no- false positives and false negatives - serology cannot diagnose coeliac disease on its own - small intestinal biopsies required

Lecture 21-Coeliac Disease Flashcards by Thanuja Premkumar

what is coeliac disease?

an immune illness caused by gluten in genetically susceptible people

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3 major factors for development of coeliac disease?

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

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evolving view of coeliac disease from 1950s to 2018

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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acute exposure to gluten- symptoms for patients

within hours

vomiting
abdominal pain
diarrhoea
headache
lethargy

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chronic exposure to gluten- symptoms and implications for patients

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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coeliac disease- mouth

mouth ulcers, dental enamel defects

- unexplained- should get tested for Coeliac disease

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other clinical symptoms of coeliac disease

goitre
osteoporosis
alopecia
dermatitis herpetiformis

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

tissue transglutaminase antibody (tTG-IgA)

- deamidated gliadin peptide (DGP-IgG)

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is serology perfect?

no- false positives and false negatives

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

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gastroscopy and bowel biopsies in coeliac disease shows?

from duodenum

flattened villi
inflammation in intestine

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compare villus in normal and coeliac disease

normal- villi long, small number of IELs

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

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stages of getting coeliac disease

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

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potential pitfalls with gold standard of diagnosis

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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describe gluten protein and where it is found

sticky, elasticky protein

found in wheat, barley, rye, (oats)

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

gliadin and glutenin

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why is the gluten free diet not an easy treatment?

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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is the gluten free diet nutritionally superior? explain

what are the implications?

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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what is essential for gluten to be toxic?

post translational modification

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what does post translational modification of gluten allow?

efficient antigen binding to HLA

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

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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role of tissue transglutaminase (TG2)

introduces site specific glutamate residues to HLA molecules

HLA molecules favour?

negatively charged AAs in certain binding pockets

-different motifs for HLA DQ 2.5, 2.2, 8

P3 anchor for DQ2.2 patients

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

what does proline in gliadin and glutenin do?

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

what clusters in areas of high proline?

immunogenic regions (immunodominant T cell epitopes)

what is the key genetic link in coeliac disease?

strong HLA association implicates T cells | - CD4+ T cell recognition of gluten peptides

what does DQ2.5 form?

heterodimer

which HLA molecule has the highest risk for coeliac disease?

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)

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

99.6%

why cant the HLA types be solely used for diagnosis?

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

reasons for use of HLA types for diagnosis?

- result does not depend on gluten intake | - absence of HLA-DQ2/8 excludes coeliac disease (strong negative predictive value)

HLA binding focuses on?

short linear peptides | gluten T cell epitopes

CD4+ gluten specific T cells express?

a4B7 | IFN-gamma, IL-21 (pro inflammatory phenotype)

how can CD4+ gluten specific T cells be induced?

in peripheral blood by oral gluten challenge | - already present in intestine of people with active CD (untreated)

coeliac disease pathogenesis

- 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

what features does coeliac disease share with autoimmune diseases?

- 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)

feature unique to coeliac, not in autoimmune diseases

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

coeliac disease has tight overlap with what?

``` inflammatory diseases (CD, UC) autoimmune diseases (RA, SLE, T1D, MS) ```

geographic distribution of coeliac disease correlates with?

wheat (gluten) consumption and HLA susceptibility - yet doesnt hold true that the higher frequency of these correlates with high prevalence - therefore env factors

env factors that increase risk of coeliac disease

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

env factors that have unclear risk of coeliac disease

- breast feeding - timing of gluten introduction - quantity of gluten exposure at young age

what happens to microbiome in Coeliac disease?

dysbiosis due to many factors - host genetics - delivery mode - feeding type - treatment - env exposures

how does dysbiosis trigger coeliac disease?

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

lactobacilli

cleave gluten to reduce immunotoxicity

reovirus and coeliac disease

coeliac disease patients have higher anti-reovirus titres | - mouse models- reovirus promotes Th1 biased immunity to dietary antigen and suppresses T reg generation

function of larazotide

zonulin antagonist | - reduce uptake of gluten by decreasing permeability of tight junctions

function of glutenases

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

function of binding agents

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

quantitative method of therapy

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

qualitative method of therapy?

induce/restore tolerance to gluten

Nexvax2 function

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

hookworm therapy use

based on hygiene hypothesis - modulate immune response in Coeliac disease patients - results promising, in trials now