Interferon-α accelerates murine systemic lupus erythematosus in a T cell-dependent manner

Zheng Liu, Ramalingam Bethunaickan, Weiqing Huang, Umairullah Lodhi, Ingrid Solano, Michael P. Madaio, Anne Davidson

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89 Scopus citations

Abstract

Objective To investigate the mechanism by which interferon-α (IFNα) accelerates systemic lupus erythematosus (SLE) in (NZB à - NZW)F1 (NZB/NZW) mice. Methods NZB/NZW mice were treated with an adenovirus expressing IFNα. In some mice, T cells were depleted with an anti-CD4 antibody. The production of anti-double-stranded DNA (anti-dsDNA) antibodies was measured by enzyme-linked immunosorbent assay and enzyme-linked immunospot assay. Germinal centers and antibody-secreting cells (ASCs) in spleens and IgG deposition and leukocyte infiltrates in kidneys were visualized by immunofluorescence staining. The phenotype of splenic cells was determined by flow cytometry. Finally, somatic hypermutation and gene usage in VH regions of IgG2a and IgG3 were studied by single-cell polymerase chain reaction. Results IFNα-accelerated lupus in NZB/NZW mice was associated with elevated serum levels of IgG2 and IgG3 anti-dsDNA antibodies and accumulation of many IgG ASCs in the spleen, which did not develop into long-lived plasma cells. Furthermore, IgG2a and IgG3 antibodies in the mice were highly somatically mutated and used distinct repertoires of VH genes. The induction of SLE in the mice was associated with an increase in B cell Toll-like receptor 7 expression, increased serum levels of BAFF, interleukin-6 (IL-6), and tumor necrosis factor α, and induction of T cells expressing IL-21. Although IFNα drove a T cell-independent increase in serum levels of IgG, autoantibody induction and the development of nephritis were both completely dependent on CD4+ T cell help. Conclusion These findings demonstrate that, although IFNα activates both innate and adaptive immune responses in NZB/NZW mice, CD4+ T cells are necessary for IFNα-driven induction of anti-dsDNA antibodies and clinical SLE.

Original languageEnglish (US)
Pages (from-to)219-229
Number of pages11
JournalArthritis and Rheumatism
Volume63
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Liu, Z., Bethunaickan, R., Huang, W., Lodhi, U., Solano, I., Madaio, M. P., & Davidson, A. (2011). Interferon-α accelerates murine systemic lupus erythematosus in a T cell-dependent manner. Arthritis and Rheumatism, 63(1), 219-229. https://doi.org/10.1002/art.30087