Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5.
Ilaria CallegariJohanna OechteringMika SchneiderSylvain PerriotAmandine MathiasMargarete M VoortmanAlessandro CagolUlrike LannerMartin DieboldSebastian HoldermannVictor KreinerBurkhard BecherCristina GranzieraAndreas JunkerRenaud Du PasquierMichael KhalilJens KuhleLudwig KapposNicholas S R SandersonTobias DerfussPublished in: Brain : a journal of neurology (2023)
Intrathecal IgM production in multiple sclerosis (MS) is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in MS, CSF from two independent cohorts, including MS patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS- related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of MS donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterisation and antigen identification. We produced 5 cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR + plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an EAE model. CSF IgM might contribute to CNS inflammation in MS by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain.
Keyphrases
- multiple sclerosis
- mass spectrometry
- single cell
- ms ms
- white matter
- liquid chromatography
- end stage renal disease
- cell migration
- cell therapy
- cell surface
- gene expression
- chronic kidney disease
- high performance liquid chromatography
- binding protein
- high resolution
- blood brain barrier
- ejection fraction
- spinal cord
- dendritic cells
- dna binding
- gas chromatography
- peritoneal dialysis
- oxidative stress
- stress induced
- small molecule
- cell proliferation
- immune response
- patient reported outcomes
- subarachnoid hemorrhage
- kidney transplantation
- functional connectivity
- protein protein
- bioinformatics analysis