Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus

The cause of systemic lupus erythematosus (SLE) is unknown. IFN-alpha has been suggested as a causative agent of SLE; however, it was not proven, and to what extent and how IFN-alpha contributes to the disease is unknown. We studied the contribution of IFN-alpha to SLE by generating inducible IFN-alpha transgenic mice and directly show that conditional upregulation of IFN-alpha alone induces a typical manifestation of SLE in the mice not prone to autoimmunity, such as serum immune complex, autoantibody against dsDNA (anti-dsDNA Ab), and the organ manifestations classical to SLE, such as immune complex-deposited glomerulonephritis, classical splenic onion-skin lesion, alopecia, epidermal liquefaction, and positive lupus band test of the skin. In the spleen of mice, activated effector CD4 T cells, IFN-gamma-producing CD8 T cells, B220(+) CD86(+) cells, and CD11c(+)CD86(+) cells were increased, and the T cells produced increased amounts of IL-4, IL-6, IL-17, and IFN-gamma and decreased IL-2. In particular, activated CD3(+)CD4(-)CD8(-) doub-lenegative T cells positive for TCR alpha beta, B220, CD1d-teteramer, PD-1, and Helios (that produced increased amounts of IFN-gamma, IL-4, IL-17, and TNF-alpha) were significantly expanded. They infiltrated into kidney and induced de novo glomerulonephritis and alopecia when transferred into naive recipients. Thus, sole upregulation of IFN-alpha is sufficient to induce SLE, and the double-negative T cells expanded by IFN-alpha are directly responsible for the organ manifestations, such as lupus skin disease or nephritis.