title: Sequence changes at the V-D junction of the VH1 heavy chain of anti-phosphocholine antibodies alter binding to and protection against Streptococcus pneumoniae.
abstract: X-linked immune deficient (Xid) mice fail to produce anti-phosphocholine (PC) antibodies even after immunization with Streptococcus pneumoniae. Consequently, Xid mice are extremely susceptible to infection with S. pneumoniae, PC-specific B cells appear to undergo clonal deletion in Xid mice; however, a new thymus-dependent form of PC, 6-(O-phosphocholine)hydroxyhexanoate (EPC), can rescue PC-specific B cells from the bone marrow presumably by providing T cell help before clonal deletion. Analysis of PC-specific IgG hybridomas from Xid mice revealed utilization of several V-D junctional variants of the VH1 gene segment rearranged to different D and JH gene segments. The majority of Xid anti-PC antibodies exhibit an Asp-->Gly95H replacement at the V-D junction. These Gly95H VH1 variants associate with kappa 1C L chains to produce anti-PC antibodies that: (1) have low relative affinity for PC, (ii) are heteroclitic for nitrophenylphosphocholine and (iii) fall to bind to or provide protection against S. pneumoniae. Single prototypic V-D variants of the T15 idiotype (Asp95H), M603 idiotype (Asn95H) and M167 idiotype (Asp95H-Ala96H) were also induced in Xid mice. The M603-like and M167-like antibodies bound to and protected against S. pneumoniae even though they exhibited Kas for PC which were lower than T15 idiotype+ antibodies. These data demonstrate that small changes in the V-D junctional sequence of the T15 (VH1) heavy chain alter L chain usage and the structure of the PC binding site so that the PC expressed on S. pneumoniae is no longer recognized.
authors.affiliation: Laboratory of Biochemical Physiology, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201, USA.
authors.forename: W X
authors.initials: WX
authors.lastname: Guo
authors.forename: A M
authors.initials: AM
authors.lastname: Burger
authors.forename: R T
authors.initials: RT
authors.lastname: Fischer
authors.forename: D G
authors.initials: DG
authors.lastname: Sieckmann
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
authors.forename: J J
authors.initials: JJ
authors.lastname: Kenny
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000235:genetics / Q000378:metabolism*; D000915:Antibody Affinity; D001422:Bacterial Adhesion / Q000276:immunology; D001483:Base Sequence; D001666:Binding Sites, Antibody; D002208:Caproates / Q000276:immunology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006241:Haptens / Q000276:immunology; D006825:Hybridomas / Q000737:chemistry; D007116:Immunization, Passive; D007126:Immunoglobulin Allotypes / Q000032:analysis; D007143:Immunoglobulin Heavy Chains / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000032:analysis; D007133:Immunoglobulin Joining Region / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007135:Immunoglobulin Variable Region / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000276:immunology*; D011008:Pneumococcal Infections / Q000382:microbiology / Q000517:prevention & control*; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity; D014774:Virulence
chemical_list: D017152:Antibodies, Antiphospholipid; D002208:Caproates; D006241:Haptens; D007126:Immunoglobulin Allotypes; D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D010767:Phosphorylcholine; C088147:4-nitrophenyl-6-(O-phosphocholine)hydroxyhexanoate