title: The in vitro resistance of IgG2 to proteolytic attack concurs with a comparative paucity of autoantibodies against peptide analogs of the IgG2 hinge.
abstract: The mammalian antibody repertoire comprises immunoglobulin (Ig) molecules of multiple isotypes and subclasses with varying functional properties. Among the four subclasses of the human IgG isotype, we found that IgG2 exhibits a particular resistance to human and bacterial proteases that readily cleave the IgG1 hinge region in vitro. Autoantibodies (IgGs) that recognize points of proteolytic cleavage in the IgG1 hinge are widespread in the healthy human population, suggesting that IgG1 fragmentation and the generation of cryptic antigens for host immune surveillance commonly occur in vivo. We previously reported that autoantibodies to cleaved IgG1s can restore Fc-mediated effector functions that are lost following proteolytic cleavage of the hinge. In contrast, it was not possible to demonstrate an analogous cohort of autoantibodies to IgG2 hinge epitope analogs, and there appeared to be no functional component in human serum with the ability to reconstitute Fc effector functions to a cell-bound IgG2 fragment. Thus, the results indicate that among the IgG subclasses, human IgG2 is uniquely resistant to a number of known pathological proteases and that autoimmune recognition to potential cleavage points in the IgG2 hinge appears to be absent in human circulation.
authors: Biologics Research; Centocor R&D Inc., Radnor, PA, USA. rbrezski@its.jnj.com
authors: Randall J
authors: RJ
authors: Brezski
authors: Allison
authors: A
authors: Oberholtzer
authors: Brandy
authors: B
authors: Strake
authors: Robert E
authors: RE
authors: Jordan
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D001323:Autoantibodies / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D052058:Hinge Exons; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D010587:Phagocytosis
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007074:Immunoglobulin G; D010455:Peptides; D003165:Complement System Proteins; D010447:Peptide Hydrolases