Golli-induced paralysis: A study in anergy and disease

The Golli-MBP transcription unit contains three Golli-specific exons as wel l as the seven exons of the classical myelin basic protein (MBP) gene and e ncodes alternatively spliced proteins that share amino acid sequence with M BP. Unlike MBP, which is a late Ag expressed only in the nervous system, Go lli exon-containing gene products are expressed both pre- and postnatally a t many sites, including lymphoid tissue, as well as in the central nervous system, To investigate whether Golli-MBP peptides unique to Golli would res ult in neurological disease, we immunized rats and observed a novel neurolo gical disease characterized by mild paralysis and the presence of groups of lymphocytes in the subarachnoid space but not in the parenchyma of the bra in. Disease was induced by Th1-type T cells that displayed an unusual activ ation phenotype. Primary stimulation in vitro induced T cell proliferation with increased surface CD45RC that did not become down-regulated as it did in other Ag-stimulated cultures, Secondary stimulation of this CD45RC(high) population with Ag, however, did not induce proliferation or IL-2 producti on, although an IFN-gamma-producing population resulted. Proliferation coul d be induced by secondary stimulation with IL-2 or PMA-ionomycin, suggestin g an anergic T cell population. Cells could adoptively transfer disease aft er secondary stimulation with IL-2, but not with Ag alone, These responses are suggestive of a chronically stimulated, anergic population that can be transiently activated to cause disease, fall back into an anergic state, an d reactivated to cause disease again. Such a scenario may be important in c hronic human disease.