Susceptibility to autoimmune disease explained?

It is well known that susceptibility to autoimmune diseases such as multiple sclerosis and uveitis varies depending on the genetic background of the individual, but the mechanism whereby this occurs is unknown. Although conventional teaching has it that potentially autoreactive lymphocytes are deleted in the thymus during development, more recent findings have indicated that there are small numbers of autoreactive T cells present in the periphery and which have presumably escaped deletion in the thymus. The extent of thymic deletion of autoreactive T lymphocytes is dependent in some part on the expression of self antigens in the thymus and it has been shown that self antigens, such as retinal and CNS proteins, previously considered to be organ specific, are expressed at low levels in the thymus. Their expression in the thymus is thought to be important for the induction of tolerance and thus protection from autoimmune disease. A recent paper (Nature Medicine2000;6:56–61) has reported a further twist to this tale. Proteolipid protein (PLP) is a major protein of myelinated nerve fibres and immunisation of animals with this protein combined with adjuvant produces a demyelinating disease with similarities to multiple sclerosis. PLP is composed of a number of antigenic peptides (epitopes) and some of these are expressed in the thymus on thymic epithelial cells. Intrathymic expression of PLP was largely restricted to the shorter splice variant of PLP, known as DM20. Expression of DM20 by thymic epithelium was sufficient to confer T cell tolerance not only to DM20 but to all other epitopes of PLP in a strain of disease resistant mice. In contrast, this major T cell activating epitope was expressed only in the central nervous system specific PLP, but not in the …