Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins.
Oligoclonal Ig bands (OCBs) of the cerebrospinal fluid are a hallmark of multiple sclerosis (MS), a disabling inflammatory disease of the central nervous system (CNS). OCBs are locally produced by clonally expanded antigen-experienced B cells and therefore are believed to hold an important clue to the pathogenesis. However, their target antigens have remained unknown, mainly because it was thus far not possible to isolate distinct OCBs against a background of polyclonal antibodies. To overcome this obstacle, we copurified disulfide-linked Ig heavy and light chains from distinct OCBs for concurrent analysis by mass spectrometry and aligned patient-specific peptides to corresponding transcriptome databases. This method revealed the full-length sequences of matching chains from distinct OCBs, allowing for antigen searches using recombinant OCB antibodies. As validation, we demonstrate that an OCB antibody from a patient with an infectious CNS disorder, neuroborreliosis, recognized a Borrelia protein. Next, we produced six recombinant antibodies from four MS patients and identified three different autoantigens. All of them are conformational epitopes of ubiquitous intracellular proteins not specific to brain tissue. Our findings indicate that the B-cell response in MS is heterogeneous and partly directed against intracellular autoantigens released during tissue destruction. In addition to helping elucidate the role of B cells in MS, our approach allows the identification of target antigens of OCB antibodies in other neuroinflammatory diseases and the production of therapeutic antibodies in infectious CNS diseases.
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany;
Simone M
SM
Brändle
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany;
Birgit
B
Obermeier
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany; Department of Neurology, University of Ulm, 89081 Ulm, Germany;
Makbule
M
Senel
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany;
Jessica
J
Bruder
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany;
Reinhard
R
Mentele
Neuroimmunology Unit, Department of Clinical Neurosciences, Center for Molecular Medicine CMM, Karolinska University Hospital, 171 76 Stockholm, Sweden;
Mohsen
M
Khademi
Neuroimmunology Unit, Department of Clinical Neurosciences, Center for Molecular Medicine CMM, Karolinska University Hospital, 171 76 Stockholm, Sweden;
Tomas
T
Olsson
Department of Neurology, University of Ulm, 89081 Ulm, Germany;
Hayrettin
H
Tumani
Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Sozialmedizinisches Zentrum Donauspital, 1220 Vienna, Austria;
Wolfgang
W
Kristoferitsch
Department for Protein Analytics, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany;
Friedrich
F
Lottspeich
Hertie Senior Professor Group Neuroimmunology, Max-Planck-Institute of Neurobiology, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, 81377 Munich, Germany.
Hartmut
H
Wekerle
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, 81377 Munich, Germany.
Reinhard
R
Hohlfeld
Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, 81377 Munich, Germany klaus.dornmair@med.uni-muenchen.de.
Klaus
K
Dornmair
D001324:Autoantigens / Q000276:immunology*; D001898:Borrelia / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D020852:Lyme Neuroborreliosis / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology*; D043025:Oligoclonal Bands / Q000276:immunology*
D001324:Autoantigens; D043025:Oligoclonal Bands
autoantigens; multiple sclerosis; oligoclonal bands; proteomics; transcriptomics