REDUCED EXPRESSION OF PEPTIDE-LOADED HLA CLASS-I MOLECULES ON MULTIPLE-SCLEROSIS LYMPHOCYTES

Lymphocytes from patients with HLA class II-linked autoimmune diseases such as type I diabetes, systemic lupus erythematosus, rheumatoid art hritis, and Graves' have recently been shown to have a decrease in the expression of self-peptide-filled HLA class I antigens on the surface of peripheral lymphocytes. The human demyelinating diseases of multip le sclerosis in some cases are also associated with the presence of ce rtain HLA class II genes, which may in turn be linked to genes in the class II region that control class I expression. Hence, we studied fre sh peripheral blood mononuclear cells (PBMCs) and newly produced Epste in-Barr virus (EBV)-transformed cell lines from multiple sclerosis pat ients for the class I defect. Unseparated PBMCs, as well as T cells, B cells, and macrophages from multiple sclerosis patients had a decreas e in the amount of conformationally correct peptide-filled HLA class I molecules on the cell surface compared with matched controls detectab le by flow cytometry. To demonstrate the independence of this defect f rom exogenous serum factors, newly produced EBV-transformed cell lines from B cells of patients with multiple sclerosis maintained the defec t. In addition, DR2 +/+, +/-, and -/- EBV-transformed B cells from the se patients similarly demonstrated the self-antigen presentation defec t. Analysis of a set of discordant multiple sclerosis twins revealed t he class I defect was exclusively found on the affected twin lymphocyt es, suggesting a role of this class I complex in disease expression. T hese data indicate that multiple sclerosis patients have abnormal pres entation of self-antigens. This phenomenon, common to a number of HLA- linked autoimmune disorders, may be associated with failed self-tolera nce and improper T-cell education secondary to faulty HLA class I asse mbly controlled by HLA class II linked genes.