title: Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms.
abstract: Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (VH) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific VH alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases.
authors.affiliation: Section for Medical Inflammation Research and 2 Section for Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Bruno
authors.initials: B
authors.lastname: Raposo
authors.forename: Doreen
authors.initials: D
authors.lastname: Dobritzsch
authors.forename: Changrong
authors.initials: C
authors.lastname: Ge
authors.forename: Diana
authors.initials: D
authors.lastname: Ekman
authors.forename: Bingze
authors.initials: B
authors.lastname: Xu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lindh
authors.forename: Michael
authors.initials: M
authors.lastname: Förster
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Uysal
authors.forename: Kutty Selva
authors.initials: KS
authors.lastname: Nandakumar
authors.forename: Gunter
authors.initials: G
authors.lastname: Schneider
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001483:Base Sequence; D024043:Collagen Type II / Q000235:genetics / Q000276:immunology*; D003461:Crystallography; D000939:Epitopes / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic / Q000235:genetics*; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D020349:Surface Plasmon Resonance
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains