KEY POINTS * Endosomal and cytosolic nucleic acid receptors sense microbial nucleic acids and initiate innate immune responses. However, in some circumstances their activation by endogenous

nucleic acids can also contribute to autoinflammation. * Nucleic acid sensors and their signalling pathways constitute promising drug targets for which synthetic oligonucleotide drugs as

well as low-molecular-weight compounds are currently being developed. * Agonists of nucleic acid sensors function as immunostimulants and have uses in cancer immunotherapy or as vaccine

adjuvants. The key challenge is to limit systemic inflammation. * Antagonists are being developed as immunomodulators for autoimmune diseases including systemic lupus erythematosus and

better molecular understanding of these indications. This, in turn, enables further drug discovery efforts for better therapy of diseases with high unmet medical need. ABSTRACT Nucleic acid

sensing by innate receptors initiates immune defences against viruses and other pathogens. A hallmark of this response is the release of interferons (IFNs), which promote protective immunity

by inducing IFN-stimulated genes (ISGs). A similar ISG signature is found in autoinflammatory and autoimmune conditions, indicating that chronic activation of nucleic acid-sensing pathways

may contribute to these diseases. Here, we review how nucleic acid-sensing pathways are currently being targeted pharmacologically with both agonists and antagonists. We discuss how an

improved understanding of the biology of these pathways is leading to novel therapies for infections, cancer, and autoimmune and autoinflammatory disorders, and how new therapeutics will, in

turn, generate a deeper understanding of these complex diseases. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS UNDERSTANDING NUCLEIC ACID SENSING AND ITS THERAPEUTIC APPLICATIONS

Article Open access 09 November 2023 DNA-SENSING PATHWAYS IN HEALTH, AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES Article 04 October 2024 THE ROLE OF THE CGAS-STING SIGNALING PATHWAY IN VIRAL

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_Science_ http://dx.doi.org/10.1126/science.aac7049 (2015). Download references ACKNOWLEDGEMENTS The authors thank E. Bartok, J. Deane, M. Hasan, P. Lötscher, D. Patel, A. Marshak-Rothstein

and A. Weber for discussion and helpful suggestions relating to the manuscript. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Autoimmunity, Transplantation and Inflammation, Novartis

Institute of Biomedical Research, Novartis Campus Forum 1, Basel, CH-4056, Switzerland Tobias Junt * German Center for Infection Research Cologne–Bonn, Institute of Clinical Chemistry and

Clinical Pharmacology, University of Bonn, Sigmund-Freud Strasse 25, Bonn, 53127, Germany Winfried Barchet Authors * Tobias Junt View author publications You can also search for this author

inPubMed Google Scholar * Winfried Barchet View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Tobias Junt. ETHICS

DECLARATIONS COMPETING INTERESTS T.J. is an employee of Novartis Pharma, AG. W.B. declares no competing financial interests. RELATED LINKS FURTHER INFORMATION ClinicalTrials.gov POWERPOINT

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SLIDE FOR TABLE 3 POWERPOINT SLIDE FOR TABLE 4 GLOSSARY * Pathophenotype A disease subtype within a complex disease that is distinguished by certain clinical symptoms. Complex diseases such

as systemic lupus erythematosus contain multiple pathophenotypes. The key challenge of molecular pathology is to match pathophenotypes to the activation of specific pathogenic pathways. *

Antinuclear antibodies (ANAs). Autoantibodies against double-stranded DNA or RNA-containing antigens (for example, Sjögren syndrome-related antigen A (SS-A; also known as Ro), SS-B (also

known as La), Sm (spliceosomal) and small nuclear ribonucleoprotein 70 kDa (snRNP70)). Their presence in patient sera is a diagnostic hallmark of autoimmune diseases such as Sjögren syndrome

and systemic lupus erythematosus. One diagnostic test for ANAs relies on specific staining pattern of cell nuclei with patient sera by immunofluorescence, hence the name. * Biomarkers

Measurable parameters that are reflective of specific biological processes in living organisms. Diagnostic biomarkers point to disease type or severity and may support patient stratification

or selection. Pharmacodynamic biomarkers are measured in clinical trials to indicate pharmacological responses to compounds. * T cell-independent type 2 antigens Polyvalent antigens that

activate B cells by efficient crosslinking of the B cell receptor (BCR), without the need of T help. They differ from T cell-independent type 1 antigens, which are polyclonal B cell

stimulants that activate B cells independently of BCR ligation. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Junt, T., Barchet, W. Translating nucleic

acid-sensing pathways into therapies. _Nat Rev Immunol_ 15, 529–544 (2015). https://doi.org/10.1038/nri3875 Download citation * Published: 21 August 2015 * Issue Date: September 2015 * DOI:

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