Coeliac Disease - Mucosal Immunology · Coeliac disease is an immune reaction to gluten (wheat,...
Transcript of Coeliac Disease - Mucosal Immunology · Coeliac disease is an immune reaction to gluten (wheat,...
What is the definition of coeliac disease?
What is the definition of non-coeliac gluten sensitivity (NCGS)?
Coeliac disease is an immune reaction to gluten (wheat, barely, rye) in an
genetic predisposed individual that results into an (small intestinal) enteropathy
- asymptomatic (subclinical) coeliac disease
- symptomatic coeliac disease
- refractory coeliac disease
- potential coeliac disease
Non-coeliac gluten sensitivity is a disorder, in which gluten intakes results in
clinical symptoms (no enteropathy, no elevated transglutaminase antibodies,
no change in permeability)
According to the Oslo classification gluten-intolerance, gluten-
sensitivity, silent coeliac disease should not be used
What is the worldwide prevalence of coeliac disease?
Prevalence (children) in Switzerland 1:132
Swiss Med. Wkly 2002;132:43-47
No CD in Burkina Faso
(low freqenecy of HLA DQ2 /DQ8 )
High incidence of CD in Finland,
Mexico, Algeria and North India
Why is there a difference in prevalence
of CD in Algeria and Tunisia?
(neighbouring countries, same gluten
Intake, same HLA DQ2 / DQ8 frequency)
What is the prevalence of coeliac disease in Switzerland?
Does the presence of HLA DQ2 / 8 alone explain the occurence of CD?
Although mucosal immunological
sensitization is an invariable feature of celiac
disease, it is not the precipitating factor for
the expression of the full intestinal lesion;
a second factor drives the enteropathy from
minimal (latent) to overt. . . Candidate factors
include an episode of hyperpermeability,
nutrient deficiency, increased dietary gluten,
impaired intraluminal digestion of ingested
gluten, adjuvant effects of intestinal infection
and a non-HLA associated gene.
Anne Ferguson
20-25% of the population are positive
for HLA DQ2/8
Annu Rev Immunol. 2011;29:493-525.
What are common symptoms of coeliac disease?
• Symptomatic malabsorption
• Diarrhea with weight loss
• Chronic diarrhoea with or without abdominal pain
• Chronic iron deficiency
• Metabolic bone disease; premature osteoporosis
• Unexplained weight loss
• Abnormal elevated liver enzymes
• Incidentally discovers villous atrophy
• Dermatitis herpetiformis
• Peripheral neuropathy
• Oral aphthous ulcers
• Growth failure
• Discoloured teeth or synchronous enamel loss
• Thyroid disease
• Down`s and Turner`s syndrome
• Type I diabetes
• Selective IgA deficiency
With what diseases is coeliac disease often associated?
How do you diagnose coeliac diases?
Serology (tissue transglutaminase IgA)
At least 6 biopsies ( bulb: 9 and 12 o‘clock position; 4 biopsies distal duodenum)
TTGA IgA 111 U/l ,
60 IEL /100 enterocytes
Marsh-Oberhuber Stadium 3b
Patient A. M. , 29/07/1940, referred to upper endoscopy, manifest osteoporosis
If there is a disagreement between serology and biopsy………
then HLA DQ2 and DQ8 genotyping
Consider selective IgA deficiency
Other reasons for villous atrophy
Marsh
modified
(Oberhuber)
Histologic criterion Corazza
Increased
intraepithelial
lymphocytesa
Crypt
hyperplasia
Villous
atrophy
Type 0 No No No None
Type 1 Yes No No Grade A
Type 2 Yes Yes No
Type 3a Yes Yes Yes (partial) Grade B1
Type 3b Yes Yes Yes (subtotal)
Type 3c Yes Yes Yes (total) Grade B2
a >40 intraepithelial lymphocytes per 100 enterocytes for Marsh modified (Oberhuber); >25 intraepithelial
lymphocytes per 100 enterocytes for Corazza.
How can the histological changes be classified?
What can cause villous atrophy?
• Tropical sprue
• Small bowel bacterial overgrowth
• Autoimmune enteropathy
• Drug-associated enteropathy (e.g. olmesartan)
• Whipple disease
• Eosinophilic enteritis
• Intestinal lymphoma
• Crohnn`s disease
• Graft versus host disease
• Malnutrition
• Acquired immune deficiency enteropathy
Why is HLADQ2 and DQ8 important?
Why is the tissue transglutaminase important?
Antigen Presenting Cell (APC)
CD4 T Cell
HLA DQ 2 or HLA DQ 8
Alpha / beta T Cell Receptor
Gluten
Proinflammatory cytokines IFNg, IL-21)
A B
Annu Rev Immunol. 2011;29:493-525.
Explain the patho-physiology of coeliac disease
Gluten intake
Presentation by HLA DQ2/8
Production of IL-15
Proliferation of the IEL
Blood. 2012 Mar 15;119(11):2458-68
Can you propose an animal model for coeliac disease?
x
HLA DQ8 IL-15tg
Gluten
+
Retinol
Proinflammatory cytokines
Breakdown of oral tolerance
wt
Gluten
+
Retinol
Tolerogenic immune response
Nature. 2011 Mar 10;471(7337):220-4
What do you consider if patients do not respond to gluten free diet?
• Gluten intake
• Bacterial overgrowth
• Microscopic colitis
• Exokrine pancreas insufficiency
• Fructose / Lactose intolerance
• Refractory coeliac disease
How is refractory coeliac disease defined?
Villous atrophy unresponsive to gluten-free diet (GFD)
How do you distinguish refractory coeliac disease type I and II?
Semin Immunopathol. 2012 Jul;34(4):601-13.
What is the importance to distinguish refractory coeliac disease
type I from II?
Blood. 2012 Mar 15;119(11):2458-68