primary prevention of coeliac disease - Associazione Italiana ...

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MECHANISMS OF ORAL TOLERANCE
the food is quite common and the reaction remits promptly after the food has been
eliminated from the diet. Food allergy often develops in early childhood but may no
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longer be clinically problematic in later years .
Concept of immune tolerance
The absent or low immune reactivity of the gut to food antigens raises the concept of
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immune tolerance . Essentially, it would appear that a limited, local reaction develops
to ingested foods and this response is confined to the bowel mucosa. This permits the
antigenicity of food to be recognised but does not allow a damaging immune response
to develop. In this situation, immune tolerance of the food is said to have taken place.
From the viewpoint of an immunologist, tolerance is defined as the inability or
failure of lymphocytes to respond to an antigen. The importance of tolerance is best
observed in the concept of self-tolerance: in this, an individual's lymphocytes fail to
react with self-antigen and as a consequence the development of autoimmune disease is
prevented. Self-tolerance is a central paradigm in immunology, first proposed some
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100 years ago by Paul Erlich who predicted that “horror autotoxicus” might develop if
such a control system was not in place.
Central and peripheral tolerance
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Immune tolerance can be divided into central and peripheral forms . Central
tolerance relates to events which take place in organs such as the thymus and bone
marrow. In this, it is envisaged that as T cells mature in the thymus, those cells which
might be capable of self reactivity (by binding strongly to self-antigens presented by
self-MHC molecules) undergo apoptosis and are thereby deleted. These events prevent
the development of T cell mediated autoimmunity. There is considerable experimental
evidence in support of such thymic events. It is also proposed that a similar mechanism
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may cause deletion of B cells in the bone marrow .
Despite the evidence for lymphocyte deletion in the thymus, it is not precisely
known how universal this process is. Indeed, it is increasingly being accepted that a low
level of autoreactivity is physiological and may even be important for normal immune
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function . Since it is improbable that all T lymphocytes capable of self-reactivity are
removed by this process, a second mechanism has been invoked: this is referred to as
peripheral tolerance (Fig. 1). In this, the potential self-reactivity of circulating
lymphocytes is curbed and these cells are rendered tolerant in the periphery. The
mechanisms involved in peripheral tolerance are not well understood.
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There is evidence that some lymphocytes are deleted in the periphery . A more popular
concept is that lymphocyte anergy develops.
One suggested basis for the development of anergy is that when lymphocytes encounter
self-antigen, they do so in the absence of the appropriate additional signals provided by
co-stimulatory molecules. These molecules include in particular the B7/CD28
interaction, which markedly enhances interleukin (IL)-2 production and hence full T
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cell activation . If such co-stimulation is absent, the lymphocyte enters a dormant state,