Abstract
We have analysed the heavy and light chain variable region genes of two monoclonal antibodies, specific for the Sm antigen (RSP1; IgG kappa) and for cardiolipin (RSP4; IgM lambda), derived from a patient with active systemic lupus erythematosus (SLE). We have established that the variable region genes of the RSP1 autoantibody are somatic mutants of two germ line genes from the VH4 and V kappa 1 gene families. RSP4 antibody uses gene segments closely related to a VH3 gene member and to a V lambda 1 gene. The presence and distribution of the somatic mutations on both monoclonal autoantibodies are compatible with an antigen-driven immune process. These data suggest that in SLE a common antigenic stimulus may govern the autoantibody response against a wide spectrum of unrelated antigens, including native DNA, cardiolipin or Sm antigens, and provide further evidence that disease-associated autoantibodies are generated through antigen-selected somatic mutations.
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- Berek C., Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987 Apr;96:23–41. doi: 10.1111/j.1600-065x.1987.tb00507.x. [DOI] [PubMed] [Google Scholar]
- 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]
- Bernard F., Chuchana P., Frippiat J. P., Buluwela L., Lefranc M. P. Genomic sequence of IGLV1S2, a human immunoglobulin variable lambda gene belonging to subgroup I. Nucleic Acids Res. 1990 Dec 11;18(23):7139–7139. doi: 10.1093/nar/18.23.7139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bloom D. D., Davignon J. L., Retter M. W., Shlomchik M. J., Pisetsky D. S., Cohen P. L., Eisenberg R. A., Clarke S. H. V region gene analysis of anti-Sm hybridomas from MRL/Mp-lpr/lpr mice. J Immunol. 1993 Feb 15;150(4):1591–1610. [PubMed] [Google Scholar]
- Brendel V., Dohlman J., Blaisdell B. E., Karlin S. Very long charge runs in systemic lupus erythematosus-associated autoantigens. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1536–1540. doi: 10.1073/pnas.88.4.1536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chastagner P., Demaison C., Thèze J., Zouali M. Clonotypic dominance and variable gene elements of pathogenic anti-DNA autoantibodies from a single patient with lupus. Scand J Immunol. 1994 Feb;39(2):165–178. doi: 10.1111/j.1365-3083.1994.tb03356.x. [DOI] [PubMed] [Google Scholar]
- Chothia C., Lesk A. M. Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol. 1987 Aug 20;196(4):901–917. doi: 10.1016/0022-2836(87)90412-8. [DOI] [PubMed] [Google Scholar]
- Chothia C., Lesk A. M., Gherardi E., Tomlinson I. M., Walter G., Marks J. D., Llewelyn M. B., Winter G. Structural repertoire of the human VH segments. J Mol Biol. 1992 Oct 5;227(3):799–817. doi: 10.1016/0022-2836(92)90224-8. [DOI] [PubMed] [Google Scholar]
- Chothia C., Lesk A. M., Tramontano A., Levitt M., Smith-Gill S. J., Air G., Sheriff S., Padlan E. A., Davies D., Tulip W. R. Conformations of immunoglobulin hypervariable regions. Nature. 1989 Dec 21;342(6252):877–883. doi: 10.1038/342877a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Desiderio S. V., Yancopoulos G. D., Paskind M., Thomas E., Boss M. A., Landau N., Alt F. W., Baltimore D. Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature. 1984 Oct 25;311(5988):752–755. doi: 10.1038/311752a0. [DOI] [PubMed] [Google Scholar]
- Diamond B., Katz J. B., Paul E., Aranow C., Lustgarten D., Scharff M. D. The role of somatic mutation in the pathogenic anti-DNA response. Annu Rev Immunol. 1992;10:731–757. doi: 10.1146/annurev.iy.10.040192.003503. [DOI] [PubMed] [Google Scholar]
- Ebling F. M., Hahn B. H. Pathogenic subsets of antibodies to DNA. Int Rev Immunol. 1989;5(1):79–95. doi: 10.3109/08830188909086990. [DOI] [PubMed] [Google Scholar]
- Eisenberg R. A., Craven S. Y., Cohen P. L. Isotype progression and clonality of anti-Sm autoantibodies in MRL/Mp-lpr/lpr mice. J Immunol. 1987 Aug 1;139(3):728–733. [PubMed] [Google Scholar]
- Eisenberg R. A., Craven S. Y., Warren R. W., Cohen P. L. Stochastic control of anti-Sm autoantibodies in MRL/Mp-lpr/lpr mice. J Clin Invest. 1987 Sep;80(3):691–697. doi: 10.1172/JCI113123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Foster M. H., Cizman B., Madaio M. P. Nephritogenic autoantibodies in systemic lupus erythematosus: immunochemical properties, mechanisms of immune deposition, and genetic origins. Lab Invest. 1993 Nov;69(5):494–507. [PubMed] [Google Scholar]
- Hope T. J., Aguilera R. J., Minie M. E., Sakano H. Endonucleolytic activity that cleaves immunoglobulin recombination sequences. Science. 1986 Mar 7;231(4742):1141–1145. doi: 10.1126/science.3003919. [DOI] [PubMed] [Google Scholar]
- Isenberg D. A., Ehrenstein M. R., Longhurst C., Kalsi J. K. The origin, sequence, structure, and consequences of developing anti-DNA antibodies. A human perspective. Arthritis Rheum. 1994 Feb;37(2):169–180. doi: 10.1002/art.1780370204. [DOI] [PubMed] [Google Scholar]
- Keeling D. M., Wilson A. J., Mackie I. J., Isenberg D. A., Machin S. J. Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro. J Clin Pathol. 1993 Oct;46(10):908–911. doi: 10.1136/jcp.46.10.908. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mackworth-Young C. Antiphospholipid antibodies: more than just a disease marker? Immunol Today. 1990 Feb;11(2):60–65. doi: 10.1016/0167-5699(90)90020-a. [DOI] [PubMed] [Google Scholar]
- Manheimer-Lory A., Katz J. B., Pillinger M., Ghossein C., Smith A., Diamond B. Molecular characteristics of antibodies bearing an anti-DNA-associated idiotype. J Exp Med. 1991 Dec 1;174(6):1639–1652. doi: 10.1084/jem.174.6.1639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mohan C., Adams S., Stanik V., Datta S. K. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med. 1993 May 1;177(5):1367–1381. doi: 10.1084/jem.177.5.1367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ohosone Y., Mimori T., Griffith A., Akizuki M., Homma M., Craft J., Hardin J. A. Molecular cloning of cDNA encoding Sm autoantigen: derivation of a cDNA for a B polypeptide of the U series of small nuclear ribonucleoprotein particles. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4249–4253. doi: 10.1073/pnas.86.11.4249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rada C., Gupta S. K., Gherardi E., Milstein C. Mutation and selection during the secondary response to 2-phenyloxazolone. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5508–5512. doi: 10.1073/pnas.88.13.5508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Ravirajan C. T., Kalsi J., Wiloch H. W., Barakat S., Tuaillon N., Irvine W., Cockayne A., Harris A., Williams D. G., Williams W. Antigen-binding diversity of human hybridoma autoantibodies derived from splenocytes of patients with SLE. Lupus. 1992 May;1(3):157–165. doi: 10.1177/096120339200100307. [DOI] [PubMed] [Google Scholar]
- Reichlin M., Martin A., Taylor-Albert E., Tsuzaka K., Zhang W., Reichlin M. W., Koren E., Ebling F. M., Tsao B., Hahn B. H. Lupus autoantibodies to native DNA cross-react with the A and D SnRNP polypeptides. J Clin Invest. 1994 Jan;93(1):443–449. doi: 10.1172/JCI116980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanz I., Dang H., Takei M., Talal N., Capra J. D. VH sequence of a human anti-Sm autoantibody. Evidence that autoantibodies can be unmutated copies of germline genes. J Immunol. 1989 Feb 1;142(3):883–887. [PubMed] [Google Scholar]
- 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]
- Schwartz R. S., Stollar B. D. Origins of anti-DNA autoantibodies. J Clin Invest. 1985 Feb;75(2):321–327. doi: 10.1172/JCI111704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott M. G., Crimmins D. L., McCourt D. W., Chung G., Schäble K. F., Thiebe R., Quenzel E. M., Zachau H. G., Nahm M. H. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. IV. The less frequently expressed VL are heterogeneous. J Immunol. 1991 Dec 1;147(11):4007–4013. [PubMed] [Google Scholar]
- Suzuki N., Harada T., Mizushima Y., Sakane T. Possible pathogenic role of cationic anti-DNA autoantibodies in the development of nephritis in patients with systemic lupus erythematosus. J Immunol. 1993 Jul 15;151(2):1128–1136. [PubMed] [Google Scholar]
- Tomlinson I. M., Walter G., Marks J. D., Llewelyn M. B., 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. doi: 10.1016/0022-2836(92)90223-7. [DOI] [PubMed] [Google Scholar]
- Van Es J. H., Aanstoot H., Gmelig-Meyling F. H., Derksen R. H., Logtenberg T. A human systemic lupus erythematosus-related anti-cardiolipin/single-stranded DNA autoantibody is encoded by a somatically mutated variant of the developmentally restricted 51P1 VH gene. J Immunol. 1992 Sep 15;149(6):2234–2240. [PubMed] [Google Scholar]
- Winkler T. H., Fehr H., Kalden J. R. Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas. Eur J Immunol. 1992 Jul;22(7):1719–1728. doi: 10.1002/eji.1830220709. [DOI] [PubMed] [Google Scholar]
- Wise J. A. Guides to the heart of the spliceosome. Science. 1993 Dec 24;262(5142):1978–1979. doi: 10.1126/science.8266091. [DOI] [PubMed] [Google Scholar]
- Zouali M., Madaio M. P., Canoso R. T., Stollar B. D. Restriction fragment length polymorphism analysis of the V kappa locus in human lupus. Eur J Immunol. 1989 Sep;19(9):1757–1760. doi: 10.1002/eji.1830190934. [DOI] [PubMed] [Google Scholar]
- van Es J. H., Gmelig Meyling F. H., van de Akker W. R., Aanstoot H., Derksen R. H., Logtenberg T. Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus. J Exp Med. 1991 Feb 1;173(2):461–470. doi: 10.1084/jem.173.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]