title: In vivo detection of peripherin-specific autoreactive B cells during type 1 diabetes pathogenesis.
abstract: Autoreactive B cells are essential for the pathogenesis of type 1 diabetes. The genesis and dynamics of autoreactive B cells remain unknown. In this study, we analyzed the immune response in the NOD mouse model to the neuronal protein peripherin (PRPH), a target Ag of islet-infiltrating B cells. PRPH autoreactive B cells recognized a single linear epitope of this protein, in contrast to the multiple epitope recognition commonly observed during autoreactive B cell responses. Autoantibodies to this epitope were also detected in the disease-resistant NOR and C57BL/6 strains. To specifically detect the accumulation of these B cells, we developed a novel approach, octameric peptide display, to follow the dynamics and localization of anti-PRPH B cells during disease progression. Before extended insulitis was established, anti-PRPH B cells preferentially accumulated in the peritoneum. Anti-PRPH B cells were likewise detected in C57BL/6 mice, albeit at lower frequencies. As disease unfolded in NOD mice, anti-PRPH B cells invaded the islets and increased in number at the peritoneum of diabetic but not prediabetic mice. Isotype-switched B cells were only detected in the peritoneum. Anti-PRPH B cells represent a heterogeneous population composed of both B1 and B2 subsets. In the spleen, anti-PRPH B cell were predominantly in the follicular subset. Therefore, anti-PRPH B cells represent a heterogeneous population that is generated early in life but proliferates as diabetes is established. These findings on the temporal and spatial progression of autoreactive B cells should be relevant for our understanding of B cell function in diabetes pathogenesis.
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain;
authors.forename: Nahir
authors.initials: N
authors.lastname: Garabatos
authors.forename: Raimon
authors.initials: R
authors.lastname: Alvarez
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrillo
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrascal
authors.forename: Cristina
authors.initials: C
authors.lastname: Izquierdo
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Presa
authors.forename: Conchi
authors.initials: C
authors.lastname: Mora
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Joan
authors.initials: J
authors.lastname: Verdaguer
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D018604:Epitope Mapping / Q000379:methods; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D064531:Peripherins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010537:Peritoneum / Q000276:immunology / Q000378:metabolism; D020033:Protein Isoforms / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D018985:Epitopes, B-Lymphocyte; D064531:Peripherins; D020033:Protein Isoforms