Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants.
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.
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
Kevin
K
Blauth
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.|Neuroscience Program, University of Colorado Denver, Aurora, CO, USA.
John
J
Soltys
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
Adeline
A
Matschulat
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
Cory R
CR
Reiter
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
Alanna
A
Ritchie
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.
Nicholas L
NL
Baird
Department of Neurology, University of Colorado Denver, Aurora, CO, USA.|Neuroscience Program, University of Colorado Denver, Aurora, CO, USA.|Department of Ophthalmology, University of Colorado Denver, Aurora, CO, USA.
Jeffrey L
JL
Bennett
Department of Neurology, University of Colorado Denver, Aurora, CO, USA. greg.owens@ucdenver.edu.
Gregory P
GP
Owens
D000328:Adult; D000818:Animals; D021461:Animals, Outbred Strains; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000276:immunology / Q000473:pathology; D003711:Demyelinating Diseases / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D057026:Induced Pluripotent Stem Cells / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology*; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D046509:Tissue Culture Techniques
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007074:Immunoglobulin G; D011994:Recombinant Proteins
Autoimmunity; Demyelination; Monoclonal antibody; Multiple sclerosis; Neuroimmunology; Spinal cord slice cultures