Monoclonal IgM Rheumatoid Factors Bind IgG at a Discontinuous Epitope Comprised of Amino Acid Loops from Heavy-Chain Constant-Region Domains 2 and 3

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 89; no. 1; pp. 94 - 98
• Main Authors: Artandi, S. E., Calame, K. L., Morrison, S. L., Bonagura, V. R.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.01.1992; National Acad Sciences; National Academy of Sciences
• Subjects: Amino Acid Sequence; Amino acids; Antibodies; Antibodies, Anti-Idiotypic - metabolism; Antibodies, Anti-Idiotypic - ultrastructure; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - ultrastructure; Antigen-Antibody Reactions; Arthritis; Autoantibodies; Autoimmunity (experimental aspects and models); Binding sites; Binding Sites, Antibody; Biological and medical sciences; Cellular biology; Computer Graphics; DNA Mutational Analysis; Epitopes; Exons; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hybridity; Immunity (Disease); Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin G - ultrastructure; Immunoglobulin Heavy Chains - chemistry; Immunoglobulin Heavy Chains - immunology; Immunoglobulin M - metabolism; Immunology; Medical research; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Reactivity; Rheumatoid Factor - metabolism; Rheumatoid Factor - ultrastructure; Structure-Activity Relationship; Autoantibody; IgG; Rheumatoid factor; Immunoglobulins; Binding site; Antigenic determinant
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.1.94

A combination of site-directed mutagenesis and exon exchange has been used to further define the structure on IgG recognized by monoclonal IgM rheumatoid factors (RFs) from patients with Waldenstrom macroglobulinemia. Most of these RFs bound IgG1, -2, and -4 but not IgG3. For these RFs, His-435 is a critical residue for binding and replacing it with arginine, the residue present in IgG3, destroys or reduces RF binding. However, additional polymorphic sequences in both the heavy-chain constant-region domains (CH) 2 and 3 are important for RF binding. Among the important residues in CH2 are amino acids 252-254 and 309-311, which are conserved among IgG isotypes and comprise two loops of amino acids on the surface of the domain. Therefore, at least three regions, two from CH2 and one from CH3, contribute significantly to the epitope recognized by the RFs. Although this epitope contains many of the same residues as the staphylococcal protein A binding site on IgG, the binding specificities of staphylococcal protein A and monoclonal RFs are not identical. Sera from patients with rheumatoid arthritis contain antibodies directed not only at this epitope but also at other sites on IgG.