Exploring the role of type I interferon pathway in autoimmune disease


Bill Rees

AstraZeneca and MedImmune are committed to the development of treatments for autoimmune and inflammatory diseases. Our work relies on building a deep understanding of the clinical, genetic, molecular and biological mechanisms that underpin and drive disease.

A focus on research is central to our commitment to bringing personalized therapeutic options to patients with chronic autoimmune disease, including diseases with diverse systemic and organ-specific manifestations such as systemic lupus erythematosus (SLE).

SLE is such a complex condition. Symptoms can manifest in the lungs, skin, kidneys, joints, or nervous system with no SLE patient having quite the same collection of symptoms as another. In addition, the disease waxes and wanes over time.1  Existing SLE treatment approaches can prove ineffective as the majority of patients still suffer from active disease symptoms, creating a significant unmet medical need.2

Thus, there is a great need for targeted therapies with improved efficacy and safety that can be directed to the patients most likely to benefit.

Breaking the Lupus code

SLE is a multisystem autoimmune disease where the complex interplay between environmental and genetic factors leads to progressive loss of tolerance to certain self antigens over time.1 AstraZeneca’s disruptive research, complementing outside research in the field, is making it increasingly clear that dysregulated type I interferons play a key role in lupus. Research is showing that three quarters of moderate-to-severe SLE patients have evidence of type I interferon inducible gene expression in their blood.3,4

There is a growing body of evidence linking type I interferons and SLE:

  • Elevated type I interferons are found in the blood of SLE patients and the levels are associated with disease activity5,6
  • Elevated transcription from large numbers of genes known to be inducible by type I interferons can be found in the blood of SLE patients, and this dramatic effect on gene expression is termed the type I interferon signature7,8
  • Affected tissues in SLE patients tend to have an infiltration of plasmacytoid dendritic cells, a key cellular player in the maintenance of chronic disease.9
  • Autoantibodies specific for nucleic acids (anti-DNA and anti-RNA autoantibodies) that are common in lupus patients, are capable of inducing strong interferon secretion from plasmacytoid dendritic cells9
  • Use of type I interferons as therapeutics in hepatitis C and oncology patients is associated with the de novo appearance or exacerbation of existing autoimmune conditions including SLE10
  • Polymorphism, or DNA sequence variants, in important genes in the type I interferon pathway, including interferon regulatory factor 5 and tyrosine kinase 2, are associated with susceptibility to developing SLE11

One step closer to personalized treatments

The recognition of the importance of the type I interferon pathway in SLE led to the development of investigational therapeutics that inhibit the activity of interferons in different ways. Patients receiving an inhibitor of the type I interferon receptor that blocks the effects of interferons on sensitive cells, had greater rates of improvements across a range of systemic and organ-specific disease measures as well as reductions in steroid use compared to placebo.3 In addition, patients with evidence of a type I interferon gene expression signature in their blood had more pronounced improvements than patients with no evidence of type I interferon inducible activity.3 We are therefore developing a diagnostic tool in tandem with clinical trials that might help identify patients more likely to respond to therapies that inhibit type I interferon activity.

The effects of the type I interferon pathway would appear to extend beyond SLE. The type I interferon inducible gene expression signature, elevated levels of interferon proteins and mRNA, autoantibodies against nucleic acids or nucleic acid binding proteins, and those plasmacytoid dendritic cells have also been found in other systemic rheumatologic diseases. These include myositis, Sjogren’s syndrome and scleroderma and diseases as seemingly far afield as alopecia areata, vitiligo and autoimmune thyroiditis.12,13,14 Future clinical trials will help us understand whether these seemingly very different patients might benefit from treatments inhibiting the type I interferon pathway, particularly in patients with evidence of strong type I interferon activity. The ability to identify patients by the underlying molecular mechanisms triggering or amplifying their disease, and a therapy capable of effectively inhibiting that pathway, should bring us a step closer giving doctors and patients personalized approaches to treatment.

AstraZeneca’s goal is to deliver on this promise of personalized, or precision medicine. We are currently utilizing our collective strengths in molecular diagnostics, imaging and bioinformatics to make this ambition a reality for patients.



1. Bello, Ghalib A., et al. "Development and validation of a simple lupus severity index using ACR criteria for classification of SLE." Lupus science & medicine 3.1 (2016): e000136.

2. Mosca M, et al. New drugs in systemic lupus erythematosus: when to start and when to stop. Clin Exp Rheumatol 2013; 31 (Suppl. 78): S82-S85.

3. Furie, Richard, et al. "Anifrolumab, an Anti‐Interferon‐Alpha Receptor Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus." Arthritis & Rheumatology. 2017;69(2):376-86

4. Khamashta M, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus (NCT01283139).

5. Ytterberg, S.R. and T.J. Schnitzer, Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum, 1982. 25(4): p. 401-6.

6. Hooks, J.J., et al., Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med, 1979. 301(1): p. 5-8.

7. Bennett, L., et al., Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med, 2003. 197(6): p. 711-23.

8. Yao, Y., et al., Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-alpha Monoclonal Antibody Trials in Systemic Lupus Erythematosus. Hum Genomics Proteomics, 2009. doi:10.4061/2009/374312

9. Bave, U., et al., Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG. J Immunol, 2003. 171(6): p. 3296-302.

10. Ioannou, Y. and D.A. Isenberg, Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum, 2000. 43(7): p. 1431-42.

11. Sigurdsson, S., et al., Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet, 2005. 76(3): p. 528-37.

12. Emamian, E.S., et al., Peripheral blood gene expression profiling in Sjogren's syndrome. Genes Immun, 2009. 10(4): p. 285-96.

13. Higgs, B.W., et al., Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis, 2011. 70(11): p. 2029-36.

14. Harris, John E. "Vitiligo and alopecia areata: apples and oranges?." Experimental dermatology 22.12 (2013): 785-789.

Veeva ID: Z4-4557
Date of next review: May 2018