correspondence

160 nature genetics• volume 21• february 1999 that SJL/J mice have an Il2 sequence identical to that of NOD mice; similarly, B10. S mice were found to have a sequence identical to that of B6 (Table 1). As in the NOD allele, the SJL/J allele differs from the B6 allele by a single base change (T to C) that results in a serine-to-proline substitution in the sixth amino acid residue of the mature protein. The SJL/J allele also has a duplication of a 12-bp segment of DNA that results in a 4-aa insertion, and a compensatory 12-bp deletion that results in a deletion of 4 glutamines from a stretch of 12 consecutive glutamines. Compared with the Il-2 protein produced by B6 mice, NOD-produced Il-2 shows differences in glycosylation that may affect its functional half-life (LSW, manuscript in preparation). If the NOD/SJL allele of Il2 influences EAE and diabetes susceptibility, a possible mechanism may lie in its role in T-cell selection in the thymus or in its function in the peripheral immune compartment. Insufficient levels of Il-2 may affect negative selection in the thymus, allowing the escape of self-reactive T cells12. Il-2 is also important in an autocrine feedback loop that regulates the expansion of antigenspecific, T-cell clones by inducing apoptotic cell death13, and is essential for the maintenance of self-tolerance as evidenced by the development of severe autoimmunity in Il2−/− mice14. The identification of a narrowly defined locus that has effects in both EAE and diabetes may indicate that there are individual genes that contribute to the susceptibility to several autoimmune diseases. By using congenic mice to precisely define each of the loci contributing to EAE and diabetes susceptibility, we can begin to put together the pieces that determine the development of the autoimmune phenotype.