Abstract
A method to stimulate T lymphocytes with a broad range of brain antigens would facilitate identification of the autoantigens for multiple sclerosis and enable definition of the pathogenic mechanisms important for multiple sclerosis. In a previous work, we found that the obvious approach of culturing leukocytes with homogenized brain tissue does not work because the brain homogenate suppresses antigen-specific lymphocyte proliferation. We now report a method that substantially reduces the suppressive activity. We used this non-suppressive brain homogenate to stimulate leukocytes from multiple sclerosis patients and controls. We also stimulated with common viruses for comparison. We measured proliferation, selected the responding CD3+ cells with flow cytometry, and sequenced their transcriptomes for mRNA and T-cell receptor sequences. The mRNA expression suggested that the brain-responding cells from MS patients are potentially pathogenic. The T-cell receptor repertoire of the brain-responding cells was clonal with minimal overlap with virus antigens.
Highlights
Multiple sclerosis (MS) is a human disease characterized by inflammation and demyelination in the central nervous system (CNS), which often causes significant neurologic deficits
Our previous work on suppression of in vitro proliferation with brain homogenate was done with lymph node cells from mice immunized with ovalbumin in RPMI-1640 media with 10% FBS, using ovalbumin as the stimulating antigen and freshly prepared mouse brain homogenate for suppression [22]
When using RPMI-1640 media supplemented with FBS, the results were consistent with our previous work
Summary
Multiple sclerosis (MS) is a human disease characterized by inflammation and demyelination in the central nervous system (CNS), which often causes significant neurologic deficits. Unlike some other autoimmune diseases, the target autoantigen in MS is unknown. There are no diagnostic autoantibodies, and a target T-cell antigen has not been identified. The major structural proteins of myelin, such as myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), are obvious candidate autoantigens. These proteins have been extensively investigated [1,2,3,4,5], but we doubt that they are the primary autoantigen. Recent elegant studies have suggested two non-myelin target antigens [6, 7]
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