Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation

doi:10.1084/jem.171.1.265

This Article

	Full Text (PDF, 1713K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Shlomchik, M.
	Articles by Weigert, M.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Shlomchik, M.
	Articles by Weigert, M.


Social Bookmarking

	What's this?

ARTICLES

Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation

M Shlomchik, M Mascelli, H Shan, MZ Radic, D Pisetsky, A Marshak-Rothstein and M Weigert
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.

The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti- DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti- idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Makdasi, E., Fischel, R., Kat, I., Eilat, D. (2009). Autoreactive Anti-DNA Transgenic B Cells in Lupus-Prone New Zealand Black/New Zealand White Mice Show Near Perfect L Chain Allelic Exclusion. J. Immunol. 182: 6143-6148 [Abstract] [Full Text]
Guth, A, Detanico, T, Smith, D, Tung, K., Bonorino, C, Wysocki, L. (2009). Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3. Lupus 18: 299-308 [Abstract]
Mortensen, E. S., Rekvig, O. P. (2009). Nephritogenic Potential of Anti-DNA Antibodies against Necrotic Nucleosomes. J. Am. Soc. Nephrol. 20: 696-704 [Abstract] [Full Text]
Nakajima, P. B., Kiefer, K., Price, A., Bosma, G. C., Bosma, M. J. (2009). Two Distinct Populations of H Chain-Edited B Cells Show Differential Surrogate L Chain Dependence. J. Immunol. 182: 3583-3596 [Abstract] [Full Text]
Ota, T., Aoki-Ota, M., Tsunoda, K., Nishikawa, T., Koyasu, S., Amagai, M. (2008). Autoreactive B-cell elimination by pathogenic IgG specific for the same antigen: implications for peripheral tolerance. Int Immunol 20: 1351-1360 [Abstract] [Full Text]
Radic, M. (2008). Tracking and Trapping Somatic Mutations in Ig Genes. J. Immunol. 180: 5763-5764 [Full Text]
Kang, H.-K., Liu, M., Datta, S. K. (2007). Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells. J. Immunol. 178: 7849-7858 [Abstract] [Full Text]
Jiang, C., Foley, J., Clayton, N., Kissling, G., Jokinen, M., Herbert, R., Diaz, M. (2007). Abrogation of Lupus Nephritis in Activation-Induced Deaminase-Deficient MRL/lpr Mice. J. Immunol. 178: 7422-7431 [Abstract] [Full Text]
Qian, Y., Diaz, L. A., Ye, J., Clarke, S. H. (2007). Dissecting the Anti-Desmoglein Autoreactive B Cell Repertoire in Pemphigus Vulgaris Patients. J. Immunol. 178: 5982-5990 [Abstract] [Full Text]
Hondowicz, B. D., Alexander, S. T., Quinn, W. J. III, Pagan, A. J., Metzgar, M. H., Cancro, M. P., Erikson, J. (2007). The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. Int Immunol 19: 465-475 [Abstract] [Full Text]
Tuominen, A., Miller, Y. I., Hansen, L. F., Kesaniemi, Y. A., Witztum, J. L., Horkko, S. (2006). A Natural Antibody to Oxidized Cardiolipin Binds to Oxidized Low-Density Lipoprotein, Apoptotic Cells, and Atherosclerotic Lesions. Arterioscler. Thromb. Vasc. Bio. 26: 2096-2102 [Abstract] [Full Text]
Watson, L. C., Moffatt-Blue, C. S., McDonald, R. Z., Kompfner, E., Ait-Azzouzene, D., Nemazee, D., Theofilopoulos, A. N., Kono, D. H., Feeney, A. J. (2006). Paucity of V-D-D-J Rearrangements and VH Replacement Events in Lupus Prone and Nonautoimmune TdT-/- and TdT+/+ Mice. J. Immunol. 177: 1120-1128 [Abstract] [Full Text]
Witsch, E. J., Cao, H., Fukuyama, H., Weigert, M. (2006). Light chain editing generates polyreactive antibodies in chronic graft-versus-host reaction. JEM 203: 1761-1772 [Abstract] [Full Text]
Beaudette-Zlatanova, B. C., Ling, T., Shlomchik, M. J., Marshak-Rothstein, A., Rifkin, I. R. (2006). B Cells and Dendritic Cells from V{kappa}8 Light Chain Transgenic Mice Activate MRL-lpr/gld CD4+ T Cells. J. Immunol. 177: 45-52 [Abstract] [Full Text]
Ippolito, G. C., Schelonka, R. L., Zemlin, M., Ivanov, I. I., Kobayashi, R., Zemlin, C., Gartland, G. L., Nitschke, L., Pelkonen, J., Fujihashi, K., Rajewsky, K., Schroeder, H. W. Jr. (2006). Forced usage of positively charged amino acids in immunoglobulin CDR-H3 impairs B cell development and antibody production. JEM 203: 1567-1578 [Abstract] [Full Text]
Chen, C., Li, H., Tian, Q., Beardall, M., Xu, Y., Casanova, N., Weigert, M. (2006). Selection of Anti-Double-Stranded DNA B Cells in Autoimmune MRL-lpr/lpr Mice. J. Immunol. 176: 5183-5190 [Abstract] [Full Text]
Qiao, B., Wu, J., Chu, Y. W., Wang, Y., Wang, D. P., Wu, H. S., Xiong, S. D. (2005). Induction of systemic lupus erythematosus-like syndrome in syngeneic mice by immunization with activated lymphocyte-derived DNA. Rheumatology (Oxford) 44: 1108-1114 [Abstract] [Full Text]
Guo, W., Smith, D., Guth, A., Aviszus, K., Wysocki, L. J. (2005). T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse. J. Immunol. 175: 2184-2190 [Abstract] [Full Text]
Woodward, E. J., Thomas, J. W. (2005). Multiple Germline {kappa} Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice. J. Immunol. 175: 1073-1079 [Abstract] [Full Text]
Ivanov, I. I., Schelonka, R. L., Zhuang, Y., Gartland, G. L., Zemlin, M., Schroeder, H. W. Jr. (2005). Development of the Expressed Ig CDR-H3 Repertoire Is Marked by Focusing of Constraints in Length, Amino Acid Use, and Charge That Are First Established in Early B Cell Progenitors. J. Immunol. 174: 7773-7780 [Abstract] [Full Text]
Grimaldi, C. M., Hicks, R., Diamond, B. (2005). B Cell Selection and Susceptibility to Autoimmunity. J. Immunol. 174: 1775-1781 [Abstract] [Full Text]
Koefoed, K., Ditzel, H. J. (2004). Identification of talin head domain as an immunodominant epitope of the antiplatelet antibody response in patients with HIV-1-associated thrombocytopenia. Blood 104: 4054-4062 [Abstract] [Full Text]
Wardemann, H., Hammersen, J., Nussenzweig, M. C. (2004). Human Autoantibody Silencing by Immunoglobulin Light Chains. JEM 200: 191-199 [Abstract] [Full Text]
Sekine, H., Watanabe, H., Gilkeson, G. S. (2004). Enrichment of Anti-Glomerular Antigen Antibody-Producing Cells in the Kidneys of MRL/MpJ-Faslpr Mice. J. Immunol. 172: 3913-3921 [Abstract] [Full Text]
Liang, Z., Xie, C., Chen, C., Kreska, D., Hsu, K., Li, L., Zhou, X. J., Mohan, C. (2004). Pathogenic Profiles and Molecular Signatures of Antinuclear Autoantibodies Rescued from NZM2410 Lupus Mice. JEM 199: 381-398 [Abstract] [Full Text]
Caricchio, R., McPhie, L., Cohen, P. L. (2003). Ultraviolet B Radiation-Induced Cell Death: Critical Role of Ultraviolet Dose in Inflammation and Lupus Autoantigen Redistribution. J. Immunol. 171: 5778-5786 [Abstract] [Full Text]
Guth, A. M., Zhang, X., Smith, D., Detanico, T., Wysocki, L. J. (2003). Chromatin Specificity of Anti-Double-Stranded DNA Antibodies and a Role for Arg Residues in the Third Complementarity-Determining Region of the Heavy Chain. J. Immunol. 171: 6260-6266 [Abstract] [Full Text]
Martin, D. A., Bradl, H., Collins, T. J., Roth, E., Jack, H.-M., Wu, G. E. (2003). Selection of Ig {micro} Heavy Chains by Complementarity-Determining Region 3 Length and Amino Acid Composition. J. Immunol. 171: 4663-4671 [Abstract] [Full Text]
Liang, Z., Chen, C., Mohan, C. (2003). Molecular Signatures of Anti-nuclear Antibodies: Contributions of Specific Light Chain Residues and a Novel New Zealand Black V{kappa}1 Germline Gene. J. Immunol. 171: 3886-3894 [Abstract] [Full Text]
Satoh, M., Mizutani, A., Behney, K. M., Kuroda, Y., Akaogi, J., Yoshida, H., Nacionales, D. C., Hirakata, M., Ono, N., Reeves, W. H. (2003). X-linked immunodeficient mice spontaneously produce lupus-related anti-RNA helicase A autoantibodies, but are resistant to pristane-induced lupus. Int Immunol 15: 1117-1124 [Abstract] [Full Text]
Sekiguchi, D. R., Eisenberg, R. A., Weigert, M. (2003). Secondary Heavy Chain Rearrangement: A Mechanism for Generating Anti-double-stranded DNA B Cells. JEM 197: 27-39 [Abstract] [Full Text]
Li, Y., Li, H., Ni, D., Weigert, M. (2002). Anti-DNA B Cells in MRL/lpr Mice Show Altered Differentiation and Editing Pattern. JEM 196: 1543-1552 [Abstract] [Full Text]
William, J., Euler, C., Christensen, S., Shlomchik, M. J. (2002). Evolution of Autoantibody Responses via Somatic Hypermutation Outside of Germinal Centers. Science 297: 2066-2070 [Abstract] [Full Text]
Roark, J. H., Bussel, J. B., Cines, D. B., Siegel, D. L. (2002). Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 100: 1388-1398 [Abstract] [Full Text]
Kuroki, A., Kuroda, Y., Kikuchi, S., Lajaunias, F., Fulpius, T., Pastore, Y., Fossati-Jimack, L., Reininger, L., Toda, T., Nakata, M., Kojima, N., Mizuochi, T., Izui, S. (2002). Level of galactosylation determines cryoglobulin activity of murine IgG3 monoclonal rheumatoid factor. Blood 99: 2922-2928 [Abstract] [Full Text]
Ferri, C, Zignego, A L, Pileri, S A (2002). Cryoglobulins. J. Clin. Pathol. 55: 4-13 [Abstract] [Full Text]
Kompfner, E., Oliveira, P., Montalbano, A., Feeney, A. J. (2001). Unusual Germline DSP2 Gene Accounts for All Apparent V-D-D-J Rearrangements in Newborn, But Not Adult, MRL Mice. J. Immunol. 167: 6933-6938 [Abstract] [Full Text]
Wellmann, U., Letz, M., Schneider, A., Amann, K., Winkler, T. H. (2001). An Ig {micro}-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice. Int Immunol 13: 1461-1469 [Abstract] [Full Text]
Sun, J., Takahashi, N., Kakinuma, H., Nishi, Y. (2001). Molecular Evolution of Catalytic Antibodies in Autoimmune Mice. J. Immunol. 167: 5775-5785 [Abstract] [Full Text]
Feeney, A. J., Lawson, B. R., Kono, D. H., Theofilopoulos, A. N. (2001). Terminal Deoxynucleotidyl Transferase Deficiency Decreases Autoimmune Disease in MRL-Faslpr Mice. J. Immunol. 167: 3486-3493 [Abstract] [Full Text]
Grimaldi, C. M., Michael, D. J., Diamond, B. (2001). Cutting Edge: Expansion and Activation of A Population of Autoreactive Marginal Zone B Cells in a Model of Estrogen-Induced Lupus. J. Immunol. 167: 1886-1890 [Abstract] [Full Text]
Zhang, X., Smith, D. S., Guth, A., Wysocki, L. J. (2001). A Receptor Presentation Hypothesis for T Cell Help That Recruits Autoreactive B Cells. J. Immunol. 166: 1562-1571 [Abstract] [Full Text]
Khalil, M., Inaba, K., Steinman, R., Ravetch, J., Diamond, B. (2001). T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus. J. Immunol. 166: 1667-1674 [Abstract] [Full Text]
Reed, A. J., Riley, M. P., Caton, A. J. (2000). Virus-Induced Maturation and Activation of Autoreactive Memory B Cells. JEM 192: 1763-1774 [Abstract] [Full Text]
Klonowski, K. D., Monestier, M. (2000). Heavy Chain Revision in MRL Mice: A Potential Mechanism for the Development of Autoreactive B Cell Precursors. J. Immunol. 165: 4487-4493 [Abstract] [Full Text]
Jethwa, H. S., Clarke, S. H., Itoh-Lindstrom, Y., Falk, R. J., Jennette, J. C., Nachman, P. H. (2000). Restriction in V{kappa} Gene Use and Antigen Selection in Anti-Myeloperoxidase Response in Mice. J. Immunol. 165: 3890-3897 [Abstract] [Full Text]
Wilson, P. C., Wilson, K., Liu, Y.-J., Banchereau, J., Pascual, V., Capra, J. D. (2000). Receptor Revision of Immunoglobulin Heavy Chain Variable Region Genes in Normal Human B Lymphocytes. JEM 191: 1881-1894 [Abstract] [Full Text]
Eaton-Bassiri, A. S., Mandik-Nayak, L., Seo, S.-j., Madaio, M. P., Cancro, M. P., Erikson, J. (2000). Alterations in splenic architecture and the localization of anti-double-stranded DNA B cells in aged mice. Int Immunol 12: 915-926 [Abstract] [Full Text]
Putterman, C., Deocharan, B., Diamond, B. (2000). Molecular Analysis of the Autoantibody Response in Peptide-Induced Autoimmunity. J. Immunol. 164: 2542-2549 [Abstract] [Full Text]
Lossos, I. S., Okada, C. Y., Tibshirani, R., Warnke, R., Vose, J. M., Greiner, T. C., Levy, R. (2000). Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas. Blood 95: 1797-1803 [Abstract] [Full Text]
Mandik-Nayak, L., Seo, S.-j., Eaton-Bassiri, A., Allman, D., Hardy, R. R., Erikson, J. (2000). Functional Consequences of the Developmental Arrest and Follicular Exclusion of Anti-Double-Stranded DNA B Cells. J. Immunol. 164: 1161-1168 [Abstract] [Full Text]
Stoll, M. L., Gavalchin, J. (2000). Systemic lupus erythematosus--messages from experimental models. Rheumatology (Oxford) 39: 18-27 [Full Text]
Fossati-Jimack, L., Reininger, L., Chicheportiche, Y., Clynes, R., Ravetch, J. V., Honjo, T., Izui, S. (1999). High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia. JEM 190: 1689-1696 [Abstract] [Full Text]
Brard, F., Shannon, M., Prak, E. L., Litwin, S., Weigert, M. (1999). Somatic Mutation and Light Chain Rearrangement Generate Autoimmunity in Anti-Single-Stranded DNA Transgenic Mrl/lpr Mice. JEM 190: 691-704 [Abstract] [Full Text]
Wang, H., Shlomchik, M. J. (1999). Autoantigen-Specific B Cell Activation in FAS-Deficient Rheumatoid Factor Immunoglobulin Transgenic Mice. JEM 190: 639-650 [Abstract] [Full Text]
Seery, J. P., Wang, E. C. Y., Cattell, V., Carroll, J. M., Owen, M. J., Watt, F. M. (1999). A Central Role for {alpha}{beta} T Cells in the Pathogenesis of Murine Lupus. J. Immunol. 162: 7241-7248 [Abstract] [Full Text]
Shinde, S., Gee, R., Santulli-Marotto, S., Bockenstedt, L. K., Clarke, S. H., Mamula, M. J. (1999). T Cell Autoimmunity in Ig Transgenic Mice. J. Immunol. 162: 7519-7524 [Abstract] [Full Text]
Mandik-Nayak, L., Seo, S.-j., Sokol, C., Potts, K. M., Bui, A., Erikson, J. (1999). MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti-double-stranded DNA B Cells. JEM 189: 1799-1814 [Abstract] [Full Text]
Noorchashm, H., Bui, A., Li, H.-L., Eaton, A., Mandik-Nayak, L., Sokol, C., Potts, K. M., Pure, E., Erikson, J. (1999). Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process. Int Immunol 11: 765-776 [Abstract] [Full Text]
O'Keefe, T. L., Williams, G. T., Batista, F. D., Neuberger, M. S. (1999). Deficiency in CD22, a B Cell-specific Inhibitory Receptor, Is Sufficient to Predispose to Development of High Affinity Autoantibodies. JEM 189: 1307-1313 [Abstract] [Full Text]
Whitcomb, E. A., Haines, B. B., Parmelee, A. P., Pearlman, A. M., Brodeur, P. H. (1999). Germline Structure and Differential Utilization of Igha and Ighb VH10 Genes. J. Immunol. 162: 1541-1550 [Abstract] [Full Text]
Klonowski, K. D., Primiano, L. L., Monestier, M. (1999). Atypical VH-D-JH Rearrangements in Newborn Autoimmune MRL Mice. J. Immunol. 162: 1566-1572 [Abstract] [Full Text]
Kretz-Rommel, A., Rubin, R. L. (1999). Persistence of Autoreactive T Cell Drive Is Required to Elicit Anti-Chromatin Antibodies in a Murine Model of Drug-Induced Lupus. J. Immunol. 162: 813-820 [Abstract] [Full Text]
Conde, C., Weller, S., Gilfillan, S., Marcellin, L., Martin, T., Pasquali, J.-L. (1998). Terminal Deoxynucleotidyl Transferase Deficiency Reduces the Incidence of Autoimmune Nephritis in (New Zealand Black New Zealand White)F1 Mice. J. Immunol. 161: 7023-7030 [Abstract] [Full Text]
Pewzner-Jung, Y., Friedmann, D., Sonoda, E., Jung, S., Rajewsky, K., Eilat, D. (1998). B Cell Deletion, Anergy, and Receptor Editing in ""Knock In"" Mice Targeted with a Germline-Encoded or Somatically Mutated Anti-DNA Heavy Chain. J. Immunol. 161: 4634-4645 [Abstract] [Full Text]
Hahn, B H, Singh, R R, Ebling, F M (1998). Self Ig peptides that help anti-DNA antibody production: importance of charged residues. Lupus 7: 307-313 [Abstract]
Wang, H., Shlomchik, M. J. (1998). Maternal Ig Mediates Neonatal Tolerance in Rheumatoid Factor Transgenic Mice but Tolerance Breaks Down in Adult Mice. J. Immunol. 160: 2263-2271 [Abstract] [Full Text]
Chan, O., J. Shlomchik, M. (1998). A New Role for B Cells in Systemic Autoimmunity: B Cells Promote Spontaneous T Cell Activation in MRL-lpr/lpr Mice. J. Immunol. 160: 51-59 [Abstract] [Full Text]
Mandik-Nayak, L., Bui, A., Noorchashm, H., Eaton, A., Erikson, J. (1997). Regulation of Anti-double-stranded DNA B Cells in Nonautoimmune Mice: Localization to the T-B Interface of the Splenic Follicle. JEM 186: 1257-1267 [Abstract] [Full Text]
Isenberg, D.A., Ravirajan, C.T., Rahman, A., Kalsi, J. (1997). The role of antibodies to DNA in systemic lupus erythematosus-- A review and introduction to an international workshop on DNA antibodies held in London, May 1996. Lupus 6: 290-304
Waisman, A., Ruiz, P.J., Mozes, E. (1996). Review : Variable regions of two murine antibodies that bind the SLE associated 16/6 idiotype. Lupus 5: 279-287 [Abstract]
Komissarov, A. A., Calcutt, M. J., Marchbank, M. T., Peletskaya, E. N., Deutscher, S. L. (1996). Equilibrium Binding Studies of Recombinant Anti-single-stranded DNA Fab. J. Biol. Chem. 271: 12241-12246 [Abstract] [Full Text]
Kalsi, J.K., Martin, A.C.R., Isenberg, D.A. (1995). Structure-Function Relationships of Anti-DNA Antibodies. Lupus 4: 245-248
Green, L.M., LaBue, M., Lazarus, J.P., Colburn, K.K. (1995). Characterization of autoimmune thyroiditis in MRL-lpr/lpr mice. Lupus 4: 187-196 [Abstract]
Kieber-Emmons, T., Von Feldt, J. M., Godillot, A. P., McCallus, D., Srikantan, V., Weiner, D. B., Williams, W. V. (1994). Isolated VH4 Heavy Chain Variable Regions Bind DNA Characterization of a Recombinant Antibody Heavy Chain Library Derived from Patient(s) with Active SLE. Lupus 3: 379-392 [Abstract]
Koike, T. (1994). Anticardiolipin Antibodies in NZW x BXSB F1 Mice. Lupus 3: 241-246
Winkler, T.H., Kalden, J.R. (1994). Origin of Anti-DNA Autoantibodies in SLE. Lupus 3: 75-76
Watts, R.A., Hillson, J.L., Oppliger, I.R., Mackenzie, L., Lydyard, P.M., Mackworth Young, C.G., Brown, C., Staines, N.A., Isenberg, D.A. (1991). Sequence Analysis and Idiotypic Relationships of BEG-2, a Human Fetal Antibody Reactive with DNA. Lupus 1: 9-17 [Abstract]