• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Dec 20, 1994; 91(26): 12917–12921.

Control of autoantibody affinity by selection against amino acid replacements in the complementarity-determining regions.


Rheumatoid factor (RF) autoantibodies can be produced in healthy individuals after infections or immunizations and thus escape normal tolerization mechanisms. It has not been clear whether such autoantibodies can undergo somatic hypermutation and affinity maturation similar to antibodies to exogenous antigens. We have investigated how these autoantibodies are regulated in normal individuals by analyzing the sequences of monoclonal IgM RFs obtained as hybridomas from donors after immunization. The variable regions undergo extensive hypermutation, but in contrast to antibodies against exogenous antigens, there is a strong selection against mutations that result in replacement of amino acids in the hypervariable, or complementarity-determining, regions. Furthermore, we found no increase in affinity of these RFs with the accumulation of mutations. This suggests that high-affinity variants are tolerized during the hypermutation process and there is a peripheral mechanism operating on certain autoreactive B cells that, while not deleting or anergizing all autoreactive cells, prevents the generation of high-affinity autoantibodies. Comparison of RFs by using the VH1 DP-10 heavy chain variable region segment from both normal individuals and rheumatoid arthritis (RA) patients suggests that RF from RA patients may not be subject to such a controlling mechanism.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Chiller JM, Habicht GS, Weigle WO. Cellular sites of immunologic unresponsiveness. Proc Natl Acad Sci U S A. 1970 Mar;65(3):551–556. [PMC free article] [PubMed]
  • Nemazee D, Buerki K. Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8039–8043. [PMC free article] [PubMed]
  • Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K, et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 1988 Aug 25;334(6184):676–682. [PubMed]
  • Shlomchik MJ, Zharhary D, Saunders T, Camper SA, Weigert MG. A rheumatoid factor transgenic mouse model of autoantibody regulation. Int Immunol. 1993 Oct;5(10):1329–1341. [PubMed]
  • AHO K, WAGER O. Production of anti-antibodies in rabbits. Ann Med Exp Biol Fenn. 1961;39:79–87. [PubMed]
  • Welch MJ, Fong S, Vaughan J, Carson D. Increased frequency of rheumatoid factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Clin Exp Immunol. 1983 Feb;51(2):299–304. [PMC free article] [PubMed]
  • Nemazee DA. Immune complexes can trigger specific, T cell-dependent, autoanti-IgG antibody production in mice. J Exp Med. 1985 Jan 1;161(1):242–256. [PMC free article] [PubMed]
  • Van Snick JL, Van Roost E, Markowetz B, Cambiaso CL, Masson PL. Enhancement by IgM rheumatoid factor of in vitro ingestion by macrophages and in vivo clearance of aggregated IgG or antigen-antibody complexes. Eur J Immunol. 1978 Apr;8(4):279–285. [PubMed]
  • Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med. 1991 Feb 1;173(2):487–489. [PMC free article] [PubMed]
  • Adelstein S, Pritchard-Briscoe H, Anderson TA, Crosbie J, Gammon G, Loblay RH, Basten A, Goodnow CC. Induction of self-tolerance in T cells but not B cells of transgenic mice expressing little self antigen. Science. 1991 Mar 8;251(4998):1223–1225. [PubMed]
  • Bikoff EK. Tolerance for self IG at the level of the Ly1+ T cell. J Exp Med. 1983 Dec 1;158(6):1868–1880. [PMC free article] [PubMed]
  • Bogen B, Dembic Z, Weiss S. Clonal deletion of specific thymocytes by an immunoglobulin idiotype. EMBO J. 1993 Jan;12(1):357–363. [PMC free article] [PubMed]
  • Maizels N, Bothwell A. The T-cell-independent immune response to the hapten NP uses a large repertoire of heavy chain genes. Cell. 1985 Dec;43(3 Pt 2):715–720. [PubMed]
  • Karvelas M, Nossal GJ. Memory cell generation ablated by soluble protein antigen by means of effects on T- and B-lymphocyte compartments. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3150–3154. [PMC free article] [PubMed]
  • Randen I, Thompson KM, Pascual V, Victor K, Beale D, Coadwell J, Førre O, Capra JD, Natvig JB. Rheumatoid factor V genes from patients with rheumatoid arthritis are diverse and show evidence of an antigen-driven response. Immunol Rev. 1992 Aug;128:49–71. [PubMed]
  • Randen I, Brown D, Thompson KM, Hughes-Jones N, Pascual V, Victor K, Capra JD, Førre O, Natvig JB. Clonally related IgM rheumatoid factors undergo affinity maturation in the rheumatoid synovial tissue. J Immunol. 1992 May 15;148(10):3296–3301. [PubMed]
  • Thompson KM, Randen I, Natvig JB, Mageed RA, Jefferis R, Carson DA, Tighe H, Forre O. Human monoclonal rheumatoid factors derived from the polyclonal repertoire of rheumatoid synovial tissue: incidence of cross-reactive idiotopes and expression of VH and V kappa subgroups. Eur J Immunol. 1990 Apr;20(4):863–868. [PubMed]
  • Randen I, Pascual V, Victor K, Thompson KM, Førre O, Capra JD, Natvig JB. Synovial IgG rheumatoid factors show evidence of an antigen-driven immune response and a shift in the V gene repertoire compared to IgM rheumatoid factors. Eur J Immunol. 1993 Jun;23(6):1220–1225. [PubMed]
  • Thompson KM, Hough DW, Maddison PJ, Melamed MD, Hughes-Jones N. The efficient production of stable, human monoclonal antibody-secreting hybridomas from EBV-transformed lymphocytes using the mouse myeloma X63-Ag8.653 as a fusion partner. J Immunol Methods. 1986 Nov 20;94(1-2):7–12. [PubMed]
  • Thompson K, Barden G, Sutherland J, Beldon I, Melamed M. Human monoclonal antibodies to C, c, E, e and G antigens of the Rh system. Immunology. 1990 Nov;71(3):323–327. [PMC free article] [PubMed]
  • Mageed RA, Dearlove M, Goodall DM, Jefferis R. Immunogenic and antigenic epitopes of immunoglobulins. XVII--Monoclonal antibodies reactive with common and restricted idiotopes to the heavy chain of human rheumatoid factors. Rheumatol Int. 1986;6(4):179–183. [PubMed]
  • Crowley JJ, Mageed RA, Silverman GJ, Chen PP, Kozin F, Erger RA, Jefferis R, Carson DA. The incidence of a new human cross-reactive idiotype linked to subgroup VHIII heavy chains. Mol Immunol. 1990 Jan;27(1):87–94. [PubMed]
  • Radoux V, Chen PP, Sorge JA, Carson DA. A conserved human germline V kappa gene directly encodes rheumatoid factor light chains. J Exp Med. 1986 Dec 1;164(6):2119–2124. [PMC free article] [PubMed]
  • Thompson KM, Randen I, Børretzen M, Førre O, Natvig JB. Variable region gene usage of human monoclonal rheumatoid factors derived from healthy donors following immunization. Eur J Immunol. 1994 Aug;24(8):1771–1778. [PubMed]
  • Victor KD, Randen I, Thompson K, Forre O, Natvig JB, Fu SM, Capra JD. Rheumatoid factors isolated from patients with autoimmune disorders are derived from germline genes distinct from those encoding the Wa, Po, and Bla cross-reactive idiotypes. J Clin Invest. 1991 May;87(5):1603–1613. [PMC free article] [PubMed]
  • Perry DJ, Carrell RW. CpG dinucleotides are "hotspots" for mutation in the antithrombin III gene. Twelve variants identified using the polymerase chain reaction. Mol Biol Med. 1989 Jun;6(3):239–243. [PubMed]
  • Chen PP, Liu MF, Glass CA, Sinha S, Kipps TJ, Carson DA. Characterization of two immunoglobulin VH genes that are homologous to human rheumatoid factors. Arthritis Rheum. 1989 Jan;32(1):72–76. [PubMed]
  • Friguet B, Chaffotte AF, Djavadi-Ohaniance L, Goldberg ME. Measurements of the true affinity constant in solution of antigen-antibody complexes by enzyme-linked immunosorbent assay. J Immunol Methods. 1985 Mar 18;77(2):305–319. [PubMed]
  • Tomlinson IM, Walter G, Marks JD, Llewelyn MB, Winter G. The repertoire of human germline VH sequences reveals about fifty groups of VH segments with different hypervariable loops. J Mol Biol. 1992 Oct 5;227(3):776–798. [PubMed]
  • Sasso EH, Willems van Dijk K, Bull AP, Milner EC. A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles. J Clin Invest. 1993 Jun;91(6):2358–2367. [PMC free article] [PubMed]
  • Pascual V, Randen I, Thompson K, Sioud M, Forre O, Natvig J, Capra JD. The complete nucleotide sequences of the heavy chain variable regions of six monospecific rheumatoid factors derived from Epstein-Barr virus-transformed B cells isolated from the synovial tissue of patients with rheumatoid arthritis. Further evidence that some autoantibodies are unmutated copies of germ line genes. J Clin Invest. 1990 Oct;86(4):1320–1328. [PMC free article] [PubMed]
  • Mantovani L, Wilder RL, Casali P. Human rheumatoid B-1a (CD5+ B) cells make somatically hypermutated high affinity IgM rheumatoid factors. J Immunol. 1993 Jul 1;151(1):473–488. [PubMed]
  • Ezaki I, Kanda H, Sakai K, Fukui N, Shingu M, Nobunaga M, Watanabe T. Restricted diversity of the variable region nucleotide sequences of the heavy and light chains of a human rheumatoid factor. Arthritis Rheum. 1991 Mar;34(3):343–350. [PubMed]
  • Youngblood K, Fruchter L, Ding G, Lopez J, Bonagura V, Davidson A. Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated. J Clin Invest. 1994 Feb;93(2):852–861. [PMC free article] [PubMed]
  • Bye JM, Carter C, Cui Y, Gorick BD, Songsivilai S, Winter G, Hughes-Jones NC, Marks JD. Germline variable region gene segment derivation of human monoclonal anti-Rh(D) antibodies. Evidence for affinity maturation by somatic hypermutation and repertoire shift. J Clin Invest. 1992 Dec;90(6):2481–2490. [PMC free article] [PubMed]
  • Huang C, Stollar BD. A majority of Ig H chain cDNA of normal human adult blood lymphocytes resembles cDNA for fetal Ig and natural autoantibodies. J Immunol. 1993 Nov 15;151(10):5290–5300. [PubMed]
  • MacLennan IC, Gray D. Antigen-driven selection of virgin and memory B cells. Immunol Rev. 1986 Jun;91:61–85. [PubMed]
  • Berek C, Ziegner M. The maturation of the immune response. Immunol Today. 1993 Aug;14(8):400–404. [PubMed]
  • Linton PJ, Rudie A, Klinman NR. Tolerance susceptibility of newly generating memory B cells. J Immunol. 1991 Jun 15;146(12):4099–4104. [PubMed]
  • Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. [PubMed]
  • Shlomchik MJ, Marshak-Rothstein A, Wolfowicz CB, Rothstein TL, Weigert MG. The role of clonal selection and somatic mutation in autoimmunity. Nature. 328(6133):805–811. [PubMed]
  • Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. [PubMed]
  • Diamond B, Katz JB, Paul E, Aranow C, Lustgarten D, Scharff MD. The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol. 1992;10:731–757. [PubMed]
  • Jacobson BA, Sharon J, Shan H, Shlomchik M, Weigert MG, Marshak-Rothstein A. An isotype switched and somatically mutated rheumatoid factor clone isolated from a MRL-lpr/lpr mouse exhibits limited intraclonal affinity maturation. J Immunol. 1994 May 1;152(9):4489–4499. [PubMed]
  • Küppers R, Zhao M, Hansmann ML, Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 1993 Dec 15;12(13):4955–4967. [PMC free article] [PubMed]
  • Munthe E, Natvig JB. Immunglobulin classes, subclasses and complexes of IgG rheumatoid factor in rheumatoid plasma cells. Clin Exp Immunol. 1972 Sep;12(1):55–70. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...