Type I interferons (IFNs), including IFN-α, IFN-β, IFN-ω and IFN-κ, represent an essential host defense mechanism stimulated by virus infection.^1–4 In that setting, type I IFN is tightly regulated with duration of expression limited to several days. When its production is sustained, its protean effects on immune cell function can be damaging. Activation of the type I IFN pathway, typically defined by elevated expression of type I IFN-inducible gene transcripts or their protein products, is a feature of nearly all children diagnosed with systemic lupus erythematosus (SLE), as well as the majority of adult lupus patients. Taken together with insights from murine models, studies of lupus patients have supported the conclusion that type I IFNs comprise a family of pathogenic mediators that contribute to autoimmunity, inflammation and ultimately tissue damage in patients with SLE and some other systemic autoimmune diseases, particularly primary Sjogren’s syndrome and dermatomyositis.

Coordinated expression of type I IFN-stimulated genes is a feature of most patients with SLE, but the relationship of the IFN signature to disease activity has been debated. In addition, the inducers of IFN and the molecular pathways and signaling molecules that result in IFN production have not been well defined. Endogenous nucleic acids have been identified as the relevant drivers of type I IFN production, but the specific features of those nucleic acids have not been well characterized. It is not apparent whether the endosomal toll-like receptors or cytosolic nucleic acid sensors are most relevant to IFN expression in individual patients. Finally, the mechanisms that regulate activation of the IFN pathway – or fail to regulate that pathway in some lupus patients – have not been well defined. To gain insight into these issues, we collected extensive longitudinal clinical, serologic, proteomic and gene expression data to assess the correlates of IFN pathway activation, and to establish new hypotheses regarding the relationship of autoantibody specificity and environmental exposures to production of IFN and induction of IFN-stimulated genes.

Analysis of proteomic and gene expression data collected for up to 4 years on individual patients was analyzed to understand temporal patterns among relevant autoantibodies and the IFN signature in relation to disease flares. Our data suggest a potential role for microbial triggers in driving the immune system activation that leads to disease flares and support activation of the type I IFN as highly associated with disease flare in many patients.

Learning Objectives

• Describe potential mechanisms of type I IFN induction in SL

• Describe individual temporal patterns in immune system activation based on longitudinal patient data

• Explain possible interpretations of longitudinal patient data with regard to triggers of lupus flare

References

1. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192(12):5459–68.

2. Mavragani CP, Sagalovskiy I, Guo Q, et al.Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of Type I Interferon in Patients With Systemic Autoimmune Disease. Arthritis Rheumatol. 2016;68(11):2686–96.

3. Crow MK, Olferiev M, Kirou KA. Type I Interferons in Autoimmune Disease. Annu Rev Pathol. 2019;14:369–93.

4. Barrat FJ, Crow MK, Ivashkiv LB. Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol. 2019;20(12):1574–83.