title: VH4.21-encoded natural autoantibodies with anti-i specificity mirror those associated with cold hemagglutinin disease.
abstract: The Ig VH regions of virtually all human pathogenic cold agglutinin (CA) anti-i/l autoantibodies are encoded by a single Ig VH gene segment, VH4.21, in conjunction with a highly variable CDR3 structure. The anti-I specificity is often associated with V kappa III-encoded L chains, whereas anti-i autoantibodies appear to use a broader array of kappa and lambda VL gene segments. B cells expressing VH4.21 are abundantly present in adult lymphoid tissues from healthy individuals but their relationship with B cells secreting pathogenic CA is unknown. Herein we have analyzed the distribution of VH4.21-expressing B cells in fetal, neonatal, and adult B cell populations using the monoclonal anti-VH4.21 antibody 9G4. In addition, we have analyzed the anti-i and anti-I binding capacity and V regions of 19 VH4.21-encoded mAb secreted by cord and adult blood-derived cell lines from healthy individuals. The results show that VH4.21 expressing B cells are overrepresented in all repertoires studied and are evenly distributed over cord blood CD5+ and CD5- B cell populations. VH4.21-encoded H chains strongly predispose for anti-i binding capacity, regardless of the VL regions or H chain CDR3 structure. The avidity of some of these antibodies was similar to those of pathogenic CA. In addition, we found evidence for monospecific anti-I binding in antibodies encoded by other members of the VH4 gene family. We conclude that VH4.21-encoded antibodies with anti-i specificity from the normal B cell repertoire mirror their pathogenic counterparts and that naturally occurring anti-I antibodies may be encoded by a more diverse array of VH4 genes.
authors.affiliation: Department of Immunology, University Hospital Utrecht, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Schutte
authors.forename: J H
authors.initials: JH
authors.lastname: van Es
authors.forename: L E
authors.initials: LE
authors.lastname: Silberstein
authors.forename: T
authors.initials: T
authors.lastname: Logtenberg
mesh_terms: D000373:Agglutinins / Q000235:genetics; D000595:Amino Acid Sequence; D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D015703:Antigens, CD / Q000032:analysis; D001323:Autoantibodies / Q000235:genetics*; D001483:Base Sequence; D018956:CD5 Antigens; D002461:Cell Line, Transformed; D003450:Cryoglobulins; D005260:Female; D005803:Genes, Immunoglobulin; D006801:Humans; D007048:I Blood-Group System / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008969:Molecular Sequence Data; D011247:Pregnancy
chemical_list: D000373:Agglutinins; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; D018956:CD5 Antigens; D003450:Cryoglobulins; D007048:I Blood-Group System; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C029443:cold agglutinins