A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM

Zhuang H, Han S, Li Y, Kienhöfer D, Lee P, Shumyak S, Meyerholz R, Rosadzinski K, Rosner D, Chan A, Xu Y, Segal M, Sobel E, Yang LJ, Hoffmann M, Reeves WH (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Arthritis and Rheumatology Wiley

Book Volume: 68

Pages Range: 2917-2928

Journal Issue: 12

DOI: 10.1002/art.39781

Abstract

In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fc? receptor-mediated uptake of nucleic acid-containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo.Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects.Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (?MT), C3(-/-) , and CD18(-/-) mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in ?MT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of "natural" IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature.These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.

Authors with CRIS profile

Markus Hoffmann Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

University of Florida US United States (USA) (US) Boston Children's Hospital US United States (USA) (US)

How to cite

APA:

Zhuang, H., Han, S., Li, Y., Kienhöfer, D., Lee, P., Shumyak, S.,... Reeves, W.H. (2016). A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM. Arthritis and Rheumatology, 68(12), 2917-2928. https://doi.org/10.1002/art.39781

MLA:

Zhuang, Haoyang, et al. "A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM." Arthritis and Rheumatology 68.12 (2016): 2917-2928.

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