Interferon-alpha Accelerates Murine Systemic Lupus Erythematosus in a T Cell-Dependent Manner

Objective. To investigate the mechanism by which interferon-alpha (IFN alpha) accelerates systemic lupus erythematosus (SLE) in (NZB X NZW)F-1 (NZB/NZW) mice. Methods. NZB/NZW mice were treated with an adenovirus expressing IFN alpha. 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 V-H regions of IgG2a and IgG3 were studied by single-cell polymerase chain reaction. Results. IFN alpha-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 V-H 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 alpha, and induction of T cells expressing IL-21. Although IFN alpha 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 IFN alpha activates both innate and adaptive immune responses in NZB/NZW mice, CD4+ T cells are necessary for IFN alpha-driven induction of anti-dsDNA antibodies and clinical SLE.