primary prevention of coeliac disease - Associazione Italiana ...

64 MECHANISMS OF ORAL TOLERANCE
potential for antigen interaction at mucosal surfaces is even greater. The nature of skin,
a multi-layered relatively impermeable structure, inhibits the penetration of harmful
antigenic structures such as bacteria. In contrast, mucosal surfaces are typically
protected by a single layer of epithelial cells. This makes the task of antigen access all
the easier. Furthermore, in sites such as the small intestine which have a major role in
absorption of nutrients, constant sampling of luminal material takes place. Thus, the
mucosal immune system needs to differentiate between harmful antigens (such as
pathogenic bacteria) and innocuous antigens (such as food).
The organisation of the mucosal immune response is structured to permit a local
response to the majority of antigens which penetrate to the lamina propria cells of the
mucosa. However, this immune response is typically of low intensity and remains local.
Systemic reaction to such antigen is either minimal or totally absent. Precisely how this
type of response is achieved is not fully understood. Secretory IgA produced in the
mucosa may play an important role but other immune components are doubtless also
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involved . This controlled mucosal immune response could be considered as a form of
peripheral tolerance and the term “oral tolerance” is frequently used.
Oral tolerance
The phenomenon of oral tolerance has been extensively investigated in various
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animal model systems over the past 30 years . As with all experimental models, they
may not precisely replicate the normal in vivo situation but may nonetheless be
informative about how local mucosal immune responses are regulated. The essential
feature of experimental oral tolerance is that by feeding an antigen orally, the induction
of a systemic immune response to that antigen is prevented.
A typical experiment examining oral tolerance is to study what happens to an animal
after oral administration of ovalbumin: when the animal is later exposed to ovalbumin
systemically (by injection), circulating lymphocyte responsiveness to that antigen is
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either absent or significantly diminished . Animals not pre-fed ovalbumin have a
normal systemic response to the antigen. This effect of oral feeding causing systemic
tolerance could be regarded as a form of induced peripheral tolerance. In oral tolerance,
although hyporesponsiveness of both specific T and B lymphocytes is noted, T cells
seem to be more profoundly affected. There is no well validated equivalent experiment
confirming the induction of oral tolerance in man.
Relevance of oral tolerance to coeliac and other gastrointestinal diseases
The essence of the concept of oral tolerance is that local gut mucosal immune
responses are regulated and prevent systemic reactions to orally ingested antigens. If,
for whatever reason, a breakdown in oral tolerance develops, an excessive
inflammatory mucosal reaction may take place. Thus, such a breakdown may be
regarded as central to the development of inflammatory gastrointestinal disorders.
Examples of these include coeliac disease, Crohn's disease and ulcerative colitis. In the
latter two diseases the responsible gut antigens are not known, although bacterial
antigens are suspected. In the case of CD, it is well established since the 1950s that
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gluten is the causative agent . It is postulated that immune tolerance of gluten, found in
normal subjects, is lost in CD patients and the consequence is inflammation at the major