Catalytic activity of anti-ground state antibodies, antibody subunits, and human autoantibodies.
Catalytic antibodies may be produced over the natural course of antibody-affinity maturation by placement of chemically reactive residues in antibody-active sites by somatic hypermutation or V-D-J-gene rearrangement. This hypothesis has received support from recent observations on the chemical reactivity of antibodies to vasoactive intestinal peptide (VIP), DNA, and steroid- and dinitrophenyl-esters. Recent studies reveal that monoclonal antibodies raised against the ground state of VIP can accelerate the cleavage of peptide bonds. The light-chain (L-chain) subunit of human autoantibodies display increased hydrolytic rate and diminished VIP-binding affinity compared to the parent antibody, consistent with increased turnover owing to weaker binding of the substrate ground state. These observations reveal an essential limitation of catalytic antibodies, i.e., large turnover rates may be associated with diminished substrate specificity. The hydrolysis of VIP by IgG purified by affinity chromatography from asthma patients and nonasthmatic controls was compared. IgG from the majority of asthma patients displayed VIP-hydrolyzing activity. Vmax values for IgG from asthmatics tended to be higher than those from the nonasthmatic group. In principle, catalysis by antibodies may be an important mediator of immunological defense, regulation, and autoimmune dysfunction. The verification of these possibilities will require studies that utilize efficient assays of antibody catalysis during experimental immunization and autoimmune disease, as well as mechanistic investigation of catalysis by antibodies and their subunits.
Paul
S
S
Department of Anesthesiology, University of Nebraska Medical Center, Omaha.
D000595:Amino Acid Sequence; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D017151:Antibodies, Catalytic / Q000276:immunology / Q000378:metabolism*; D000937:Antigen-Antibody Reactions; D001249:Asthma / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D002846:Chromatography, Affinity; D004247:DNA / Q000276:immunology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007525:Isoelectric Focusing; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D017151:Antibodies, Catalytic; D001323:Autoantibodies; D007074:Immunoglobulin G; D014660:Vasoactive Intestinal Peptide; D004247:DNA