Multiple Sclerosis II-Binding CD4 Cells in Patients with Oligodendrocyte Glycoprotein/MHC Class Increased Frequencies of Myelin

Multiple sclerosis (MS) is an autoimmune disease characterized by infiltration of pathogenic immune cells in the CNS resulting in destruction of the myelin sheath and surrounding axons. We and others have previously measured the frequency of human myelin-reactive T cells in peripheral blood. Using T cell cloning techniques, a modest increase in the frequency of myelin-reactive T cells in patients as compared with control subjects was observed. In this study, we investigated whether myelin oligodendrocyte glycoprotein (MOG)-specific T cells could be detected and their frequency was measured using DRB1*0401/MOG 97–109(107E-S) tetramers in MS subjects and healthy controls expressing HLA class II DRB1*0401. We defined the optimal culture conditions for expansion of MOG-reactive T cells upon MOG peptide stimulation of PMBCs. MOG 97–109-reactive CD4 + T cells, isolated with DRB1*0401/ MOG 97–109 tetramers, and after a short-term culture of PMBCs with MOG 97–109 peptides, were detected more frequently from patients with MS as compared with healthy controls. T cell clones from single cell cloning of DRB1*0401/MOG 97–109(107E-S) tetramer + cells confirmed that these T cell clones were responsive to both the native and the substituted MOG peptide. These data indicate that autoantigen-specific T cells can be detected and enumerated from the blood of subjects using class II tetramers, and the frequency of MOG 97–109-reactive T cells is greater in patients with MS as compared with healthy controls. M ultiple sclerosis (MS) is a genetically mediated auto-immune disease of the CNS with loss of neurologic function (1–3). Specifically, focal T cell and macro-phage infiltrates result in demyelination and loss of surrounding axons (4). It is postulated that T cell recognition of peptides derived from myelin proteins in the context of MHC presented by microglia is involved in the pathogenesis of the disease. Autoreactive T cells are found at approximately the same frequency in normal individuals and patients with MS (5–8), although in subjects with the disease , autoreactive T cells are in a more activated state as compared with T cells from normal individuals (9–11). Although the underlying etiology for the dysregulated immune system in MS is not known, fully replicated genome-wide association scans have identified a number of allelic variants in immune-related genes, including IL2RA, IL7R, CD58, CD226, CD6, IRF8, and MHC class II, that are associated with MS susceptibility (12, 13). We first identified T cell epitopes of myelin basic protein and proteolipid protein in both patients with MS and …