DNA and RNA autoantigens as autoadjuvants

Abstract

AM14 B cells are a prototype for those low affinity autoreactive B cells that routinely mature as naïve cells in peripheral lymphoid tissues. These cells express a transgene-encoded receptor specific for IgG2a and can be effectively activated by immune complexes that incorporate either mammalian DNA or mammalian RNA that has been released from dead or dying cells. Activation depends on the ability of the B-cell receptor to deliver antigen to an internal vesicular compartment containing either Toll-like receptor-9 (TLR9) or TLR7. Since TLR9 and TLR7 are thought to recognize microbial DNA and RNA preferentially, it is important to determine under what conditions mammalian DNA and RNA become effective TLR ligands, and whether the determining factor is delivery or structure. This issue has been addressed by using IgG2a mAbs to deliver immune complexes preloaded with defined fragments of DNA or RNA, or by using modified ODNs/ORNs. The data demonstrate that only certain nucleic acid sequences or structures can induce autoreactive B-cell proliferation, even when delivery to the appropriate TLR compartment is facilitated by uptake through the B-cell receptor (BCR).

Keywords

Autoantibodies DNA/RNA-associated autoantigens inflammation Toll-like receptors systemic autoimmune disease

References

Lovgren T. , Eloranta ML , Bave U. , Alm GV , Ronnblom L. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 2004; 50: 1861—1872.

Banchereau J. , Pascual V. , Palucka AK Autoimmunity through cytokine-induced dendritic cell activation. Immunity 2004; 20: 539—550.

Leadbetter EA , Rifkin IR , Hohlbaum AM et al. Chromatin-IgG complexes activate autoreactive B cells by dual engagement of sIgM and Toll-like receptors. Nature 2002; 416: 603—607.

Lau CM , Broughton C. , Tabor AS et al. RNA-associated autoantigens activate B cells by combined BCR/Toll-like receptor 7 engagement. J Exp Med 2005; 202: 1171—1177.

Viglianti GA , Lau CM , Hanley TM et al. Activation of autoreactive B cells by CpG dsDNA. Immunity 2003; 19: 837—847.

Barton GM , Kagan JC , Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 2006; 7: 49—56.

Collins LV , Hajizadeh S. , Holme E. , Jonsson IM , Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol 2004; 75: 995—1000.

Busconi L. et al. Oxidized guanine present in DNA oligonucleotides activates antigen presenting cells through a TLR9-dependent mechanism. 2006; Submitted for publication.

Christensen SR , Kashgarian M. , Alexopoulou L. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 2005; 202: 312—331.

10.

Wu X. , Peng SL Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 2006; 54: 336—342.

11.

Hemmi H. , Takeuchi O. , Kawai T. et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408: 740—745.

12.

Marshak-Rothstein A. , Busconi L. , Lau CM et al. Comparison of CpG s-ODNs, chromatin immune complexes, and dsDNA fragment immune complexes in the TLR9-dependent activation of rheumatoid factor B cells. J Endotoxin Res 2004; 10: 247—251.

13.

Tabeta K. , Hoebe K. , Janssen EM et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 2006; 7: 156—164.

14.

Monestier M. , Novick KE Specificities and genetic characteristics of nucleosome-reactive antibodies from autoimmune mice. Mol Immunol 1996; 33: 89—99.

15.

Eilat D. , Fischel R. Recurrent utilization of genetic elements in V regions of antinucleic acid antibodies from autoimmune mice. J Immunol 1991; 147: 361—368.

16.

Heil F. , Hemmi H. , Hochrein H. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 2004; 303: 1526—1529.

17.

Diebold SS , Kaisho T. , Hemmi H. , Akira S. , Reis E. Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004; 303: 1529—1531.

18.

Vollmer J. , Tluk S. , Schmitz C. et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs induce innate immunity through Toll-like receptors 7 and 8. J Exp Med 2005; 202: 1575—1585.

19.

Kariko K. , Buckstein M. , Ni H. , Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005; 23: 165—175.

20.

Hofer T. , Badouard C. , Bajak E. et al. Hydrogen peroxide causes greater oxidation in cellular RNA than in DNA. Biol Chem 2005; 386: 333—338.

21.

Lee J. , Chuang T-H. , Redecke V. et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 2003; 100: 6646—6651.

22.

Losman M. , Fasy TM , Novick KE , Monestier M. Monoclonal autoantibodies to subnucleosomes from a MRL/Mp- +/+ mouse. J Immunol 1992; 148: 1561—1569.

23.

Leadbetter EA , Rifkin IR , Marshak-Rothstein A. Toll-like receptors and activation of autoreactive B cells. Curr Dir Autoimmun 2003; 6: 105—122.

24.

Barrat FJ , Meeker T. , Gregorio J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 2005; 202: 1131—1140.

25.

Radic M. , Marion T. , Monestier M. Nucleosomes are exposed at the cell surface in apoptosis. J Immunol 2004; 172: 6692—6700.

26.

Pereira LF , Marco FM , Boimorto R. et al. Histones interact with anionic phospholipids with high avidity; its relevance for the binding of histone-antihistone immune complexes. Clin Exp Immunol 1994; 97: 175—180.