B cell-T cell crosstalk in celiac disease

PROJECT SUMMARY/ABSTRACT
Celiac disease (CeD) is a complex intestinal inflammatory disorder that is triggered by dietary gluten and
develops in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules. 1% of the
worldwide population is affected by this disease for which the only effective treatment is a lifelong and
restrictive gluten-free diet (GFD). Yet, persistent symptoms and enteropathy remain commonplace even
among CeD patients that adhere to a GFD. This stresses the need to develop non-dietary interventions for
CeD. The development of new therapies has however proven challenging because of our incomplete
understanding of the immune mechanisms underlying CeD pathogenesis and the lack of a suitable mouse
model. CeD is characterized by the loss of oral tolerance to gluten manifested by HLA-DQ2 or HLA-DQ8-
restricted anti-gluten inflammatory CD4 T cells in the small intestinal mucosa and by a massive expansion of
cytotoxic intraepithelial CD8+ lymphocytes (IE-CTLs) that are involved in the killing of intestinal epithelial cells.
These observations have led to the general idea that CeD is primarily a T cell-mediated immune disorder. We
hypothesize, however, that B cells also play a critical role. This hypothesis stems from several observations.
First, CeD is characterized by a considerable expansion of plasma cells in the mucosa of CeD patients as well
as the development of anti-deamidated gluten peptides (DGP) antibodies and autoantibodies against the
enzyme tissue transglutaminase 2 (TG2). Second, the main model to explain the production of anti-DGP and
anti-TG2 antibodies is that gluten-specific CD4+ T cells provide help to B cells suggesting that B cells could act
as antigen-presenting cells for T cells and promote the amplification of the anti-gluten CD4 T cell response.
Finally, several case reports on patients having CeD associated with another autoimmune disease suggest
that B cell depletion therapy can provide clinical benefit in CeD, and we have demonstrated that B cell
depletion significantly reduces intestinal tissue damage in our mouse model of CeD. The objective of this
application is to characterize in vivo the role of B cells in amplifying the anti-gluten T cell response and allow it
to reach a sufficient magnitude to promote tissue destruction. This project is innovative as it employs unique
mouse models of CeD allowing to manipulate B lymphocytes, gluten-specific T cells, the gluten antigen, and
the CeD predisposing HLA molecule to 1) assess the contribution of B cells as antigen-presenting to the
activation and amplification of the anti-gluten CD4+ T cell response, and 2) assess the role of B cells and
antibodies in the activation of IE-CTLs and tissue destruction. The knowledge gained from this study will
provide unprecedented insights into the mechanisms by which B cell-mediated immunity contribute to the
pathogenesis of CeD and will assess for the first time the therapeutic potential of B cell depletion therapy in an
experimental mouse model of CeD.

Grant Number: 5R01DK128352-05
NIH Institute/Center: NIH
Principal Investigator: Valerie Abadie