Abstract
Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.
Highlights
Inflammatory diseases of the central nervous system (CNS) comprise a broad spectrum of disorders, multiple sclerosis is the most abundant one
Autoantibodies against oligodendrocyte myelin glycoprotein (OMGP) in patients with CNS diseases To identify patients with autoantibodies to OMGP, we developed two cell-based assay (CBA), OMGP displayed in the membrane with a transmembrane part (OMGP-TM) or with its physiological GPI anchor (Fig. S1)
In the inflammatory neurological disease control group (INDC), as well as neuromyelitis optica spectrum disorders (NMOSD) group and patients diagnosed with myelin oligodendrocyte glycoprotein (MOG) antibodyassociated disease (MOGAD), no OMGP autoantibodies are detected (Fig. 1)
Summary
Inflammatory diseases of the CNS comprise a broad spectrum of disorders, multiple sclerosis is the most abundant one. This study analyzes autoimmunity to oligodendrocyte myelin glycoprotein (OMGP), because this protein is expressed in the CNS and there found on both oligodendrocytes and neurons. OMGP is a GPI-anchored protein and was originally identified as a 105 kDa glycoprotein of myelin in the CNS [48], which is expressed by neurons [25]. An autoimmune response against OMGP had been considered in studies looking at multiple CNS targets [13, 46], their abundance in patients has not yet been thoroughly determined and the pathogenic potential of Abs or T cells directed against OMGP was unknown. To gain further insight into the source and presence of OMGP in the CNS, we analyzed cultured oligodendrocytes and neurons from rodents and human oligodendrocytes derived from induced pluripotent stem cells (iPSCs) [17] and proved the presence of OMGP on these cells
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