Human Lupus Autoantibody-DNA Complexes Activate DCs Through Cooperation of CD32 and TLR9

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2005 Jan 26

PMID 15668740

Citations 317

Authors

Terry K Means

Eicke Latz

Fumitaka Hayashi

Mandakolathur R Murali

Douglas T Golenbock

Andrew D Luster

Affiliations

Soon will be listed here.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcgammaRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32+, but not CD32-, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.

Citing Articles

Ultraviolet Radiation-Induced Tolerogenic Dendritic Cells in Skin: Insights and Mechanisms.

Ghajar-Rahimi G, Yusuf N, Xu H Cells. 2025; 14(4).

PMID: 39996779 PMC: 11854269. DOI: 10.3390/cells14040308.

FPR1 affects acute rejection in kidney transplantation by regulating iron metabolism in neutrophils.

Li P, Ji W, Zhang B, Jia H, Wang J, Sun Z Mol Med. 2025; 31(1):23.

PMID: 39849390 PMC: 11758745. DOI: 10.1186/s10020-025-01077-w.

The Role of Podocytes in Lupus Pathology.

Maeda K, Abdi R, Tsokos G Curr Rheumatol Rep. 2024; 27(1):10.

PMID: 39731699 DOI: 10.1007/s11926-024-01175-4.

Type I IFN drives unconventional IL-1β secretion in lupus monocytes.

Caielli S, Balasubramanian P, Rodriguez-Alcazar J, Balaji U, Robinson L, Wan Z Immunity. 2024; 57(11):2497-2513.e12.

PMID: 39378884 PMC: 11563874. DOI: 10.1016/j.immuni.2024.09.004.

Interferon Inhibition in SLE: From Bench to Bedside.

Deligeorgakis D, Skouvaklidou E, Adamichou C Mediterr J Rheumatol. 2024; 35(Suppl 2):354-364.

PMID: 39193183 PMC: 11345605. DOI: 10.31138/mjr.010324.iis.

References

Ronnblom L, Alm G . A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J Exp Med. 2001; 194(12):F59-63. PMC: 2193578. DOI: 10.1084/jem.194.12.f59. View

Antequera F, Bird A . Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A. 1993; 90(24):11995-9. PMC: 48112. DOI: 10.1073/pnas.90.24.11995. View

Tesch G, Maifert S, Schwarting A, Rollins B, Kelley V . Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. J Exp Med. 1999; 190(12):1813-24. PMC: 2195716. DOI: 10.1084/jem.190.12.1813. View

Aderem A, Ulevitch R . Toll-like receptors in the induction of the innate immune response. Nature. 2000; 406(6797):782-7. DOI: 10.1038/35021228. View

Bave U, Alm G, Ronnblom L . The combination of apoptotic U937 cells and lupus IgG is a potent IFN-alpha inducer. J Immunol. 2000; 165(6):3519-26. DOI: 10.4049/jimmunol.165.6.3519. View

Narumi S, Takeuchi T, Kobayashi Y, Konishi K . Serum levels of ifn-inducible PROTEIN-10 relating to the activity of systemic lupus erythematosus. Cytokine. 2000; 12(10):1561-5. DOI: 10.1006/cyto.2000.0757. View

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

Means T, Golenbock D, Fenton M . Structure and function of Toll-like receptor proteins. Life Sci. 2001; 68(3):241-58. DOI: 10.1016/s0024-3205(00)00939-5. View

Hayashi F, Smith K, Ozinsky A, Hawn T, Yi E, Goodlett D . The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001; 410(6832):1099-103. DOI: 10.1038/35074106. View

10.

Akira S, Takeda K, Kaisho T . Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001; 2(8):675-80. DOI: 10.1038/90609. View

11.

Bauer S, Kirschning C, Hacker H, Redecke V, Hausmann S, Akira S . Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A. 2001; 98(16):9237-42. PMC: 55404. DOI: 10.1073/pnas.161293498. View

12.

Bave U, Vallin H, Alm G, Ronnblom L . Activation of natural interferon-alpha producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines. J Autoimmun. 2001; 17(1):71-80. DOI: 10.1006/jaut.2001.0519. View

13.

Kadowaki N, Ho S, Antonenko S, Malefyt R, Kastelein R, Bazan F . Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001; 194(6):863-9. PMC: 2195968. DOI: 10.1084/jem.194.6.863. View

14.

Lenert P, Stunz L, Yi A, Krieg A, Ashman R . CpG stimulation of primary mouse B cells is blocked by inhibitory oligodeoxyribonucleotides at a site proximal to NF-kappaB activation. Antisense Nucleic Acid Drug Dev. 2001; 11(4):247-56. DOI: 10.1089/108729001317022241. View

15.

Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R . Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol. 2001; 31(10):3026-37. DOI: 10.1002/1521-4141(2001010)31:10<3026::aid-immu3026>3.0.co;2-h. View

16.

Blanco P, Palucka A, Gill M, Pascual V, Banchereau J . Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001; 294(5546):1540-3. DOI: 10.1126/science.1064890. View

17.

Sieling P, Modlin R . Toll-like receptors: mammalian "taste receptors" for a smorgasbord of microbial invaders. Curr Opin Microbiol. 2002; 5(1):70-5. DOI: 10.1016/s1369-5274(02)00288-6. View

18.

Krieg A . CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002; 20:709-60. DOI: 10.1146/annurev.immunol.20.100301.064842. View

19.

Leadbetter E, Rifkin I, Hohlbaum A, Beaudette B, Shlomchik M, Marshak-Rothstein A . Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002; 416(6881):603-7. DOI: 10.1038/416603a. View

20.

Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T . Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002; 168(9):4531-7. DOI: 10.4049/jimmunol.168.9.4531. View