primary prevention of coeliac disease - Associazione Italiana ...

MECHANISMS OF ORAL TOLERANCE
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site of gluten exposure, the small intestine.
Experimental models of oral tolerance differ from CD in certain respects. In CD, the
most prominent evidence of inflammation occurs locally, where antigen exposure takes
place. This is not the case in animals in which the effect of abrogation of oral tolerance
predominantly affects systemic immune responses. However, in some animal models,
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oral challenge with the antigen was shown to cause a mild mucosal lesion . Of interest,
there is also evidence that gluten intolerance is associated with systemic damage in
some individuals, as represented by diseases such as dermatitis herpetiformis, epilepsy
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and cerebellar ataxia . Moreover, there is some evidence that CD is also associated
with inflammation in the distal intestine and rectal histological changes have been
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reported . Finally, it is worth noting that systemic antibody responses to gluten are
found in a range of disorders, in the absence of local gut damage or evidence that these
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antibodies have a systemic pathogenic significance .
Interest in oral tolerance
Over the decades, an interest in the topic of oral tolerance has persisted, in the belief
that its study could lead to a more fundamental understanding of homeostasis of the
immune system. Furthermore, it is postulated that systemic inflammatory diseases
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might be controlled by inducing oral tolerance to the stimulating antigen . According
to this concept, the administration of oral antigen (such as the autoantigenic target of
systemic disease) could lead to a reduced or aborted systemic response to this antigen.
Thus various feeding studies with myelin basic protein (in patients with multiple
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sclerosis ) and collagen (in patients with rheumatoid arthritis ) have been described.
Little therapeutic benefit has been noted in these studies to-date.
Finally, an understanding of oral tolerance mechanisms is pertinent to the
development of oral vaccines, since this route of vaccination is designed to give not
only a local protective immune response, but also systemic protection.
Factors involved in control of the mucosal immune response
A clear understanding of the homeostatic mechanisms responsible for controlling
the mucosal immune response has yet to be reached. Undoubtedly, many interrelated
factors play a role (Fig. 2) and these will be considered briefly here.
The epithelial lining layer “outpost” of mucosal immunity
The epithelial cell sitting on its basement membrane, in a sense guards the mucosal
tissue from full, free exposure to antigen. However, the epithelial cell is not an absolute
barrier and it permits rapid absorption of soluble antigen. Thus, epithelial cells, like
many other cells in the body, constantly sample the external milieu. We know that food
antigens can rapidly penetrate this epithelial layer, since these antigens are found in the
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circulation even within minutes of food ingestion .
In addition to antigen absorption, epithelial cells have also been shown to process
and load antigen into MHC II molecules. This was demonstrated in the case of gliadin,
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using immuno-electron microscopy . Furthermore, it is known that MHC class II
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molecules are expressed or can be induced on intestinal epithelial cells . These
findings raise the possibility that epithelial cells might function as antigen presenting