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Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination.

ABSTRACT: We previously identified the remyelinating activity of a natural IgMkappa oligodendrocyte-reactive autoantibody (SCH94.03), using a virus-induced murine model of multiple sclerosis. We now describe a second mouse IgMkappa monoclonal antibody (mAb) (SCH79.08) raised against normal mouse spinal cord homogenate, which reacts with myelin basic protein and also promotes remyelination. Because these two mAbs recognize different oligodendrocyte antigens, several previously identified oligodendrocyte-reactive IgMkappa mAbs (O1, O4, A2B5, and HNK-1), each with distinct antigen specificities, were evaluated and found to promote remyelination. In contrast, IgMkappa mAbs that did not bind to oligodendrocytes showed no remyelination. One of these, CH12 IgMkappa mAb, which shares variable region cDNA sequences with SCH94.03 except for amino acid differences in the complementarity-determining region 3 in both heavy and light chains, did not bind to oligodendrocytes and did not promote remyelination. The fact that multiple oligodendrocyte-reactive antibodies with distinct antigen reactivities induce remyelination argues against direct activation by a unique cell surface receptor. These findings are most consistent with the hypothesis that the binding of mAbs to oligodendrocytes in the lesions induces myelin repair via indirect immune effector mechanisms initiated by the mu-chain. Importantly, these studies indicate that oligodendrocyte-reactive natural autoantibodies may provide a powerful and novel therapeutic means to induce remyelination in multiple sclerosis patients.

SUBMITTER: Asakura K

PROVIDER: S-EPMC6793011 | biostudies-literature | 1998 Oct

REPOSITORIES: biostudies-literature

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Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination.

Asakura K K Miller D J DJ Pease L R LR Rodriguez M M

The Journal of neuroscience : the official journal of the Society for Neuroscience 19981001 19

We previously identified the remyelinating activity of a natural IgMkappa oligodendrocyte-reactive autoantibody (SCH94.03), using a virus-induced murine model of multiple sclerosis. We now describe a second mouse IgMkappa monoclonal antibody (mAb) (SCH79.08) raised against normal mouse spinal cord homogenate, which reacts with myelin basic protein and also promotes remyelination. Because these two mAbs recognize different oligodendrocyte antigens, several previously identified oligodendrocyte-re ...[more]

PMID: 9742140

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Project description:We used transcription-profiling to identify mitogen-activated protein kinase (Mapk) signaling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signaling by elevation of intracellular levels of cAMP using administration of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolyzing enzyme phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin-induced demyelination and a consequent acceleration of remyelination. Study was conducted to identify the genes that are differentialy regulated during early time point of OPC differentiation. This study includes reanalyzed data from the following 6 Samples available in GSE24821: [i] 5 days post lesion (dpl) laser captured caudal cerebellar peduncle (CCP) replicates 1-3 (GSM610956-GSM610958), and [ii] 14 dpl laser captured CCP replicates 1-3 (GSM610959-GSM610961). For the reanalyzed data, raw data files were background-corrected, normalized and summarized using the RMA algorithm as implemented in the R statistical programming environment (http://www.r-project.org). Differential expression between sample groups was assessed using the moderated t-test as implemented in the limma package for the Bioconductor suite of R bioinformatics software (http://bioconductor.org). In order to correct for hypothesis testing on such a scale, P-values relating to differential expression were corrected for multiple testing using FDR correction. Differential expression across sample groups was deemed significant at an FDR of 5% (q < 0.05). The processed data for the reanalyzed dataset is linked below as supplementary file 'GSE50042_reanalyzed_Samples.txt'. The processed data for Samples GSM1213100-GSM1213114 is linked below as supplementary file 'GSE50042_processed_data.txt'.

Dataset Information

Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination.

Publications

Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination.

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