title: Effect of immunoglobulin variable region structure on C3b and C4b deposition.
abstract: Many of the biological activities of immunoglobulins, including interaction with the complement system, are attributed to the structure of the heavy chain constant domains. However, previous studies indicated that immune complexes formed with independently derived isotype-matched pairs of monoclonal antibodies vary with respect to their capacity to activate complement and to serve as targets for C3b and C4b deposition. The goal of the present study was to provide a structural basis for explaining how variable domains influence C3b and C4b deposition on immunoglobulins. Heavy and light chain variable domains from a pair of IgG2a antibodies previously shown to differ in terms of complement activation and C3b and C4b deposition were cloned and sequenced. The two clones utilize distinct heavy and light variable region genes and the translated amino acid sequence reveals several residues that could serve as potential targets for complement deposition which differs between the two antibodies. Molecular modeling suggests that many of the relevant differences between the two antibodies are located in solvent exposed portions of the heavy and light chain variable domains and that some of the relevant sites are located within the complementarity determining regions. Differences in antibody affinity do not provide an explanation for the previously observed role of variable domains on interactions with the complement system. These data suggest that sequence variations within solvent-exposed variable domain residues may play a key role in C3b and C4b deposition on immunoglobulins.
authors.affiliation: Department of Microbiology, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: White
authors.forename: M B
authors.initials: MB
authors.lastname: Frank
authors.forename: S
authors.initials: S
authors.lastname: Foundling
authors.forename: F J
authors.initials: FJ
authors.lastname: Waxman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000915:Antibody Affinity; D001483:Base Sequence; D003179:Complement C3b / Q000187:drug effects / Q000378:metabolism*; D015935:Complement C4b / Q000187:drug effects / Q000378:metabolism*; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000494:pharmacology*; D007526:Isoelectric Point; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
chemical_list: D007135:Immunoglobulin Variable Region; D003179:Complement C3b; D015935:Complement C4b