The steroidogenic
enzyme 21-hydroxylase (21OH) is the main
autoantigen in autoimmune primary adrenal failure (
Addison's disease).
Autoantibodies against 21OH are immunological markers of an ongoing autoimmune process but are not directly involved in the tissue destruction. Autoreactive T cells are thought to mediate tissue damage, but the T cell
antigen(s) has not been identified. To find out whether 21OH contains important
immunodominant epitopes for T cells, we first immunized BALB/c and SJL inbred mouse strains with recombinant 21OH and showed that lymph node cells proliferated effectively following in vitro stimulation with recombinant 21OH (stimulation indices (SI) 20-40). We further synthesized a series of
peptides based on 21OH with amino acid sequences with propensity to bind to major histocompatibility complex class II molecules. Only a few
peptides could trigger lymphocytes of 21OH-primed mice to proliferate. One of these, 21OH (342-361), stimulated effectively 21OH-primed lymph node cells of SJL mice (SI = 4-8) and also, although to a lesser extent, of BALB/c mice (SI = 2.5). When SJL mice were immunized with 21OH (342-361), the immunizing
peptide as well as
peptide 21OH (346-361) triggered a significant proliferative response (SI = 24). A
peptide from another part of 21OH, namely 21OH (191-202), did not stimulate the 21OH (342-361)-primed cells. Moreover, stimulation of lymph node cells of mice immunized with 21OH (342-361) with 21OH resulted in a significant proliferative response. We conclude that 21OH (342-361) is an
immunodominant determinant for T cells in SJL and probably BALB/c mice. 21OH (342-361) corresponds to the substrate binding site of the
enzyme. The p342-361 region may be involved in the pathogenesis of autoimmune adrenal failure in humans.