Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Sep 1;174(3):525–537. doi: 10.1084/jem.174.3.525

The role of clonal selection in the pathogenesis of an autoreactive human B cell lymphoma

PMCID: PMC2118944  PMID: 1908508

Abstract

To study the association of autoimmunity and human B cell neoplasia, we have established a model of a B cell lymphoma which expresses a pathogenic autoantibody of defined specificity. The Ig VH gene expressed in this neoplasm was analyzed longitudinally using clinical specimens taken from the splenic lymphoma (S) at diagnosis and from lymph node relapses 3 and 4 yr later (N3 and N4). Southern analysis and oligonucleotide hybridization experiments demonstrated that clonally related predominant and minor tumor cell populations were present in S at diagnosis, and that the minor population became the predominant population in the relapse specimens, N3 and N4. Although the Ig specificity and idiotype were the same at diagnosis and at both relapses, analysis of the expressed VH gene sequences showed 14 base changes between S and N3, and 2 further changes at N4. Little sequence heterogeneity was observed at each sampling time, indicating that the ongoing mutation frequency was low. The relevant germline precursor VH gene was determined from autologous germline DNA and compared to the expressed genes. Based on the pattern of shared and unshared mutations, we were able to establish the genealogic relationship of the germline VH gene and the expressed clonotypes of S, N3 and N4. Taken together, the findings from Southern blotting, oligonucleotide hybridization, and sequence analysis permit us to describe a molecular aspect of tumor progression, "clonotypic shift", wherein subpopulations of the malignant clone, marked by different V gene clonotypes, emerge and predominate at different time points in the evolution of the lymphoma. Furthermore, the sequential and nonrandom pattern of the VH mutations, correlated with the observed conservation of autospecificity and idiotype, implies that clonal selection may have influenced the pathogenesis of the lymphoma.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arnold A., Cossman J., Bakhshi A., Jaffe E. S., Waldmann T. A., Korsmeyer S. J. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med. 1983 Dec 29;309(26):1593–1599. doi: 10.1056/NEJM198312293092601. [DOI] [PubMed] [Google Scholar]
  2. Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carroll W. L., Yu M., Link M. P., Korsmeyer S. J. Absence of Ig V region gene somatic hypermutation in advanced Burkitt's lymphoma. J Immunol. 1989 Jul 15;143(2):692–698. [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. Clarke S. H., Huppi K., Ruezinsky D., Staudt L., Gerhard W., Weigert M. Inter- and intraclonal diversity in the antibody response to influenza hemagglutinin. J Exp Med. 1985 Apr 1;161(4):687–704. doi: 10.1084/jem.161.4.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cleary M. L., Chao J., Warnke R., Sklar J. Immunoglobulin gene rearrangement as a diagnostic criterion of B-cell lymphoma. Proc Natl Acad Sci U S A. 1984 Jan;81(2):593–597. doi: 10.1073/pnas.81.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cleary M. L., Galili N., Trela M., Levy R., Sklar J. Single cell origin of bigenotypic and biphenotypic B cell proliferations in human follicular lymphomas. J Exp Med. 1988 Feb 1;167(2):582–597. doi: 10.1084/jem.167.2.582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coleclough C., Cooper D., Perry R. P. Rearrangement of immunoglobulin heavy chain genes during B-lymphocyte development as revealed by studies of mouse plasmacytoma cells. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1422–1426. doi: 10.1073/pnas.77.3.1422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Crews S., Griffin J., Huang H., Calame K., Hood L. A single VH gene segment encodes the immune response to phosphorylcholine: somatic mutation is correlated with the class of the antibody. Cell. 1981 Jul;25(1):59–66. doi: 10.1016/0092-8674(81)90231-2. [DOI] [PubMed] [Google Scholar]
  10. Croce C. M., Shander M., Martinis J., Cicurel L., D'Ancona G. G., Dolby T. W., Koprowski H. Chromosomal location of the genes for human immunoglobulin heavy chains. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3416–3419. doi: 10.1073/pnas.76.7.3416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Downing J. R., Grossi C. E., Smedberg C. T., Burrows P. D. Diffuse large cell lymphoma in a patient with hairy cell leukemia: immunoglobulin gene analysis reveals separate clonal origins. Blood. 1986 Mar;67(3):739–744. [PubMed] [Google Scholar]
  13. Erikson J., Finan J., Nowell P. C., Croce C. M. Translocation of immunoglobulin VH genes in Burkitt lymphoma. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5611–5615. doi: 10.1073/pnas.79.18.5611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ersbøll J., Schultz H. B., Pedersen-Bjergaard J., Nissen N. I. Follicular low-grade non-Hodgkin's lymphoma: long-term outcome with or without tumor progression. Eur J Haematol. 1989 Feb;42(2):155–163. doi: 10.1111/j.1600-0609.1989.tb01205.x. [DOI] [PubMed] [Google Scholar]
  15. Hamblin T. J., Oscier D. G., Young B. J. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol. 1986 Jul;39(7):713–716. doi: 10.1136/jcp.39.7.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hayakawa K., Hardy R. R. Murine CD4+ T cell subsets defined. J Exp Med. 1988 Nov 1;168(5):1825–1838. doi: 10.1084/jem.168.5.1825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hieter P. A., Maizel J. V., Jr, Leder P. Evolution of human immunoglobulin kappa J region genes. J Biol Chem. 1982 Feb 10;257(3):1516–1522. [PubMed] [Google Scholar]
  18. Jefferies L. C., Stevenson F. K., Goldman J., Bennett I. M., Spitalnik S. L., Silberstein L. E. Anti-idiotypic antibodies specific for a pathologic anti-Pr2 cold agglutinin. Transfusion. 1990 Jul-Aug;30(6):495–502. doi: 10.1046/j.1537-2995.1990.30690333478.x. [DOI] [PubMed] [Google Scholar]
  19. Jukes T. H., King J. L. Evolutionary nucleotide replacements in DNA. Nature. 1979 Oct 18;281(5732):605–606. doi: 10.1038/281605a0. [DOI] [PubMed] [Google Scholar]
  20. Kon S., Levy S., Levy R. Retention of an idiotypic determinant in a human B-cell lymphoma undergoing immunoglobulin variable-region mutation. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5053–5057. doi: 10.1073/pnas.84.14.5053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Levy S., Mendel E., Kon S. A rapid method for cloning and sequencing variable-region genes of expressed immunoglobulins. Gene. 1987;54(2-3):167–173. doi: 10.1016/0378-1119(87)90484-7. [DOI] [PubMed] [Google Scholar]
  22. Maizels N. Diversity achieved by diverse mechanisms: gene conversion in developing B cells of the chicken. Cell. 1987 Feb 13;48(3):359–360. doi: 10.1016/0092-8674(87)90439-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Manser T. Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte. J Exp Med. 1989 Oct 1;170(4):1211–1230. doi: 10.1084/jem.170.4.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Matsuda F., Lee K. H., Nakai S., Sato T., Kodaira M., Zong S. Q., Ohno H., Fukuhara S., Honjo T. Dispersed localization of D segments in the human immunoglobulin heavy-chain locus. EMBO J. 1988 Apr;7(4):1047–1051. doi: 10.1002/j.1460-2075.1988.tb02912.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McKean D., Huppi K., Bell M., Staudt L., Gerhard W., Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 1984 May;81(10):3180–3184. doi: 10.1073/pnas.81.10.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Miller D. G. The association of immune disease and malignant lymphoma. Ann Intern Med. 1967 Mar;66(3):507–521. doi: 10.7326/0003-4819-66-3-507. [DOI] [PubMed] [Google Scholar]
  27. Miyamura K., Osada H., Yamauchi T., Itoh M., Kodera Y., Suchi T., Takahashi T., Ueda R. Single clonal origin of neoplastic B-cells with different immunoglobulin light chains in a patient with Richter's syndrome. Cancer. 1990 Jul 1;66(1):140–144. doi: 10.1002/1097-0142(19900701)66:1<140::aid-cncr2820660125>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  28. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer. 1982 May 15;49(10):2112–2135. doi: 10.1002/1097-0142(19820515)49:10<2112::aid-cncr2820491024>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  29. Nowell P. C. Chromosomal and molecular clues to tumor progression. Semin Oncol. 1989 Apr;16(2):116–127. [PubMed] [Google Scholar]
  30. Oste C. Polymerase chain reaction. Biotechniques. 1988 Feb;6(2):162–167. [PubMed] [Google Scholar]
  31. Pirofsky B. Autoimmune hemolytic anemia and neoplasia of the reticuloendothelium. With a hypothesis concerning etiologic relationships. Ann Intern Med. 1968 Jan;68(1):109–121. doi: 10.7326/0003-4819-68-1-109. [DOI] [PubMed] [Google Scholar]
  32. Rajewsky K., Förster I., Cumano A. Evolutionary and somatic selection of the antibody repertoire in the mouse. Science. 1987 Nov 20;238(4830):1088–1094. doi: 10.1126/science.3317826. [DOI] [PubMed] [Google Scholar]
  33. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  34. Riordan J. R., Deuchars K., Kartner N., Alon N., Trent J., Ling V. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. 1985 Aug 29-Sep 4Nature. 316(6031):817–819. doi: 10.1038/316817a0. [DOI] [PubMed] [Google Scholar]
  35. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Early restriction of the human antibody repertoire. Science. 1987 Nov 6;238(4828):791–793. doi: 10.1126/science.3118465. [DOI] [PubMed] [Google Scholar]
  37. Schroeder H. W., Jr, Walter M. A., Hofker M. H., Ebens A., Willems van Dijk K., Liao L. C., Cox D. W., Milner E. C., Perlmutter R. M. Physical linkage of a human immunoglobulin heavy chain variable region gene segment to diversity and joining region elements. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8196–8200. doi: 10.1073/pnas.85.21.8196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schultz H. B., Ersbøll J., Hougaard P. Prognostic significance of architectural patterns in non-Hodgkin lymphomas. Scand J Haematol. 1985 Sep;35(3):270–283. doi: 10.1111/j.1600-0609.1985.tb01706.x. [DOI] [PubMed] [Google Scholar]
  39. Scotto K. W., Biedler J. L., Melera P. W. Amplification and expression of genes associated with multidrug resistance in mammalian cells. Science. 1986 May 9;232(4751):751–755. doi: 10.1126/science.2421411. [DOI] [PubMed] [Google Scholar]
  40. Shlomchik M. J., Aucoin A. H., Pisetsky D. S., Weigert M. G. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9150–9154. doi: 10.1073/pnas.84.24.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Silberstein L. E., Goldman J., Kant J. A., Spitalnik S. L. Comparative biochemical and genetic characterization of clonally related human B-cell lines secreting pathogenic anti-Pr2 cold agglutinins. Arch Biochem Biophys. 1988 Jul;264(1):244–252. doi: 10.1016/0003-9861(88)90591-7. [DOI] [PubMed] [Google Scholar]
  42. Silberstein L. E., Robertson G. A., Harris A. C., Moreau L., Besa E., Nowell P. C. Etiologic aspects of cold agglutinin disease: evidence for cytogenetically defined clones of lymphoid cells and the demonstration that an anti-Pr cold autoantibody is derived from a chromosomally aberrant B cell clone. Blood. 1986 Jun;67(6):1705–1709. [PubMed] [Google Scholar]
  43. Siminovitch K. A., Jensen J. P., Epstein A. L., Korsmeyer S. J. Immunoglobulin gene rearrangements and expression in diffuse histiocytic lymphomas reveal cellular lineage, molecular defects, and sites of chromosomal translocation. Blood. 1986 Feb;67(2):391–397. [PubMed] [Google Scholar]
  44. Tindall K. R., Kunkel T. A. Fidelity of DNA synthesis by the Thermus aquaticus DNA polymerase. Biochemistry. 1988 Aug 9;27(16):6008–6013. doi: 10.1021/bi00416a027. [DOI] [PubMed] [Google Scholar]
  45. Weill J. C., Reynaud C. A. The chicken B cell compartment. Science. 1987 Nov 20;238(4830):1094–1098. doi: 10.1126/science.3317827. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES