E3

Table E3.1. Key features of autoimmunity by design theory

Autoreactive T cells are released from the thymus by design Autoreactivity is not equivalent to autoimmune disease

Autoreactive T cells usually prevent inflammation through dominant regulatory mechanisms but can be corrupted into becoming pathogenic

The lack of inflammation is an active process involving autoreactive regulatory T cells interacting with parenchymal tissues

The inflammatory (or quiescent) states of individual microenvironments are regulated independently

The phenotypic expression of inflammation at a given site is dependent on the presence or absence of proinflammatory versus tolerogenic signals expressed by cells of that organ, and the relative numbers of pathogenic versus regulatory T cells at that site.

ontogeny that must be controlled in order to prevent autoimmune disease. The "autoimmunity by design" model assumes that autoreactivity is not equivalent to autoimmune disease; the specificity of a T cell does not define its functional capabilities. Implicit in the model is the concept that a naïve T cell has an ability to differentiate into an effector cell with proinflammatory features (for example, an IFNy-producing TH1 cell) or into one with a protective phenotype (for example, a TGF-p- or IL-10-producing Tr1 cell) depending on the specific environmental conditions encountered by the lymphocyte. In this view the process of T cell ontogeny has evolved such that a small number of positively selected, autoreactive T cells are released from the thymus, rather than escape from the thymic deletion process. The TCRs expressed by the autoreactive T cells are likely to have relatively low affinities for their ligands (as the T cells expressing the highest affinity TCRs are presumably deleted centrally). There are some data to suggest that a proportion of these autoreactive T cells can be preconditioned centrally to have a regulatory or suppressor phenotype after encountering self-antigens on thymic APCs.6,7 However, as all self-antigens are not expressed in the thymus, some autoreactive T cells are likely to be released into the periphery as naïve precursors. These latter autoreactive T cells are hypothesized to home to secondary lymphoid tissues where they have the opportunity to interact with self-APCs expressing self-antigens. If and when the naïve autoreactive T cells encounter their antigenic ligand on a nonactivated (or immature) APC, they have the potential to differentiate into a regulatory or suppressor cell.

Activated, regulatory T cells (either deriving directly from the thymus or after priming in the periphery) would then circulate widely where they could re-encounter their antigenic ligands expressed on normal tissues. These interactive events are hypothesized to result in reciprocal down regulatory signals: the autoreactive T cells are hypothesized to encounter self-antigen in the absence of proinflammatory stimuli (i.e., no costimulation) and thereby maintain and reinforce their anergic/suppressive phenotype. The induced regulatory characteristics would prevent activation or effector function of small numbers of other potentially pathogenic T cells that infiltrate the organ, either through direct cell: cell contact or through bystander (possibly cytokine-mediated) effects. At the same

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