30003- Frontiers in Human Disease (20 decks)

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