Skip to main content
Top

19-11-2015 | Systemic lupus erythematosus | Review | Article

Anti-DNA antibodies — quintessential biomarkers of SLE

Journal: Nature Reviews Rheumatology

Author: David S. Pisetsky

Author: David S. Pisetsky

Publisher: Nature Publishing Group UK

Abstract

Antibodies that recognize and bind to DNA (anti-DNA antibodies) are serological hallmarks of systemic lupus erythematosus (SLE) and key markers for diagnosis and disease activity. In addition to common use in the clinic, anti-DNA antibody testing now also determines eligibility for clinical trials, raising important questions about the nature of the antibody–antigen interaction. At present, no 'gold standard' for serological assessment exists, and anti-DNA antibody binding can be measured with a variety of assay formats, which differ in the nature of the DNA substrates and in the conditions for binding and detection of antibodies. A mechanism called monogamous bivalency — in which high avidity results from simultaneous interaction of IgG Fab sites with a single polynucleotide chain — determines anti-DNA antibody binding; this mechanism might affect antibody detection in different assay formats. Although anti-DNA antibodies can promote pathogenesis by depositing in the kidney or driving cytokine production, they are not all alike, pathologically, and anti-DNA antibody expression does not necessarily correlate with active disease. Levels of anti-DNA antibodies in patients with SLE can vary over time, distinguishing anti-DNA antibodies from other pathogenic antinuclear antibodies. Elucidation of the binding specificities and the pathogenic roles of anti-DNA antibodies in SLE should enable improvements in the design of informative assays for both clinical and research purposes.

Nat Rev Rheumatol 2016;12:102–110. doi:10.1038/nrrheum.2015.151

Literature
1.
Hahn, B. H. Antibodies to DNA. N. Engl. J. Med. 338, 1359–1368 (1998).PubMedCrossRef
2.
Jang, Y. J. & Stollar, B. D. Anti-DNA antibodies: aspects of structure and pathogenicity. Cell. Mol. Life Sci. 60, 309–320 (2003).PubMedCrossRef
3.
Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).PubMedCrossRef
4.
Breden, F. et al. Comparison of antibody repertoires produced by HIV-1 infection, other chronic and acute infections, and systemic autoimmune disease. PLoS ONE 6, e16857 (2011).PubMedPubMedCentralCrossRef
5.
Dörner, T., Giesecke, C. & Lipsky, P. E. Mechanisms of B cell autoimmunity in SLE. Arthritis Res. Ther. 13, 243 (2011).PubMedPubMedCentralCrossRef
6.
Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).PubMedPubMedCentralCrossRef
7.
van Vollenhoven, R. F. et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann. Rheum. Dis. 71, 1343–1349 (2012).PubMedCrossRef
8.
Egner, W. The use of laboratory tests in the diagnosis of SLE. J. Clin. Pathol. 53, 424–432 (2000).PubMedPubMedCentralCrossRef
9.
Rekvig, O. P. The anti-DNA antibody: origin and impact, dogmas and controversies. Nat. Rev. Rheumatol. 11, 530–540 (2015).PubMedCrossRef
10.
Ceppellini, R., Polli, E. & Celada, F. A DNA-reacting factor in serum of a patient with lupus erythematosus diffusus. Proc. Soc. Exp. Biol. Med. 96, 572–574 (1957).PubMedCrossRef
11.
Miescher, P. & Strassle, R. New serological methods for the detection of the L.E. factor. Vox Sang. 2, 283–287 (1957).PubMedCrossRef
12.
Robbins, W. C., Holman, H. R., Deicher, H. & Kunkel, H. G. Complement fixation with cell nuclei and DNA in lupus erythematosus. Proc. Soc. Exp. Biol. Med. 96, 575–579 (1957).PubMedCrossRef
13.
Seligmann, M. [Demonstration in the blood of patients with disseminated lupus erythematosus a substance determining a precipitation reaction with desoxyribonucleic acid][French]. C. R. Hebd. Seances Acad. Sci. 245, 243–245 (1957).PubMed
14.
Stollar, B. D. & Papalian, M. Secondary structure in denatured DNA is responsible for its reaction with antinative DNA antibodies of systemic lupus erythematosus sera. J. Clin. Invest. 66, 210–219 (1980).PubMedPubMedCentralCrossRef
15.
Pisetsky, D. S. Standardization of anti-DNA antibody assays. Immunol. Res. 56, 420–424 (2013).PubMedCrossRef
16.
Stollar, B. D. The specificity and applications of antibodies to helical nucleic acids. CRC Crit. Rev. Biochem. 3, 45–69 (1975).PubMedCrossRef
17.
van Steensel, B. Chromatin: constructing the big picture. EMBO J. 30, 1885–1895 (2011).PubMedPubMedCentralCrossRef
18.
Khorasanizadeh, S. The nucleosome: from genomic organization to genomic regulation. Cell 116, 259–272 (2004).PubMedCrossRef
19.
Choy, J. S. & Lee, T. H. Structural dynamics of nucleosomes at single-molecule resolution. Trends Biochem. Sci. 37, 425–435 (2012).PubMedPubMedCentralCrossRef
20.
Grootscholten, C. et al. A prospective study of anti-chromatin and anti-C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/methylprednisolone. Ann. Rheum. Dis. 66, 693–696 (2007).PubMedCrossRef
21.
Bigler, C. et al. Antinucleosome antibodies as a marker of active proliferative lupus nephritis. Am. J. Kidney Dis. 51, 624–629 (2008).PubMedCrossRef
22.
Mehra, S. & Fritzler, M. J. The spectrum of anti-chromatin/nucleosome autoantibodies: independent and interdependent biomarkers of disease. J. Immunol. Res. 2014, 368274 (2014).PubMedPubMedCentralCrossRef
23.
Rekvig, O. P., van der Vlag, J. & Seredkina, N. Review: antinucleosome antibodies: a critical reflection on their specificities and diagnostic impact. Arthritis Rheumatol. 66, 1061–1069 (2014).PubMedCrossRef
24.
Li, T. et al. Anti-nucleosome antibodies outperform traditional biomarkers as longitudinal indicators of disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 54, 449–457 (2015).CrossRef
25.
Burlingame, R. W., Rubin, R. L., Balderas, R. S. & Theofilopoulos, A. N. Genesis and evolution of antichromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. J. Clin. Invest. 91, 1687–1696 (1993).PubMedPubMedCentralCrossRef
26.
Burlingame, R. W., Boey, M. L., Starkebaum, G. & Rubin, R. L. The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J. Clin. Invest. 94, 184–192 (1994).PubMedPubMedCentralCrossRef
27.
Jahr, S. et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 61, 1659–1665 (2001).PubMed
28.
Jiang, N., Reich, C. F. 3rd & Pisetsky, D. S. Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells. Blood 102, 2243–2250 (2003).PubMedCrossRef
29.
Tsang, J. C. & Lo, Y. M. Circulating nucleic acids in plasma/serum. Pathology 39, 197–207 (2007).PubMedCrossRef
30.
Schwarzenbach, H., Hoon, D. S. & Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. Cancer 11, 426–437 (2011).PubMedCrossRef
31.
Pisetsky, D. S. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin. Immunol. 144, 32–40 (2012).PubMedPubMedCentralCrossRef
32.
Pisetsky, D. S. The translocation of nuclear molecules during inflammation and cell death. Antioxid. Redox Signal. 20, 1117–1125 (2014).PubMedPubMedCentralCrossRef
33.
Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015).PubMedCrossRef
34.
Nyström, S. et al. TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis. EMBO J. 32, 86–99 (2013).PubMedCrossRef
35.
Yang, H., Antoine, D. J., Andersson, U. & Tracey, K. J. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J. Leukoc. Biol. 93, 865–873 (2013).PubMedPubMedCentralCrossRef
36.
Pisetsky, D. S. The complex role of DNA, histones and HMGB1 in the pathogenesis of SLE. Autoimmunity 47, 487–493 (2014).PubMedPubMedCentralCrossRef
37.
Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011).PubMedCrossRef
38.
Leffler, J. et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J. Immunol. 188, 3522–3531 (2012).PubMedCrossRef
39.
Atamaniuk, J. et al. Analysing cell-free plasma DNA and SLE disease activity. Eur. J. Clin. Invest. 41, 579–583 (2011).PubMedCrossRef
40.
Zhang, S. et al. Elevated plasma cfDNA may be associated with active lupus nephritis and partially attributed to abnormal regulation of neutrophil extracellular traps (NETs) in patients with systemic lupus erythematosus. Intern. Med. 53, 2763–2771 (2014).PubMedCrossRef
41.
Ullal, A. J. et al. Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus. J. Autoimmun. 36, 173–180 (2011).PubMedCrossRef
42.
Nielsen, C. T. et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum. 64, 1227–1236 (2012).PubMedCrossRef
43.
Petri, M. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 64, 2677–2686 (2012).PubMedPubMedCentralCrossRef
44.
Rekvig, O. P. Anti-dsDNA antibodies as a classification criterion and a diagnostic marker for systemic lupus erythematosus: critical remarks. Clin. Exp. Immunol. 179, 5–10 (2015).PubMedCrossRef
45.
Ward, M. M., Pisetsky, D. S. & Christenson, V. D. Antidouble stranded DNA antibody assays in systemic lupus erythematosus: correlations of longitudinal antibody measurements. J. Rheumatol. 16, 609–613 (1989).PubMed
46.
Venner, A. A. et al. Comparison of three anti-dsDNA assays: performance and correlation with systemic lupus erythematosus disease activity. Clin. Biochem. 46, 317–320 (2013).PubMedCrossRef
47.
Enocsson, H. et al. Four anti-dsDNA antibody assays in relation to systemic lupus erythematosus disease specificity and activity. J. Rheumatol. 42, 817–825 (2015).PubMedCrossRef
48.
Arden, L. A., Lakmaker, F. & Feltkamp, T. E. Immunology of DNA. II. The effect of size and structure of the antigen on the Farr assay. J. Immunol. Methods 10, 39–48 (1976).PubMedCrossRef
49.
Hillebrand, J. J., Bernelot Moens, H. J. & Mulder, A. H. Changes in Farr radioimmunoassay and EliA fluorescence immunoassay anti-dsDNA in relation to exacerbation of SLE. Lupus 22, 1169–1173 (2013).PubMedCrossRef
50.
Crothers, D. M. & Metzger, H. The influence of polyvalency on the binding properties of antibodies. Immunochemistry 9, 341–357 (1972).PubMedCrossRef
51.
Romans, D. G., Tilley, C. A. & Dorrington, K. J. Monogamous bivalency of IgG antibodies. I. Deficiency of branched ABHI-active oligosaccharide chains on red cells of infants causes the weak antiglobulin reactions in hemolytic disease of the newborn due to ABO incompatibility. J. Immunol. 124, 2807–2811 (1980).PubMed
52.
Kaufman, E. N. & Jain, R. K. Effect of bivalent interaction upon apparent antibody affinity: experimental confirmation of theory using fluorescence photobleaching and implications for antibody binding assays. Cancer Res. 52, 4157–4167 (1992).PubMed
53.
Werner, T. C., Bunting, J. R. & Cathou, R. E. The shape of immunoglobulin G molecules in solution. Proc. Natl Acad. Sci. USA 69, 795–799 (1972).PubMedPubMedCentralCrossRef
54.
Papalian, M., Lafer, E., Wong, R. & Stollar, B. D. Reaction of systemic lupus erythematosus antinative DNA antibodies with native DNA fragments from 20 to 1,200 base pairs. J. Clin. Invest. 65, 469–477 (1980).PubMedPubMedCentralCrossRef
55.
Ali, R., Dersimonian, H. & Stollar, B. D. Binding of monoclonal anti-native DNA autoantibodies to DNA of varying size and conformation. Mol. Immunol. 22, 1415–1422 (1985).PubMedCrossRef
56.
Pisetsky, D. S. & Reich, C. F. The influence of DNA size on the binding of anti-DNA antibodies in the solid and fluid phase. Clin. Immunol. Immunopathol. 72, 350–356 (1994).PubMedCrossRef
57.
Lennek, R., Baldwin, A. S. Jr, Waller, S. J., Morley, K. W. & Taylor, R. P. Studies of the physical biochemistry and complement-fixing properties of DNA/anti-DNA immune complexes. J. Immunol. 127, 602–608 (1981).PubMed
58.
Waller, S. J., Taylor, R. P., Wright, E. L., Morley, K. W. & Johns, M. DNA/anti-DNA complexes: correlation of size and complement fixation. Arthritis Rheum. 24, 651–657 (1981).PubMedCrossRef
59.
Radic, M. Z. et al. Residues that mediate DNA binding of autoimmune antibodies. J. Immunol. 150, 4966–4977 (1993).PubMed
60.
Radic, M. Z. & Weigert, M. Genetic and structural evidence for antigen selection of anti-DNA antibodies. Ann. Rev. Immunol. 12, 487–520 (1994).CrossRef
61.
Li, Z., Schettino, E. W., Padlan, E. A., Ikematsu, H. & Casali, P. Structure-function analysis of a lupus anti-DNA autoantibody: central role of the heavy chain complementarity-determining region 3 Arg in binding of double- and single-stranded DNA. Eur. J. Immunol. 30, 2015–2026 (2000).PubMedPubMedCentralCrossRef
62.
Zhang, J., Jacobi, A. M., Wang, T. & Diamond, B. Pathogenic autoantibodies in systemic lupus erythematosus are derived from both self-reactive and non-self-reactive B cells. Mol. Med. 14, 675–681 (2008).PubMedPubMedCentralCrossRef
63.
Richardson, C. et al. Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. J. Immunol. 191, 4926–4939 (2013).PubMedPubMedCentralCrossRef
64.
Schroeder, K., Herrmann, M. & Winkler, T. H. The role of somatic hypermutation in the generation of pathogenic antibodies in SLE. Autoimmunity 46, 121–127 (2013).PubMedCrossRef
65.
Mohan, C., Adams, S., Stanik, V. & Datta, S. K. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J. Exp. Med. 177, 1367–1381 (1993).PubMedCrossRef
66.
Kaliyaperumal, A., Mohan, C., Wu, W. & Datta, S. K. Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J. Exp. Med. 183, 2459–2469 (1996).PubMedCrossRef
67.
Sano, H. & Morimoto, C. DNA isolated from DNA/anti-DNA antibody immune complexes in systemic lupus erythematosus is rich in guanine-cytosine content. J. Immunol. 128, 1341–1345 (1982).PubMed
68.
Rumore, P. M. & Steinman, C. R. Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J. Clin. Invest. 86, 69–74 (1990).PubMedPubMedCentralCrossRef
69.
Chan, R. W. et al. Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing. Proc. Natl Acad. Sci. USA 111, E5302–E5311 (2014).PubMedPubMedCentral
70.
Sano, H. et al. Binding properties of human anti-DNA antibodies to cloned human DNA fragments. Scand. J. Immunol. 30, 51–63 (1989).PubMedCrossRef
71.
Uccellini, M. B., Busto, P., Debatis, M., Marshak-Rothstein, A. & Viglianti, G. A. Selective binding of anti-DNA antibodies to native dsDNA fragments of differing sequence. Immunol. Lett. 143, 85–91 (2012).PubMedPubMedCentralCrossRef
72.
Karounos, D. G., Grudier, J. P. & Pisetsky, D. S. Spontaneous expression of antibodies to DNA of various species origin in sera of normal subjects and patients with systemic lupus erythematosus. J. Immunol. 140, 451–455 (1988).PubMed
73.
Robertson, C. R., Gilkeson, G. S., Ward, M. M. & Pisetsky, D. S. Patterns of heavy and light chain utilization in the antibody response to single-stranded bacterial DNA in normal human subjects and patients with systemic lupus erythematosus. Clin. Immunol. Immunopathol. 62, 25–32 (1992).PubMedCrossRef
74.
Bunyard, M. P. & Pisetsky, D. S. Characterization of antibodies to bacterial double-stranded DNA in the sera of normal human subjects. Int. Arch. Allergy Immunol. 105, 122–127 (1994).PubMedCrossRef
75.
Fredriksen, K., Skogsholm, A., Flaegstad, T., Traavik, T. & Rekvig, O. P. Antibodies to dsDNA are produced during primary BK virus infection in man, indicating that anti-dsDNA antibodies may be related to virus replication in vivo. Scand. J. Immunol. 38, 401–406 (1993).PubMedCrossRef
76.
Fredriksen, K., Osei, A., Sundsfjord, A., Traavik, T. & Rekvig, O. P. On the biological origin of anti-double-stranded (ds) DNA antibodies: systemic lupus erythematosus-related anti-dsDNA antibodies are induced by polyomavirus BK in lupus-prone (NZBxNZW) F1 hybrids, but not in normal mice. Eur. J. Immunol. 24, 66–70 (1994).PubMedCrossRef
77.
Pisetsky, D. S. & Drayton, D. M. Deficient expression of antibodies specific for bacterial DNA by patients with systemic lupus erythematosus. Proc. Assoc. Am. Physicians 109, 237–244 (1997).PubMed
78.
Hamilton, K. J., Schett, G., Reich, C. F. 3rd, Smolen, J. S. & Pisetsky, D. S. The binding of sera of patients with SLE to bacterial and mammalian DNA. Clin. Immunol. 118, 209–218 (2006).PubMedCrossRef
79.
Wang, X., Stearns, N. A., Li, X. & Pisetsky, D. S. The effect of polyamines on the binding of anti-DNA antibodies from patients with SLE and normal human subjects. Clin. Immunol. 153, 94–103 (2014).PubMedPubMedCentralCrossRef
80.
Koffler, D., Agnello, V., Thoburn, R. & Kunkel, H. G. Systemic lupus erythematosus: prototype of immune complex nephritis in man. J. Exp. Med. 134, 169–179 (1971).PubMedPubMedCentralCrossRef
81.
Bruneau, C. & Benveniste, J. Circulating DNA:anti-DNA complexes in systemic lupus erythematosus. Detection and characterization by ultracentrifugation. J. Clin. Invest. 64, 191–198 (1979).PubMedPubMedCentralCrossRef
82.
Morimoto, C., Sano, H., Abe, T., Homma, M. & Steinberg, A. D. Correlation between clinical activity of systemic lupus erythematosus and the amounts of DNA in DNA/anti-DNA antibody immune complexes. J. Immunol. 129, 1960–1965 (1982).PubMed
83.
Tron, F., Letarte, J., Roque-Antunes Barreira, M. C. & Lesavre, P. Specific detection of circulating DNA:anti-DNA immune complexes in human systemic lupus erythematosus sera using murine monoclonal anti-DNA antibody. Clin. Exp. Immunol. 49, 481–487 (1982).PubMedPubMedCentral
84.
Bengtsson, A., Nezlin, R., Shoenfeld, Y. & Sturfelt, G. DNA levels in circulating immune complexes decrease at severe SLE flares-correlation with complement component C1q. J. Autoimmun. 13, 111–119 (1999).PubMedCrossRef
85.
Seredkina, N., Van Der Vlag, J., Berden, J., Mortensen, E. & Rekvig, O. P. Lupus nephritis: enigmas, conflicting models and an emerging concept. Mol. Med. 19, 161–169 (2013).PubMedPubMedCentralCrossRef
86.
Krishnan, M. R., Wang, C. & Marion, T. N. Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice. Kidney Int. 82, 184–192 (2012).PubMedPubMedCentralCrossRef
87.
Bruschi, M. et al. Glomerular autoimmune multicomponents of human lupus nephritis in vivo (2): planted antigens. J. Am. Soc. Nephrol. 26, 1905–1924 (2014).PubMedPubMedCentralCrossRef
88.
Kalaaji, M., Mortensen, E., Jørgensen, L., Olsen, R. & Rekvig, O. P. Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells. Am. J. Pathol. 168, 1779–1792 (2006).PubMedPubMedCentralCrossRef
89.
Mjelle, J. E., Kalaaji, M. & Rekvig, O. P. Exposure of chromatin and not high affinity for dsDNA determines the nephritogenic impact of anti-dsDNA antibodies in (NZBxNZW)F1 mice. Autoimmunity 42, 104–111 (2009).PubMedCrossRef
90.
Zykova, S. N., Tveita, A. A. & Rekvig, O. P. Renal DNase1 enzyme activity and protein expression is selectively shut down in murine and human membranoproliferative lupus nephritis. PLoS ONE 5, e12096 (2010).PubMedPubMedCentralCrossRef
91.
Seredkina, N. & Rekvig, O. P. Acquired loss of renal nuclease activity is restricted to DNaseI and is an organ-selective feature in murine lupus nephritis. Am. J. Pathol. 179, 1120–1128 (2011).PubMedPubMedCentralCrossRef
92.
Vallin, H., Perers, A., Alm, G. V. & Rönnblom, L. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J. Immunol. 163, 6306–6313 (1999).PubMed
93.
Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).PubMedCrossRef
94.
Boulé, M. W. et al. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).PubMedPubMedCentralCrossRef
95.
Atianand, M. K. & Fitzgerald, K. A. Molecular basis of DNA recognition in the immune system. J. Immunol. 190, 1911–1918 (2013).PubMedCrossRef
96.
Bhat, N. & Fitzgerald, K. A. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur. J. Immunol. 44, 634–640 (2014).PubMedPubMedCentralCrossRef
97.
Hua, J., Kirou, K., Lee, C. & Crow, M. K. Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum. 54, 1906–1916 (2006).PubMedCrossRef
98.
Eloranta, M. L. et al. Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis Rheum. 60, 2418–2427 (2009).PubMedCrossRef
99.
DeGiorgio, L. A. et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193 (2001).PubMedCrossRef
100.
Kowal, C. et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl Acad. Sci. USA 103, 19854–19859 (2006).PubMedPubMedCentralCrossRef
101.
Mostoslavsky, G. et al. Lupus anti-DNA autoantibodies cross-react with a glomerular structural protein: a case for tissue injury by molecular mimicry. Eur. J. Immunol. 31, 1221–1227 (2001).PubMedCrossRef
102.
Zhao, Z. et al. Cross-reactivity of human lupus anti-DNA antibodies with alpha-actinin and nephritogenic potential. Arthritis Rheum. 52, 522–530 (2005).PubMedCrossRef
103.
Manson, J. J. et al. Relationship between anti-dsDNA, anti-nucleosome and anti-alpha-actinin antibodies and markers of renal disease in patients with lupus nephritis: a prospective longitudinal study. Arthritis Res. Ther. 11, R154 (2009).PubMedPubMedCentralCrossRef
104.
Steiman, A. J. et al. Anti-dsDNA and antichromatin antibody isotypes in serologically active clinically quiescent systemic lupus erythematosus. J. Rheumatol. 42, 810–816 (2015).PubMedCrossRef
105.
Mannik, M., Merrill, C. E., Stamps, L. D. & Wener, M. H. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus. J. Rheumatol. 30, 1495–1504 (2003).PubMed
106.
Xie, C., Liang, Z., Chang, S. & Mohan, C. Use of a novel elution regimen reveals the dominance of polyreactive antinuclear autoantibodies in lupus kidneys. Arthritis Rheum. 48, 2343–2352 (2003).PubMedCrossRef
107.
Leffler, J., Bengtsson, A. A. & Blom, A. M. The complement system in systemic lupus erythematosus: an update. Ann. Rheum. Dis. 73, 1601–1606 (2014).PubMedCrossRef
108.
Putterman, C. et al. Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements. Lupus Sci. Med. 1, e000056 (2014).PubMedPubMedCentralCrossRef
109.
Nielsen, C. T., Østergaard, O., Johnsen, C., Jacobsen, S. & Heegaard, N. H. Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus. Arthritis Rheum. 63, 3067–3077 (2011).PubMedCrossRef
110.
Nielsen, C. T. et al. Galectin-3 binding protein links circulating microparticles with electron dense glomerular deposits in lupus nephritis. Lupus 24, 1150–1160 (2015).PubMedCrossRef
111.
McCarty, G. A., Rice, J. R., Bembe, M. L. & Pisetsky, D. S. Independent expression of autoantibodies in systemic lupus erythematosus. J. Rheumatol. 9, 691–695 (1982).PubMed
112.
Wahren, M. et al. Ro/SS-A and La/SS-B antibody level variation in patients with Sjögren's syndrome and systemic lupus erythematosus. J. Autoimmun. 11, 29–38 (1998).PubMedCrossRef
113.
Hassan, A. B., Lundberg, I. E., Isenberg, D. & Wahren-Herlenius, M. Serial analysis of Ro/SSA and La/SSB antibody levels and correlation with clinical disease activity in patients with systemic lupus erythematosus. Scand. J. Rheumatol. 31, 133–139 (2002).PubMedCrossRef
114.
Pisetsky, D. S., Grammer, A. C., Ning, T. C. & Lipsky, P. E. Are autoantibodies the targets of B-cell-directed therapy? Nat. Rev. Rheumatol. 7, 551–556 (2011).PubMedCrossRef
115.
Mathsson, L., Ahlin, E., Sjöwall, C., Skogh, T. & Rönnelid, J. Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjogren's syndrome A antibodies. Clin. Exp. Immunol. 147, 513–520 (2007).PubMedPubMedCentralCrossRef
116.
Ahlin, E. et al. Autoantibodies associated with RNA are more enriched than anti-dsDNA antibodies in circulating immune complexes in SLE. Lupus 21, 586–595 (2012).PubMedCrossRef