primary prevention of coeliac disease - Associazione Italiana ...

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A DOMINANT EPITOPE IN GLUTEN PEPTIDES ?
intestinal lamina propria within hours of gluten challenge in subjects on gluten free diet.
Initial damage to the intestine following gluten challenge in treated coeliac disease is
likely to be due to cytokines (for example interferon gamma [IFNg] and tumour
necrosis factor [TNF]) secreted by CD4 T cells that activate macrophages causing
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release of inflammatory mediators and other cytokines that activate other cell types . In
addition to immunopathology induced by gluten-specific CD4 T cells, increasing
3
evidence suggests that gluten may also directly activate macrophages , possibly
facilitating induction of T cell responses to dietary antigen.
Disease chronicity and epitope spreading: relevance to T cell epitope mapping in
coeliac disease
Experimental autoimmune diseases, such as experimental allergic encepahalitis
(EAE), can be initiated by immunization of susceptible mice with adjuvant together
with myelin basic protein (MBP) or a specific peptide derived from this protein. This
4
peptide corresponds to the “dominant” T cell epitope of MBP . Exactly what qualities,
in addition to affinity for HLA and resistance to proteolysis during processing, that lead
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to one peptide in an antigenic protein to be dominant are not fully understood . As EAE
progresses, a variety of other peptides (sub-dominant epitopes) derived from MBP and
other myelin-associated proteins are recognized by specific T cells in a process termed
4, 6
epitope spreading (also seen in human multiple sclerosis ). Specificity of T cell
responses can also be shaped by preferential presentation of peptides by B cells
following antigen uptake via B cell receptor or Fc receptor-mediated uptake of
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antibody-antigen complexes . Post-uptake processing of antigen may also be altered by
the cytokine milieu in established immune responses giving rise to a different repertoire
8
of peptides being presented by antigen-presenting cells .
Interestingly, when MBP-specific T cells are transferred to a healthy recipient,
MBP-specific T cells are initially abundant in spleen and blood. Just before onset of
EAE, MBP-specific T cells disappear from spleen and blood, and become abundant at
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the site of antigen (central nervous system) . Consistent with this, oral administration
of antigen is initially followed by proliferation of antigen specific T cells in gut-
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associated as well as systemic lymphoid tissue . Furthermore, T cells with identical
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specificity are found in murine gut epithelium, lamina propria and the thoracic duct .
Taken together, these studies in mice indicate that T cells specific for dominant or
subdominant epitopes appear at different time points, and may be located in different
anatomical sites according to the chronicity of the immune response. Contrary to the
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widely held view in coeliac disease research , T cells with identical specificities are
present in gut and extra-intestinal sites such as blood in the early phase of immune
responses caused by gut antigen.
Multiple toxic peptides in coeliac disease identified by multiple methodologies
In coeliac disease, a variety of in vivo, ex vivo and in vitro methods have been