Targeting of type I interferon in systemic autoimmune diseases

Abstract

Increased blood levels of type I interferon (IFN-I) and expression of a broad signature of gene transcripts that reflect induction by IFN-I are observed in many patients with systemic autoimmune diseases, and that pattern is most striking in systemic lupus erythematosus (SLE). Persistent production of IFN-α, the most abundant subtype measured in these patients, is an important feature of the immunopathogenesis of lupus and has stimulated current efforts to develop and test therapeutics that either block IFN-I or its receptor directly or target components of the IFN-I pathway involved in induction of or response to IFN-I. In this review data from animal models of chronic viral infection, examples of lupus-like syndromes associated with single-gene mutations that impact the IFN-I pathway, and longitudinal studies of patients with lupus are described and support the rationale for therapeutic targeting of the IFN-I pathway. However, the complexity of IFN-I regulation and the diversity of its effects on immune system function suggest that the definitive demonstration of that pathway as a valid and productive therapeutic target will only come from clinical trials of agents tested in patients with systemic autoimmune disease, with patients with lupus likely to be the most informative.

Figure 1. Graphic depiction of predicted probability of developing renal disease activity over time based on longitudinal data obtained from 60 SLE patients

Multiple parameters were studied, and the minimum multivariate model included: plasma IFN-I activity based on reporter cell assay, level of anti-dsDNA antibodies, absolute leukocyte count, and serum total protein and serum albumin. Renal disease activity was defined as any BILAG score greater than C. The high plasma IFN-I cut-off corresponds to 12.5 IU/ml. A high level of anti-dsDNA antibodies is defined as ++ and +++ based on C. luciliae assay. Predicted values for development of renal disease activity were plotted for four patient groups based on their IFN-I and anti-dsDNA antibody status. The group with both high IFN-I and positive anti-dsDNA antibody had the highest probability of developing renal disease activity during follow up visits.