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Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants

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Abstract

B cells are implicated in the etiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.

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Acknowledgments

This work was supported by Public Health Service grants NS072141 (GPO) and EY022936 (JLB) awarded from the National Institutes of Health, and from support (JLB) provided by the Guthy-Jackson Foundation. K. B. Blauth was supported by training Grant NS007321 to D. H. Gilden from the National Institutes of Health. We kindly thank Dr. V. Wong, University of Calgary, Canada for providing human astrocyte cultures.

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Correspondence to Gregory P. Owens.

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401_2015_1500_MOESM2_ESM.jpg

Supplemental Fig. 1. Superbiochip array slides were deparaffinized and immunostained as described in the methods section. rAb immunostaining is in green, DAPI is in blue. Scale bar = 100 µm. (a) MS04-2 # 30 peripheral reactivity was punctate and often associated with epithelia. (b) MS05-3 # 38 peripheral reactivity was punctate in esophagus and pancreas but more ubiquitously expressed in ileum and skin. (c) IC05-2 # 2 reactivity was largely absent in the periphery (JPEG 89 kb)

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Blauth, K., Soltys, J., Matschulat, A. et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. Acta Neuropathol 130, 765–781 (2015). https://doi.org/10.1007/s00401-015-1500-6

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  • DOI: https://doi.org/10.1007/s00401-015-1500-6

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