title: The link between antibodies to OxLDL and natural protection against pneumococci depends on D(H) gene conservation.
abstract: Selection and physiological production of protective natural antibodies (NAbs) have been associated with exposure to endogenous antigens. The extent to which this association depends on germline NAb sequence is uncertain. Here we show that alterations in germline D(H) sequence can sever the association between the production of self-reactive NAbs and NAbs that afford protection against a pathogen. In unmanipulated hosts, the availability of the evolutionarily conserved DFL16.1 gene segment sequence profoundly affected the serum levels of NAbs against bacterial phosphorylcholine but not oxidized low-density lipoprotein. Mice with partially altered DFL16.1 sequence could use N nucleotides to recreate the amino acid sequence associated with the classical protective T15 idiotype–positive NAbs, whereas those without DFL16.1 could not. DFL16.1 gene-deficient mice proved more susceptible to challenge with live Streptococcus pneumoniae. Our findings indicate that although production of self-reactive NAbs can be independent of germline D(H) sequence, their capacity to provide protection against pathogens cannot. The potential relevance of these findings for the rational design of vaccines is discussed.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Vale
authors.forename: Pratibha
authors.initials: P
authors.lastname: Kapoor
authors.forename: Greg A
authors.initials: GA
authors.lastname: Skibinski
authors.forename: Ada
authors.initials: A
authors.lastname: Elgavish
authors.forename: Tamer I
authors.initials: TI
authors.lastname: Mahmoud
authors.forename: Cosima
authors.initials: C
authors.lastname: Zemlin
authors.forename: Michael
authors.initials: M
authors.lastname: Zemlin
authors.forename: Peter D
authors.initials: PD
authors.lastname: Burrows
authors.forename: Alberto
authors.initials: A
authors.lastname: Nobrega
authors.forename: John F
authors.initials: JF
authors.lastname: Kearney
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.forename: Harry W
authors.initials: HW
authors.lastname: Schroeder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000737:chemistry / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics*; D003429:Cross Reactions / Q000276:immunology; D019143:Evolution, Molecular; D016368:Frameshift Mutation / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D005854:Germ Cells / Q000276:immunology; D007114:Immunization; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010767:Phosphorylcholine / Q000276:immunology; D011008:Pneumococcal Infections / Q000276:immunology* / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D000906:Antibodies; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D010767:Phosphorylcholine