Interferon blockade in lupus: effects on antiviral immunity

Abstract

Targeting type I interferon immune responses is a potential strategy for the treatment of systemic lupus erythematosus. Although a phase 2 clinical trial of anifrolumab did not meet its primary end point, further studies are needed to assess the effects of interferon blockade on flare rates of lupus nephritis. However, the observed higher risk of herpes zoster associated with anifrolumab use suggests that caution is warranted with this strategy.

Fig. 1. Pathomechanisms and therapeutic targets of SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease, the triggers of which include the activation of innate viral nucleic acid recognition receptors by nucleic acid autoantigens or nucleic acids attached to nucleoproteins, leading to activation of immature dendritic cells (DCs) and the release of type I interferons (IFNs). The activation of antigen-presenting DCs by type I IFNs via IFNα receptors (IFNαR1 and IFNαR2) promotes their capacity to effectively present antigens (including self antigens) to T and B cells. The generation of T effector cells (T helper 1 (T_H1), T_H2 and T_H17 cells, as well as regulatory T (T_reg) cells) results in the production of cytokines such as interleukin (IL)-12, IL-4, IL-6 and IL-23) and the expression of cell surface molecules that support amplification of a self-directed immune response as well as inflammation via (auto)-antigen-specific T cells. In addition, the production of B cell activating factor (BAFF) by DCs induces the survival, proliferation and differentiation of B cells into plasma cells that ultimately drives autoantibody production. Current therapies include anifrolumab, which blocks IFNαR1 on non-immune and immune cells, including DCs; belimumab, which neutralizes BAFF to limit B cell growth and functions; or the calcineurin inhibitor voclosporin, which targets the cytoskeleton of podocytes at the filtration barrier as well as T cell activation and proliferation.