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Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After
Jan M Schwab1, Carmen Haider2, Marcel A Kopp2
1From the The Belford Center for Spinal Cord Injury (J.M.S., P.G.P.), The Ohio State University, Wexner Medical Center, Columbus; Departments of Neurology (J.M.S.), Physical Medicine and Rehabilitation, and Neurosciences, The Ohio State University, Columbus; Department of Neurology and Experimental Neurology (J.M.S., M.A.K., T. Liebscher, T. Lübstorf, C.B., L.S.-N., U.D., H.P.), Spinal Cord Injury Research (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Division of Neuropathology and Neurochemistry (C.H., V.E., G.R., R.H.), Department of Neurology, Medical University of Vienna, Austria; Department of Neurology (T.Z.), Medical University of Vienna, Austria; Department of Neurophysiology and Neuropharmacology (Center for Physiology and Pharmacology) (H.K.), Medical University of Vienna, Austria; Department of Orthopaedics and Trauma Surgery (T.H.), Medical University of Vienna, Austria; Treatment Centre for Spinal Cord Injuries (Thomas Liebscher), BG Hospital Unfallkrankenhaus Berlin, Germany; Spinal Cord Injury Center (A.C.), Balgrist University Hospital, Zurich, Switzerland; Division of Trauma Surgery (P.C.), University Hospital Zürich, Switzerland; IRCCS Fondazione S. Lucia (G.S.), Spinal Cord Unit, Rome, Italy; Division of Neurosurgery and Spine Program (M.G.F.), University of Toronto, ON, Canada; Ruhr-University Bochum (C. May, A.G., K.M.), Center for Protein Diagnostics (PRODI), Medical Proteome Center, Universitätsstraße 150, Bochum, Germany; Institute of Medical Immunology (C. Meisel), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; Department of Immunology (C. Meisel), Labor Berlin-Charité Vivantes GmbH, Germany; Berlin Institute of Health (U.D.), QUEST-Center for Transforming Biomedical Research, Germany; Department of Clinical Epidemiology and Applied Biostatistics (P.M.), Eberhard Karls Universität Tübingen, Germany; Department of Neurosciences (P.G.P.), The Ohio State University, Columbus; and Center for Brain Research (H.L.), Medical University of Vienna, Austria; Comprehensive Center for Clinical Neurosciences and Mental Health (C.H., T.Z., V.E., G.R., R.H.), Medical University of Vienna, Austria. jan.schwab@osumc.edu romana.hoeftberger@meduniwien.ac.at.
Background And Objectives:
Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane.
Methods:
This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored.
Results:
Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier.
Discussion:
This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes.
