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62 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 6 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 7 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 8 100 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 7 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 9 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 10 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. 7-9 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 9 cell activation . If such co-stimulation is absent, the lymphocyte enters a dormant state,
MECHANISMS OF ORAL TOLERANCE 63 Peripheral tolerance •Clonal deletion T cell apoptosis •Clonal “anergy” T cell Inactive / asleep? •Regulatory clone T reg T reg cytokines Fig. 1. Mechanisms of peripheral tolerance. T reg = regulatory T cell incapable of reacting with a specific antigen. It is possible that anergic T cells can be rescued from this state, thereby permitting such a cell to display auto-reactivity. The presence of circulating, regulatory T cells is a further mechanism that has been proposed to explain the phenomenon of peripheral tolerance. Following appropriate activation, these cells release cytokines which inhibit the auto-reactivity of the immune system. In the 1970s, considerable interest surrounded the concept of T suppressor cells performing this task. However, since no specific cell markers or specific suppressor factors could be reliably identified, the concept became disreputable and it was damaging to a research grant application or publication to mention the “S” word! However, fashions change and there is a saying that “what goes around, comes around” and there is now a growing belief that regulatory T cells play a central role in the 11 prevention of auto-immunity . According to this concept, regulatory T cells can be 12 considered to conduct the orchestra of the immune response . Finally, a fourth mechanism whereby peripheral tolerance may operate is the 7 concept of antigen “ignorance” . According to this concept, antigen internalised within a tissue or present in only very small quantities, is unable to interact productively with lymphocytes. The immune control mechanisms described above do not develop for such antigens. If tissue damage develops, antigen is released and a potentially damaging immune response may develop. Mucosal immune system Exposure to external antigens in humans commonly takes place at two different sites: the skin and the mucosal surfaces. Although antigen can enter via the skin, the
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Perspectives on Coeliac Disease Vol
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The AIC Meeting was held in the Aul
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Italian Coeliac Society, Via Picott
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Preface Coeliac disease (CD) is a u
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Contents Current understanding of t
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2 THE BASIS OF COELIAC DISEASE hapl
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4 THE BASIS OF COELIAC DISEASE 1 pr
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6 THE BASIS OF COELIAC DISEASE spre
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8 THE BASIS OF COELIAC DISEASE Ackn
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10 THE BASIS OF COELIAC DISEASE glu
Page 27 and 28: Catassi C, Fasano A, Corazza GR (ed
Page 29: T CELL RESPONSES TO GLUTEN PEPTIDES
Page 32 and 33: 18 A DOMINANT EPITOPE IN GLUTEN PEP
Page 42 and 43: 28 ROLE OF A-GLIADIN 31-49 PEPTIDE
Page 47 and 48: COELIAC DISEASE IN THE SAHARAWI 33
Page 55: COELIAC DISEASE IN THE SAHARAWI 41
Page 58 and 59: 44 INFANT FEEDING PRACTICES AND COE
Page 66 and 67: Age (years) 52 INFANT FEEDING PRACT
Page 78 and 79: 64 MECHANISMS OF ORAL TOLERANCE pot
Page 80 and 81: 66 MECHANISMS OF ORAL TOLERANCE Epi
Page 82 and 83: 68 MECHANISMS OF ORAL TOLERANCE typ
Page 84 and 85: 70 MECHANISMS OF ORAL TOLERANCE 51
Page 86 and 87: 72 MECHANISMS OF ORAL TOLERANCE 23.
Page 91 and 92: GENETICALLY DETOXIFIED GRAINS 77 to
Page 93 and 94: • • GENETICALLY DETOXIFIED GRAI
Page 95 and 96: GENETICALLY DETOXIFIED GRAINS 81 3.
Page 99 and 100: IMMUNOTHERAPY OF COELIAC DISEASE 85
Page 101 and 102: IMMUNOTHERAPY OF COELIAC DISEASE 87
Page 105 and 106: RECENT ADVANCES ON GLUTEN TOXICITY
Page 107 and 108: Index A Antiendomysium antibodies (
Page 109: INDEX 95 W Wheat, 7, 23, 27, 31, 53
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