title: Anoctamin 2 identified as an autoimmune target in multiple sclerosis.
abstract: Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden; burcu@kth.se.
authors: Burcu
authors: B
authors: Ayoglu
authors: Affinity Proteomics, Science for Life Laboratory, Department of Neuroscience, Karolinska Institute, SE-17165 Stockholm, Sweden;
authors: Nicholas
authors: N
authors: Mitsios
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Ingrid
authors: I
authors: Kockum
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Mohsen
authors: M
authors: Khademi
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden;
authors: Arash
authors: A
authors: Zandian
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden;
authors: Ronald
authors: R
authors: Sjöberg
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden;
authors: Björn
authors: B
authors: Forsström
authors: Affinity Proteomics, Science for Life Laboratory, Department of Neuroscience, Karolinska Institute, SE-17165 Stockholm, Sweden;
authors: Johan
authors: J
authors: Bredenberg
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Izaura
authors: I
authors: Lima Bomfim
authors: Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Erik
authors: E
authors: Holmgren
authors: Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Hans
authors: H
authors: Grönlund
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: André Ortlieb
authors: AO
authors: Guerreiro-Cacais
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Nada
authors: N
authors: Abdelmagid
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden;
authors: Mathias
authors: M
authors: Uhlén
authors: Infection and Cancer Program, German Cancer Research Center, 69120 Heidelberg, Germany;
authors: Tim
authors: T
authors: Waterboer
authors: Institute of Environmental Medicine, Karolinska Institute, SE-17177 Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, SE-11365 Stockholm, Sweden.
authors: Lars
authors: L
authors: Alfredsson
authors: Affinity Proteomics, Science for Life Laboratory, Department of Neuroscience, Karolinska Institute, SE-17165 Stockholm, Sweden;
authors: Jan
authors: J
authors: Mulder
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden;
authors: Jochen M
authors: JM
authors: Schwenk
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, SE-17177 Stockholm, Sweden;
authors: Tomas
authors: T
authors: Olsson
authors: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology (KTH), SE-17165 Stockholm, Sweden;
authors: Peter
authors: P
authors: Nilsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000075368:Anoctamins; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000097:blood / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D018118:Chloride Channels / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D018604:Epitope Mapping; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000097:blood / Q000276:immunology; D055815:Young Adult
chemical_list: C521849:ANO2 protein, human; D000075368:Anoctamins; D001323:Autoantibodies; D001324:Autoantigens; D018118:Chloride Channels; D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen; D008565:Membrane Proteins; D010446:Peptide Fragments
keywords: affinity proteomics; autoantibodies; autoimmunity; multiple sclerosis; protein microarrays