title: Intrathecal BCR transcriptome in multiple sclerosis versus other neuroinflammation: Equally diverse and compartmentalized, but more mutated, biased and overlapping with the proteome.
abstract: The mechanisms driving the intrathecal synthesis of IgG in multiple sclerosis (MS) are unknown. We combined high-throughput sequencing of transcribed immunoglobulin heavy-chain variable (IGHV) genes and mass spectrometry to chart the diversity and compartmentalization of IgG-producing B cells in the cerebrospinal fluid (CSF) of MS patients and controls with other neuroinflammatory diseases. In both groups, a few clones dominated the intrathecal IGHV transcriptome. In most MS patients and some controls, dominant transcripts matched the CSF IgG. The IGHV transcripts in CSF of MS patients frequently carried IGHV4 genes and had more replacement mutations compared to controls. In both groups, dominant IGHV transcripts were identified within clusters of clonally related B cells that had identical or related IGHV transcripts in the blood. These findings suggest more pronounced affinity maturation, but an equal degree of diversity and compartmentalization of the intrathecal B-cell response in MS compared to other neuroinflammatory diseases.
authors.affiliation: Department of Immunology and Transfusion Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Jorunn N
authors.initials: JN
authors.lastname: Johansen
authors.affiliation: Department of Immunology and Transfusion Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Frode
authors.initials: F
authors.lastname: Vartdal
authors.affiliation: Adaptive Biotechnologies, Seattle, WA, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Desmarais
authors.affiliation: Centre for Immune Regulation, Department of Immunology and Transfusion Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Astrid E V
authors.initials: AE
authors.lastname: Tutturen
authors.affiliation: Centre for Immune Regulation, Department of Immunology and Transfusion Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo, Norway.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: de Souza
authors.affiliation: Department of Immunology and Transfusion Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address: andreas.lossius@rr-research.no.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lossius
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Trygve
authors.initials: T
authors.lastname: Holmøy
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D002493:Central Nervous System Diseases / Q000134:cerebrospinal fluid / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000276:immunology; D008297:Male; D008582:Meningitis, Aseptic / Q000134:cerebrospinal fluid / Q000235:genetics; D008590:Meningoencephalitis / Q000134:cerebrospinal fluid / Q000235:genetics; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000235:genetics*; D011128:Polyradiculopathy / Q000134:cerebrospinal fluid / Q000235:genetics; D020543:Proteome; D012333:RNA, Messenger / Q000134:cerebrospinal fluid*; D012507:Sarcoidosis / Q000134:cerebrospinal fluid / Q000235:genetics; D059467:Transcriptome / Q000276:immunology
chemical_list: D007143:Immunoglobulin Heavy Chains; D020543:Proteome; D012333:RNA, Messenger
keywords: B cells; Cerebrospinal fluid; High-throughput sequencing; IgG; Multiple sclerosis