Germ-line selection ensures embryonic autoreactivity and a positive discrimination of self mediated by supraclonal mechanisms

It is necessary to clarify principles and mechanisms of natural tolerance t o body tissues, in order to derive appropriate diagnostics, therapeutics an d prognostics of autoimmune diseases (AID). I will argue that AIDs result f rom deficits in autoreactive regulatory T cell generation and/or function, and propose a model that explains why relatively few prototypes of AID exis t,(1) as well as their organ-specificity or systemic nature. The model sugg ests that natural tolerance is achieved through evolutionarily selected dev elopmental genetic programs: (i) for patterns of V-region expression early in life that ensure auto(multi)reactivity at the outset of the system; (ii) for a cellular composition of thymic stroma that 'breeds' and activates re gulatory (autoreactive) T cells in early development; (iii) for lymphocyte differentiation and population dynamics, that results in peripheral 'educat ion' of regulatory tissue-specific cells, while allowing for 'unregulated' clonal responses to nonself. In the present model, S/NS discrimination is ' supraclonal' and 'dominant' elated to other 'systemic' properties such as t he regulation of total lymphocyte numbers, the 'open-endedness' of repertoi res, and their differences in health and disease. Dominant tolerance models in general, also solve the paradox that pathogenic autoreactivity is rare, in spite of the extensive V-region degeneracy of lymphocyte recognition an d the high frequency of cross-reactivity between S/NS; in short, it is asto nishing that we are not autoimmune everytime we get infected. As in other a reas of biomedical science, time is perhaps ripe to move from component (cl onal) analysis to system's biology, as some have proned for years.(2,3) (C) 2000 Academic Press.