Editors' ChoiceRheumatology

Unmasking Interferon Pathways in Autoimmune Disease

See allHide authors and affiliations

Science Translational Medicine  24 Oct 2012:
Vol. 4, Issue 157, pp. 157ec190
DOI: 10.1126/scitranslmed.3005157

Autoimmune rheumatic diseases such as lupus, dermatomyositis, scleroderma, and Sjögren syndrome are a heterogeneous and highly complex group of disorders in which the immune system attacks the patient’s own tissues. Not only can these disorders wreak havoc on the human body, they can also be masters of disguise, with overlapping clinical presentations and laboratory markers that make them all the more challenging to identify and treat. Some associations between autoimmune diseases and interferon (IFN) pathways have already been discovered, resulting in specific therapeutics that can precisely target individual immune pathways. However, the specific contributions of type I (IFN-α) and type II (IFN-γ) IFN pathways to these illnesses are not always clear and can be difficult to distinguish because of overlap in the genetic programs they activate. In some autoimmune diseases, such as psoriasis, genes associated with elevated IFNs have been observed, but therapeutics targeting IFN-α pathways have failed, suggesting that an alternative IFN pathway may be pathogenic. Now, Hall et al. address this gap by closely comparing the signatures of type I and II IFN in the target tissues of rheumatic diseases.

The authors focused on Sjögren syndrome, in which the salivary and lacrimal glands are targets of the immune system, leading to symptoms such as dry mouth and dry eyes. They determined which genes were induced by IFN-α and IFN-γ in a human salivary cell line after 4, 12, 24, and 48 hours and observed that 416 different transcripts were reproducibly up-regulated (greater than twofold) upon treatment of cells with either type of IFN. Within this set, a substantial number of genes were up-regulated by both IFN-α and IFN-γ, but at different kinetics. IFN-α target genes peaked at 4 hours; IFN-γ genes peaked at 48 hours. Smaller numbers of genes were specifically associated with either IFN-α (MDA5 and IFIT3) or IFN-γ (GBP1 and GBP2). These particular expression patterns were validated on the protein level as well. The authors then analyzed the protein expression of salivary glands from Sjögren syndrome patients and salivary glands of controls and compared these to muscle biopsies from patients with dermatomyositis (in which the immune system targets destruction of muscle) and their respective controls. A variable pattern of IFN pathway activation was observed in salivary gland biopsies from Sjögren patients, but the dermatomyositis patients in this study all had a more distinct IFN-α signature.

Analysis of larger groups of patients is still necessary and needs to include a variety of patients with clinically distinct and overlapping autoimmune disorders. In addition, it remains to be determined how IFN signatures in the blood correlate to tissue and how these relate to specific cell populations with a role in disease pathogenesis. Nevertheless, these observations about the activation of IFN-α and IFN-γ in Sjögren syndrome and dermatomyositis could potentially lead to changes in clinical management for individuals with these complex and often therapeutically refractory diseases. A better understanding of the overlapping and specific targets of IFN pathways in specific rheumatic diseases will help remove their disguises and appropriately tailor clinical treatment to each disorder as more precise therapeutics are developed.

J. C. Hall et al., Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc. Natl. Acad. Sci. U.S.A., published online 8 October 2012 (10.1073/pnas.1209724109). [Full Text]

Navigate This Article