primary prevention of coeliac disease - Associazione Italiana ...

Catassi C, Fasano A, Corazza GR (eds):
Primary prevention of coeliac disease. The
utopia of the new millennium? Perspectives on
Coeliac Disease, vol. 1, AIC Press, pp 17-26
Toxic gluten peptides in coeliac disease identified by
in vivo gluten challenge: A single dominant T
cell epitope?
Robert P. Anderson
The Royal Melbourne Hospital Autoimmunity and Transplantation Division, Walter and Eliza
Hall Institute c/o Post Office RMH, Victoria, Australia 3050
b.anderson@wehi.edu.au
The realization that as many as 1% of Europeans and North Americans are affected
by coeliac disease adds urgency to understanding the immunopathogenesis of coeliac
disease and developing a rational therapy without the inconvenience of a gluten free
diet.
Antigen-specific immunotherapy is highly effective in animal models of antigendriven
immune-mediated disease. Because human immune-mediated diseases are
usually only available for study when the immune response is well established, it has
been impossible to be sure what the initiating antigens are, or whether there are critical
dominant T cells epitopes that trigger disease.
Coeliac disease is unique among human immune-mediated disease since gluten is
known to maintain disease, and treatment is successful when dietary gluten is excluded.
If coeliac disease is triggered by one critical gluten component it may be possible to
develop antigen-specific therapies or preventive “vaccines”. This chapter discusses the
rationale for in vivo strategies that have allowed the identification of a critical gliadin
peptide that is the dominant coeliac-specific T cell epitope in a model alpha-gliadin
protein. A molecular model for the interaction of HLA-DQ2, dominant gliadin epitope
and T cell receptor is presented, and preliminary data indicating the potential of altered
peptide ligands to antagonize this interaction is discussed.
CD4 T cells have the potential to initiate immunopathology
Gluten and HLA-DQ2 are definitively implicated in the aetiopathogenesis of
1
coeliac disease . Since HLA-DQ2 presents peptides to CD4 T cells, there has been
intense interest in defining the specificity and phenotype of T cells in coeliac disease
that recognize gluten peptides restricted by HLA-DQ2.
CD4 T cells play a pivotal role in coordinating immune responses. CD8 T cell and
many B cell responses require CD4 T cell “help” provided directly or through CD4 T
cell activation of antigen presenting cells (particularly dendritic cells). In coeliac
disease, CD4 T cells predominantly secreting Th1-like cytokines appear in the small
17