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Review
, 111 (2), 138-46

Central and Peripheral Autoantigen Presentation in Immune Tolerance

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Review

Central and Peripheral Autoantigen Presentation in Immune Tolerance

Alberto Pugliese. Immunology.

Abstract

Recent studies in both humans and experimental rodent models provide new insight into key mechanisms regulating tolerance to self-molecules. These recent advances are bringing about a paradigm shift in our views about tolerance to self-molecules with tissue-restricted expression. There is, indeed, mounting evidence that selected antigen-presenting cells (APCs) have the ability to synthesize and express self-molecules, and that such expression is critical for self-tolerance. Insulin is a key hormone produced exclusively by pancreatic beta-cells and a critical autoantigen in type 1 diabetes. It provides an excellent example of a molecule with tissue-restricted expression that is expressed ectopically by APCs. The fact that APCs expressing insulin have been demonstrated in both thymus and peripheral lymphoid tissues suggests that they may play a role in insulin presentation in both the central and peripheral immune system. Experimental mice, in which insulin expression was altered, provide functional data that help to dissect the role of insulin presentation by APCs of the immune system. This review addresses recent literature and emerging concepts about the expression of self-molecules in the thymus and peripheral lymphoid tissues and its relation to self-tolerance.

Figures

Figure 1
Figure 1
Illustration of the relationship between the expression of insulin in the thymus and peripheral lymphoid tissues (PLT), mediated by thymic epithelial cells and bone marrow-derived dendritic cells (DCs), and diabetes development in the mouse strains. The figure also highlights the different outcomes associated with the manipulation of the Ins2 and Ins1 genes in relation to their expression in the thymus and PLT, as well as in the pancreas. Please see the text for details. NOD, non-obese diabetic.
Figure 2
Figure 2
(a) Proinsulin-positive cells in human thymus, stained on a frozen section using streptavidin–biotin–peroxidase and the AEC substrate (red), counterstained with haematoxylin (×64 magnification). (b) Proinsulin-positive cells in human spleen, stained on a frozen section using streptavidin–biotin–peroxidase and the AEC substrate (red), counterstained with haematoxylin (×128 magnification).

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