The immunoglobulin heavy chain constant region affects kinetic and thermodynamic parameters of antibody variable region interactions with antigen.
A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG(1), IgG(2a), and IgG(2b) switch variants of murine monoclonal antibody (mAb) 3E5 IgG(3) with identical V domains revealed apparent specificity differences for Cryptococcus neoformans glucuronoxylomannan (GXM). Kinetic and thermodynamic binding properties of mAbs 3E5 to a 12-mer peptide mimetic of GXM revealed differences in the affinity of these mAbs for a monovalent ligand, a result that implied that the constant (C) region affects the secondary structure of the antigen binding site, thus accounting for variations in specificity. Structural models of mAbs 3E5 suggested that isotype-related differences in binding resulted from amino acid sequence polymorphisms in the C region. This study implies that isotype switching is another mechanism for generating diversity in antigen binding and that isotype restriction of certain antibody responses may reflect structural constraints imposed by C region on V region binding. Furthermore, isotype affected the polyreactivity of V region identical antibodies, implying a role for C region in determining self-reactivity.
Torres
Marcela
M
Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Fernández-Fuentes
Narcis
N
Fiser
András
A
Casadevall
Arturo
A
D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D000946:Antigens, Fungal / Q000737:chemistry* / Q000276:immunology; D001666:Binding Sites, Antibody / Q000276:immunology; D003455:Cryptococcus neoformans / Q000737:chemistry* / Q000276:immunology; D007127:Immunoglobulin Constant Regions / Q000737:chemistry* / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000276:immunology; D007700:Kinetics; D051379:Mice; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D000946:Antigens, Fungal; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011134:Polysaccharides; C027478:glucuronoxylomannan