Individuals with IgG4-related Disease Do Not Have an Increased Frequency of the K409 Variant of IgG4 that Compromises Fab-arm Exchange

Abstract

To the Editor: Immunoglobulin (Ig)G4 is considered a noninflammatory antibody because of its relative inability to fix complement and its poor binding to activating Fc receptors1,2. This antibody is also unique in its ability to exchange “half-antibodies” comprised of 1 heavy chain and 1 light chain by a process called “Fab-arm exchange”3. Fab-arm exchange is thought to render IgG4 functionally monovalent, interfering with its ability to crosslink target antigens and limiting its ability to form large immune complexes. Apart from the limited ability of IgG4 to bind to activating Fc receptors and its inability to fix complement, Fab-arm exchange of IgG4 may also contribute to the putative immunoregulatory properties of this isotype3. Fab-arm exchange is facilitated by residues in the hinge region, as well as in the CH3 domain of IgG4, which are unique to this subclass4. An arginine residue (R409) in the CH3 domain of IgG4, unique to the IgG4 subclass, is necessary for Fab-arm exchange4. Analysis of the crystal structure of the CH3 domain of IgG4 suggests that this arginine residue (R409) facilitates Fab-arm exchange by preventing the proper formation of an interchain hydrogen bond network that is generated in other IgG … Address all correspondence to Dr. S. Pillai, Massachusetts General Hospital, 149 13th Street, Boston, Massachusetts, 02129 USA. E-mail: pillai{at}helix.mgh.harvard.edu