Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple immune system abnormalities, including production of autoantibodies that can lead to inflammation and tissue damage . SLE symptoms can range from a mild rash to life-threatening nephritis and central nervous system disease. These disease manifestations cause a significant burden of illness and can cause reduced physical function, loss of employment, lower health-related quality of life, and a lifespan shortened by about 10 years . Increased hospitalizations and side effects of medications including chronic corticosteroid and other immunosuppressive treatments add to the disease burden in SLE . No new treatment for SLE has been approved by the US Food and Drug Administration in about 50 years since hydroxychloroquine was approved for use in discoid lupus and SLE; otherwise, the existing standard of care for SLE consists of off -label medications.
The disease pathogenesis of SLE includes activation of innate immunity, with increased production of type I interferons, including IFNα, and increased plasmacytoid and myeloid dendritic cells in involved tissue [3–8]. Specific immunity, including both humoral and cellular immune systems, is activated. Autoantibodies are universally present and may precede development of clinically apparent disease . SLE-associated autoantibodies include anti-dsDNA, anti-nucleosomes, anti-RNP (ribonucleoprotein complex), and anti-Sm antibodies. Immune complexes containing anti-dsDNA or anti-RNP antibodies can activate type I interferon production [3, 4]. After internalization through Fc receptors, autoantibody-containing immune complexes bind endosomal Toll-like receptors 7 and 9, and stimulate production of type I interferon. Type I interferon stimulates myeloid dendritic cell maturation, which promotes loss of tolerance and generation of autoreactive T cells and B cells, autoantibody production, immune complex formation and further production of type I interferon, creating a self-perpetuating cycle of autoimmunity [5, 10, 11].
Type I interferons include 14 IFNα family members, IFNβ, IFNτ, IFNκ and IFNω . This cytokine family regulates immune functions of cellular components of both innate and adaptive immune systems, including dendritic cells, T cells, B cells, and natural killer cells. For example, type I interferons promote dendritic cell maturation, memory CD8+ T-cell proliferation, natural killer-cell activation, and B-cell differentiation [5, 13]. Type I interferons also enhance the expression of immunologically important molecules such as MHC class I, CD38, interleukins such as BLyS, IL-6, IL-10 and IL-15, and multiple chemokines [14–17].
Emerging data indicate a role for type I interferons in disease pathogenesis in SLE. Genetic polymorphisms associated with type I interferon pathways are associated with susceptibility to SLE [18, 19]. Treatment with IFNα has been associated with the development of autoantibodies and new or worsening clinical features of the SLE [20, 21]. Higher IFNα levels and type I interferon activity are associated with greater disease activity in SLE [3, 7]. Patients with high anti-dsDNA antibody titers, lupus nephritis, and progressive skin rashes have high serum levels of IFNα . In addition, patients with acute skin involvement tend to have elevated IFNα in blood and skin .
These clinical observations in humans are supported by data that show a key role for type I interferon in animal models of SLE. IFNα can induce glomerulonephritis in normal mice and accelerates the onset of the spontaneous autoimmune disease of NZB/W mice . Autoimmune-predisposed mice deficient in the IFNα/β receptor exhibit significantly reduced anti-erythrocyte autoantibodies, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality . Furthermore, IFNα kinoid vaccine has been shown to induce neutralizing antibodies to prevent clinical manifestations in a lupus flare murine model .
Together, these human and animal data support the hypothesis that inhibiting type I interferon may reduce disease activity in SLE.