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Proc Natl Acad Sci U S A. Jan 1, 1992; 89(1): 94–98.

Monoclonal IgM rheumatoid factors bind IgG at a discontinuous epitope comprised of amino acid loops from heavy-chain constant-region domains 2 and 3.


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.

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  • Winchester RJ, Agnello V, Kunkel HG. Gamma globulin complexes in synovial fluids of patients with rheumatoid arthritis. Partial characterization and relationship to lowered complement levels. Clin Exp Immunol. 1970 May;6(5):689–706. [PMC free article] [PubMed]
  • Hay FC, Nineham LJ, Roitt IM. Routine assay for detection of IgG and IgM antiglobulins in seronegative and seropositive rheumatoid arthritis. Br Med J. 1975 Jul 26;3(5977):203–204. [PMC free article] [PubMed]
  • Masi AT, Maldonado-Cocco JA, Kaplan SB, Feigenbaum SL, Chandler RW. Prospective study of the early course of rheumatoid arthritis in young adults: comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum. 1976 May;4(4):299–326. [PubMed]
  • Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 1971 Mar;50(2):85–95. [PubMed]
  • DRESNER E, TROMBLY P. The latex-fixation reaction in nonrheumatic diseases. N Engl J Med. 1959 Nov 12;261:981–988. [PubMed]
  • Fong S, Chen PP, Vaughan JH, Carson DA. Origin and age-associated changes in the expression of a physiologic autoantibody. Gerontology. 1985;31(4):236–250. [PubMed]
  • Levine PR, Axelrod DA. Rheumatoid factor isotypes following immunization. Clin Exp Rheumatol. 1985 Apr-Jun;3(2):147–149. [PubMed]
  • Van Snick J, Coulie P. Rheumatoid factors and secondary immune responses in the mouse. I. Frequent occurrence of hybridomas secreting IgM anti-IgG1 autoantibodies after immunization with protein antigens. Eur J Immunol. 1983 Nov;13(11):890–894. [PubMed]
  • Morrison SL, Johnson MJ, Herzenberg LA, Oi VT. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6851–6855. [PMC free article] [PubMed]
  • Artandi SE, Canfield SM, Tao MH, Calame KL, Morrison SL, Bonagura VR. Molecular analysis of IgM rheumatoid factor binding to chimeric IgG. J Immunol. 1991 Jan 15;146(2):603–610. [PubMed]
  • Sasso EH, Barber CV, Nardella FA, Yount WJ, Mannik M. Antigenic specificities of human monoclonal and polyclonal IgM rheumatoid factors. The C gamma 2-C gamma 3 interface region contains the major determinants. J Immunol. 1988 May 1;140(9):3098–3107. [PubMed]
  • Nardella FA, Teller DC, Mannik M. Studies on the antigenic determinants in the self-association of IgG rheumatoid factor. J Exp Med. 1981 Jul 1;154(1):112–125. [PMC free article] [PubMed]
  • Nardella FA, Teller DC, Barber CV, Mannik M. IgG rheumatoid factors and staphylococcal protein A bind to a common molecular site on IgG. J Exp Med. 1985 Dec 1;162(6):1811–1824. [PMC free article] [PubMed]
  • Deisenhofer J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochemistry. 1981 Apr 28;20(9):2361–2370. [PubMed]
  • Zoller MJ, Smith M. Oligonucleotide-directed mutagenesis: a simple method using two oligonucleotide primers and a single-stranded DNA template. DNA. 1984 Dec;3(6):479–488. [PubMed]
  • Kunkel TA. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. [PMC free article] [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Wedgwood JF, Hatam L, Bonagura VR. Expression of large quantities of rheumatoid factor major cross-reactive idiotype in the serum of adults with seropositive rheumatoid arthritis. Arthritis Rheum. 1991 Jul;34(7):840–845. [PubMed]
  • Jefferis R, Nik Jaafar MI, Steinitz M. Immunogenic and antigenic epitopes of immunoglobulins. VIII. A human monoclonal rheumatoid factor having specificity for a discontinuous epitope determined by histidine/arginine interchange as residue 435 of immunoglobulin G. Immunol Lett. 1984;7(4):191–194. [PubMed]
  • Laver WG, Air GM, Webster RG, Smith-Gill SJ. Epitopes on protein antigens: misconceptions and realities. Cell. 1990 May 18;61(4):553–556. [PubMed]
  • Amit AG, Mariuzza RA, Phillips SE, Poljak RJ. Three-dimensional structure of an antigen-antibody complex at 2.8 A resolution. Science. 1986 Aug 15;233(4765):747–753. [PubMed]
  • Novotny J, Bruccoleri RE, Saul FA. On the attribution of binding energy in antigen-antibody complexes McPC 603, D1.3, and HyHEL-5. Biochemistry. 1989 May 30;28(11):4735–4749. [PubMed]
  • Bentley GA, Boulot G, Riottot MM, Poljak RJ. Three-dimensional structure of an idiotope-anti-idiotope complex. Nature. 1990 Nov 15;348(6298):254–257. [PubMed]
  • Allen JC, Kunkel HG. Hidden rheumatoid factors with specificity for native gamma globulins. Arthritis Rheum. 1966 Dec;9(6):758–768. [PubMed]
  • Chen PP, Fong S, Carson DA. Rheumatoid factor. Rheum Dis Clin North Am. 1987 Dec;13(3):545–568. [PubMed]
  • Silverman GJ, Goldfien RD, Chen P, Mageed RA, Jefferis R, Goñi F, Frangione B, Fong S, Carson DA. Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans. J Clin Invest. 1988 Aug;82(2):469–475. [PMC free article] [PubMed]
  • Burton DR. Immunoglobulin G: functional sites. Mol Immunol. 1985 Mar;22(3):161–206. [PubMed]
  • Nik Jaafar MI, Lowe JA, Ling NR, Jefferis R. Immunogenic and antigenic epitopes of immunoglobulins--VII. The topographical distribution of Fc gamma epitopes and the relationship of an iso-allotypic specificity to the presence of histidine 435. Mol Immunol. 1984 Feb;21(2):137–143. [PubMed]
  • Clarkson AB, Jr, Mellow GH. Rheumatoid factor-like immunoglobulin M protects previously uninfected rat pups and dams from Trypanosoma lewisi. Science. 1981 Oct 9;214(4517):186–188. [PubMed]
  • Coutinho A, Grandien A, Faro-Rivas J, Mota-Santos TA. Idiotypes, tailors and networks. Ann Inst Pasteur Immunol. 1988 Nov-Dec;139(6):599–607. [PubMed]
  • Naparstek Y, André-Schwartz J, Manser T, Wysocki LJ, Breitman L, Stollar BD, Gefter M, Schwartz RS. A single germline VH gene segment of normal A/J mice encodes autoantibodies characteristic of systemic lupus erythematosus. J Exp Med. 1986 Aug 1;164(2):614–626. [PMC free article] [PubMed]
  • Fong S, Chen PP, Gilbertson TA, Weber JR, Fox RI, Carson DA. Expression of three cross-reactive idiotypes on rheumatoid factor autoantibodies from patients with autoimmune diseases and seropositive adults. J Immunol. 1986 Jul 1;137(1):122–128. [PubMed]
  • Huck S, Fort P, Crawford DH, Lefranc MP, Lefranc G. Sequence of a human immunoglobulin gamma 3 heavy chain constant region gene: comparison with the other human C gamma genes. Nucleic Acids Res. 1986 Feb 25;14(4):1779–1789. [PMC free article] [PubMed]

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