The cells of the central nervous system (CNS) have the peculiarity of physiologically expressing very low levels of HLA molecules. In multiple sclerosis (MS), however, as in endocrine autoimmune diseases, there is a marked increase of HLA expression in the tissue (i.e. the plaques) and this is attributable not only to infiltrating cells but also to the astrocytes. To gain an insight into the regulation of HLA in the different cell types in the CNS and to compare it to that observed in the endocrine organs, we have studied the effect of the lympho/monokines interferon (IFN)-alpha and -gamma, tumour necrosis factor (TNF)-alpha, and interleukin (IL)-2 and other agents on this aspect of the biology of human fetal brain cells in culture. A two-colour immunofluorescence technique which combines antibodies to diverse CNS cell markers and monoclonal antibodies (MoAbs) to the non-polymorphic region of HLA molecules was used throughout this study. In control cultures, only astrocytes expressed MHC class I, but after incubation with either IFN-gamma or TNF-alpha oligodendrocytes acquired class I expression. Surprisingly, astrocytes became spontaneously class II positive in culture and this was greatly enhanced by IFN-gamma. Other agents such as IL-2, epidermal growth factor, phorbolmyristate acetate and lectins had no effect. The expression of HLA molecules in the cells of the CNS both in basal conditions and in response to lymphokines is therefore selective and highly heterogenous, thus reflecting their intrinsic biological diversity. These findings may help to explain the features of the immunopathology of MS and also of latent viral infections of neural cells.