TY - JOUR
T1 - The immunoglobulin heavy chain constant region affects kinetic and thermodynamic parameters of antibody variable region interactions with antigen
AU - Torres, Marcela
AU - Fernández-Fuentes, Narcis
AU - Fiser, András
AU - Casadevall, Arturo
PY - 2007/5/4
Y1 - 2007/5/4
N2 - A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG1, IgG2a, and IgG2b switch variants of murine monoclonal antibody (mAb) 3E5 IgG3 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.
AB - A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG1, IgG2a, and IgG2b switch variants of murine monoclonal antibody (mAb) 3E5 IgG3 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.
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U2 - 10.1074/jbc.M700661200
DO - 10.1074/jbc.M700661200
M3 - Article
C2 - 17353196
AN - SCOPUS:34250318189
SN - 0021-9258
VL - 282
SP - 13917
EP - 13927
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -