This translational research project aims at defining the role of iron deficiency in tissue damage during celiac disease (CD) with the goal to provide new recommendations for the care and prevention of this frequent disease affecting 1% Caucasians.
CD is a complex autoimmune-like disorder induced in genetically predisposed individuals by dietary proteins from wheat (gluten). In CD patients, excessive activation of intestinal immune cells by dietary gluten induces small intestinal villous atrophy and, as a consequence, malnutrition. CD treatment relies on a long-life strict gluten-free diet (GFD) that allows clinical and histological recovery and prevents long-term complications. Yet, in adults, systematic follow-up of biopsies for several years after GFD has recently revealed persistent villous atrophy in more than 40 % of cases with an increased risk in older patients (up to 56%). Lack of mucosal healing has been associated with morbidity and mortality in CD. It is therefore necessary to define strategies to obtain and accelerate full recovery.
Iron deficiency is strongly associated with CD and is generally viewed as a consequence of small intestinal lesions and a symptom of malnutrition. Preliminary clinical observations by partner B and experimental work led by partners A and C suggest however that iron deficiency may sustain tissue damage and delay mucosal recovery. We suspect a pathogenic role for the transferrin receptor (CD71), which is overexpressed in the gut epithelium in case of iron deficiency. Indeed partner A has shown that CD71, when expressed at the apical surface of enterocytes, can interact with secretory IgA1 present in large amounts in the intestinal lumen, notably in CD patients. Partner C has shown that crosslinking of CD71 by polymeric IgA1 induces a spectrum of intracellular signals, which modulate the activation, differentiation, or production of inflammatory cytokines in responding cells. Our working hypothesis is therefore that iron deficiency maintains aberrant expression of CD71 at the gut epithelial surface where it can interact with IgA and induce a signalling cascade that sustains epithelial damage. To confirm this hypothesis:
1- Partner B will perform an observational study based on the retrospective and prospective analyses of data collected in a securized warehouse in the large cohort of well-characterized CD patients followed-up at Hôpital Européen Georges Pompidou since 2000 in order: i) to confirm preliminary results indicating that iron deficiency correlates with delayed mucosal recovery and ii) to show that parenteral iron supplementation initiated since 2012 in CD patients with persistent villous atrophy after one year of GFD can accelerate mucosal healing. Calculation of statistical power indicates feasibility.
2- Partners A and C will join forces to provide the biological rationale to this clinical strategy and analyse how iron deficiency may affect intestinal epithelial tissue repair. Task 1 led by partner A intends to decipher the signalling cascades triggered in intestinal epithelial cells by CD71 interactions with SIgA or IgA immune complexes and to analyse the consequences on epithelial repair. Analysis will be performed in Caco-2 epithelial cells that can be genetically modified and obtained results will be checked in primary intestinal epithelial monolayers. Task 2 led by Partner C aims at characterizing the early steps of the CD71 signalling by defining the biochemical partners of CD71 recruited upon activation by CD71 ligands. Task 3 led by partners A and C will use mice engineered to express human IgA1 to provide evidence that SIgA-CD71 interactions can operate in vivo in case of iron deficiency and promote intestinal tissue damage. Preliminary data support the hypothesis that SIgA-CD71 interactions can impair intestinal tissue repair and provide excellent hope to demonstrate a causative link between iron deficiency and delayed mucosal recovery in CD.
Madame Nadine Cerf-Bensussan (Laboratoire Immunité intestinale. INSERM U1163, Institut Imagine)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM U1163 TT Laboratoire Mécanismes Cellulaires et bases moléculaires de l'hématopoïese normale et des désordres héamtologiques. implications thérapeutiques. INSERM U1163, Insititut Imagine
CHRU Départment Hépatologie-Gastroentérologie. Hôpital Européen Georges Pompidou
INSERM U1163 NCB Laboratoire Immunité intestinale. INSERM U1163, Institut Imagine
Help of the ANR 390,000 euros
Beginning and duration of the scientific project: September 2015 - 36 Months