The association of coeliac disease with autoimmune disorders: the model of type 1 diabetes

1
The association of coeliac disease with
autoimmune disorders the model of type 1
diabetes

• Riccardo Troncone
• Department of Pediatrics and European Laboratory
  for the Investigation of Food-Induced Diseases,
  University Federico II, Naples, Italy
• International Coeliac Disease Meeting
• Genoa, 19 September 2008

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Coeliac disease as an autoimmune disorder

• Association with other autoimmune disorders
• Common features with other autoimmune disorders
• Susceptibility genes
• Gender bias (femalemale ratio 21)
• Immune mechanisms
• Autoimmune phenomena (autoantibodies)

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Coeliac diseaseassociation with other
autoimmune diseases

• Type 1 diabetes (1 in 15)
• Autoimmune thyroiditis (1 in 20)
• Sjogren syndrome (1 in 22)
• Chronic autoimmune hepatitis (1 in 16)
• Primary biliary cirrhosis (1 in 16)
• Juvenile chronic arthritis (1 in 40)

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Autoantibodies in coeliac disease

• Transglutaminase 2
• Transglutaminase 3
• Transglutaminase 6
• Factor III
• Actin
• Calreticulin
• Gangliosides
• Collagens
• Synapsin I
• Zonulin
• Cardiolipin
• ATP synthase ß chain
• Enolase a
• Adapted from Alaedini A, Green PH.
  Autoantibodies in celiac disease.
• Autoimmunity 20084119-26

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Do autoantibodies play a role in the pathogenesis
of coeliac disease?

• Weak inhibitory effect of autoantibodies on TG2
  catalytical activity (Esposito, Gut 2002
  Dieterich, Gut 2003)
• Inhibition of TG2 -mediated TGF beta activity
  (Halttunen, Gastro 1999)
• Pro-proliferative effect on intestinal epithelial
  cells leading to crypt hyperplasia (Barone,
  Gastro 2007)

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Does autoimmunity explain clinical heterogeneity
of coeliac disease?

• Wide organ deposition of TG autoantibodies
  (Korponay-Szabo, Gut 2004)
• Different TG specificity relates to clinical
  manifestations
• Anti-TG3 in the DH skin (Sardy, JEM 2002)
• Anti-TG6 in the gluten ataxia brain (Aeschlimann,
  Annales Neurology 2008)

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Gluten and induction of autoimmunity

• Gluten dependent production of some
  autoantibodies (anti-TG, anti-actin,
  anti-calreticulin, anti-Purkinje)
• Controversial evidence on the duration of gluten
  exposure vs the risk of developing autoimmune
  diseases (Ventura, Gastro 1999 Sategna, Gut
  2001)

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Autoimmunity and coeliac disease the model of
type 1 diabetes

• Analogies
• Association
• Shared genetics
• Clinical spectrum
• Effect of gluten-free diet
• Deranged immune response to gliadin and type 1
  diabetes
• Gluten-free diet and prevention of type 1 diabetes

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Prevalence of celiac disease in patients with
type 1 diabetes mellitus in the recent literature
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Type 1 diabetes and coeliac diseasecommon
susceptibility genes

• HLA DQ (6p21)
• IL2-IL21 (4q27)
• SH2B3 (12q24)
• CCR region (3p21)

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• Also in T1D patients celiac disease presents with
  a spectrum of clinical and histological
  abnormalities
• classical coeliac disease (symptoms and flat
  mucosa)
• silent coeliac disease (no symptoms, but flat
  mucosa)
• potential coeliac disease (normal jejunal mucosa,
  but serum CD-associated autoantibodies)

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Are T1D/CD patients really silent?

• Lower SDS for height and weight (Hansen,
  Diabetes Care 2006)
• Low bone mass density (Diniz-Santos Dig, Dis Sci
  2008)

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The prevalence of osteopenia in patients with
CD/T1D is related to the compliance with the
gluten-free diet
Valerio et al, 2008
15
Variations of HbA BMI gain and height velocity
after gluten-free diet in children with celiac
disease and type 1 diabetes mellitus
Franzese, JPEM 2007
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Effect of gluten free diet in type 1 diabetic
patients with coeliac disease

• No effect on diabetes control (less hypoglicemic
  episodes?)
• Gain in body mass index but not on height
  velocity
• Improvement of bone mass density

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Adherence to gluten free diet in children with
celiac disease and type 1 diabetes mellitus
Franzese, JPEM 2007
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Different policies for CD screening in type 1
diabetes

• ADA (2005) screening, biopsy of elevated TG2
  autoantibodies, GFD if villous atrophy
• NIH no screening
• NASPGHAN (2005) screening, no evidence for
  benefit from GFD

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Autoimmunity and coeliac disease the model of
type 1 diabetes

• Analogies
• Association
• Shared genetics
• Clinical spectrum
• Effect of gluten-free diet
• Deranged immune response to gliadin and type 1
  diabetes
• Gluten-free diet and prevention of type 1 diabetes

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IDDM Immunohistochemistry of intraepithelial
compartment
Increased epithelial infiltration by CD3 and gd
cells (p lt 0.05)
Auricchio R et al, Diabetes 2004
21
Immunohistochemistry in IDDM patients lamina
propria and crypt enterocytes
Increased infiltration by CD25 cells (p lt0.05)
and enhanced expression of CD54 and crypt HLA-DR
Auricchio R et al, Diabetes 2004
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• Mucosal immune response to gliadin in T1D
  patients
• with negative serum anti-TG autoantibodies
• Gluten rectal challenge
• In vitro organ culture of small intestinal
  biopsies
• Intestinal T cell lines
• Intestinal autoantibodies

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A discriminant equation based on
immunohistochemical data reveals a
gliadin-sensitized subject of T1D patients
Number of cases
Discriminant scores
Troncone et al, Am J GE 2003
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Organ culture lamina propria CD25 mononuclear
cells

300
250
lamina propria
200
150
2
100
cells/mm
50
0
MEDIUM
PT
OVA
MEDIUM
PT
T1D
Controls
Increased infiltration of CD25 mononuclear cells
in T1D biopsies cultured with gliadin
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Increased density of lamina propria CD25 cells
in T1D jejunal biopsies cultured with gliadin
medium
gliadin
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Gliadin-specific T cells are present only in the
small intestine of T1D EMA patients the
magnitude of T-cell responses relates to the
severity of mucosal damage
plt0.06
8000
7000
cells
6000
6
5000
4000
-SFC/1x10
3000
g
2000
NET IFN-
1000
0
T1D Potential CD
T1D EMA-
T1D CD
untreated CD
treated CD
-1000
(n4)
(n4)
(n6)
(n6)
(n4)
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Intestinal deposits of IgA anti-TG2 antibodies in
a patient with type 1 diabetes and negative CD
serology
TG 2
IgA
TG2 IgA
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Enteropathy in NOD mice Effect of dietary
gluten
atrophy in NOD mice on gluten containing diet
Maurano et al. Diabetologia 2003
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Serum anti-transglutaminase antibodies in NOD mice
IgA
IgG
Sblattero et al J Immunol 2005
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• Can gluten-free diet prevent type 1 diabetes?

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NOD mice animal model of T1D
Effect of dietary gluten on T1D risk
Maurano et al. Diabetologia 2003
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Dietary gluten and development of T1D

• Exposure to dietary gluten very early in life in
  offspring of mothers and fathers with T1D, or in
  subjects with T1D-associated HLA genotype, is
  associated with an increased risk of developing
  islet autoantibodies (Norris, 2003 Ziegler,
  2003)
• Removing gluten from the diet is effective,
  neither in the short nor in the long term, in
  high-risk prediabetic individuals with a fully
  activated immune response to different islet
  autoantigens, close to manifestations of T1D
  (Fuchtenbusch, 2004)

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Conclusions

• In the small and large intestine of patients with
  type 1 diabetes without CD associated serum
  antibodies (anti-TG2), gluten induces signs of
  inflammation
• However, only in T1D patients with high serum
  levels of anti-TG2 (coeliac patients) there is
  evidence of intestinal gliadin specific T cells
• Is it the inflammation observed in T1D patients
  without CD associated serum antibodies related to
  the ability of gluten to trigger innate immunity?

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Summary

• It is likely than more than association does
  exist between coeliac disease and type 1
  diabetes.
• Common genetic (HLA and non HLA genes) and
  environmental factors (intestinal viruses,
  gluten?) account for common disease patways.
• The different interplay between such
  environmental factors and disease specific genes
  might explain the evolution toward a disease or
  the other.
• The better comprehension of the relationships
  between CD and T1D may lead to a better
  comprehension of autoimmunity in general

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Contributes