Abstract
The most prominent pathological features of multiple sclerosis (MS) are demyelination and neurodegeneration. The exact pathogenesis of MS is unknown, but it is generally regarded as a T cell-mediated autoimmune disease. Increasing evidence, however, suggests that other components of the immune system, particularly B cells and antibodies, contribute to the cumulative CNS damage and worsening disability that characterize the disease course in many patients. We have previously described strongly elevated T cell reactivity to an extracellular domain of the most abundant CNS myelin protein, myelin proteolipid protein (PLP) in people with MS. The current paper addresses the question of whether this region of PLP is also a target of autoantibodies in MS. Here we show that serum levels of isotype-switched anti-PLP181−230 specific antibodies are significantly elevated in patients with MS compared to healthy individuals and patients with other neurological diseases. These anti-PLP181−230 antibodies can also live-label PLP-transfected cells, confirming that they can recognize native PLP expressed at the cell surface. Importantly, the antibodies are only elevated in patients who carry HLA molecules that allow strong T cell responses to PLP. In that subgroup of patients, there is a positive correlation between the levels of anti-PLP181−230 antibodies and the severity of MS. These results demonstrate that anti-PLP antibodies have potentially important roles to play in the pathogenesis of MS.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which affects about 2.5 million people worldwide
We have demonstrated that isotype-switched antibodies targeting PLP181−230 are significantly elevated in the serum of patients with relapsing-remitting MS (RR-MS) and secondary progressive MS (SP-MS), in those carrying proteolipid protein (PLP) response-permissive HLA types, and that there is a positive correlation between the levels of antibody and disease severity in these patients
A rabbit serum, raised against this 50-mer peptide, has been shown to be able to live label rat oligodendrocytes [37], in a pattern reminiscent of that seen when cells were labeled with the O10 monoclonal antibody, which recognizes a conformation-dependent epitope of the second extracellular loop of PLP [38]
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which affects about 2.5 million people worldwide. Because CSF drains into the blood, and activated B cells can freely enter and exit the CNS, such antibodies could enter the circulation. Numerous published studies have reported antibodies directed against myelin proteins [2,3,4,5,6,7,8,9,10,11,12] or other CNS antigens [13,14,15,16,17,18] in CSF or serum of MS patients, but only a small number of these studies have attempted to determine whether these antibodies are potentially pathogenic [3, 7, 15, 18]. Antibodies in MS patients may be merely an epiphenomenon; there are multiple examples in the non-MS literature of how antibodies targeting CNS tissues can be directly pathogenic (reviewed in [19]), and the chance that antibodies present in at least some patients with MS are pathogenic is relatively high
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