Elina Zuniga, PhD

University of California, San Diego, CA

2013 New to Lupus

Learning from Viruses How to Suppress Type I Interferons to Cure Lupus

The Study and What It Means to Patients

"Can viruses teach us new ways to treat lupus? By asking how long-term virus infections cause the immune system to stop making proteins called interferons that are implicated in driving lupus, we hope to discover new therapeutic strategies to switch off interferon production in lupus and other autoimmune diseases. "

Summary

The immune system of lupus patients produces excess amounts of anti-viral proteins called interferons, which hyper-stimulate the immune system and drive it to attack body. Large amounts of interferon are also produced during the early stages of a viral infection, but interferons are switched off if the virus persists. We are investigating why interferon production is switched off in long-term virus infections but not in lupus. Focusing on specialized interferon-producing cells called plasmacytoid dendritic cells, our research promises to open new paths to interferon-targeted therapy in lupus.

Scientific abstract

Systemic Lupus Erythematosus (SLE) is perpetuated by elevated type-1 interferon (IFN-I) levels and associated immunopathology. Plasmacytoid dendritic cells (pDCs), which are specialized to produce IFN-I, are continuously activated by self nucleic acids and play a pivotal role in disease progression. Therefore, silencing pDC IFN-I production represents an attractive strategy to ameliorate Lupus. We have characterized a pDC "exhaustion" state during which pDC IFN-I production becomes dramatically silenced despite the continuous presence of stimuli during chronic viral infection. Using a genome wide analysis, we have identified the transcriptional signature of exhausted pDCs and we propose to manipulate selected pDC exhaustion genes (e.g. those oppositely regulated in SLE) to interrupt their IFN-I production and break the pathogenic loop in lupus-prone mice. The short-term impact of our studies will be the identification of molecular determinants that can break the pathogenic IFN-I cycle in a mouse model of SLE. The unique translational design (from virus infection to lupus) that we propose will provide invaluable insight into pDC manipulation. The long-term impact of our studies will be to translate the new knowledge on IFN-I regulation into novel therapeutic modalities in SLE.

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