Abstract
Over the past two decades, the number of genetically defined autoinflammatory interferonopathies has steadily increased. Aicardi–Goutières syndrome and proteasome-associated autoinflammatory syndromes (PRAAS, also known as CANDLE) are caused by genetic defects that impair homeostatic intracellular nucleic acid and protein processing respectively. Research into these genetic defects revealed intracellular sensors that activate type I interferon production. In SAVI and COPA syndrome, genetic defects that cause chronic activation of the dinucleotide sensor stimulator of interferon genes (STING) share features of lung inflammation and fibrosis; and selected mutations that amplify interferon-α/β receptor signalling cause central nervous system manifestations resembling Aicardi–Goutières syndrome. Research into the monogenic causes of childhood-onset systemic lupus erythematosus (SLE) demonstrates the pathogenic role of autoantibodies to particle-bound extracellular nucleic acids that distinguishes monogenic SLE from the autoinflammatory interferonopathies. This Review introduces a classification for autoinflammatory interferonopathies and discusses the divergent and shared pathomechanisms of interferon production and signalling in these diseases. Early success with drugs that block type I interferon signalling, new insights into the roles of cytoplasmic DNA or RNA sensors, pathways in type I interferon production and organ-specific pathology of the autoinflammatory interferonopathies and monogenic SLE, reveal novel drug targets that could personalize treatment approaches.
Key points
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Genetic defects impairing intracellular nucleic acid and protein processing and/or STING activation cause autoinflammatory interferonopathies, indicating that intracellular sensor-mediated type I interferon production exhibits disease-specific and disease-overlapping clinical features.
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Identification of the genetic causes of monogenic systemic lupus erythematosus (SLE) reveals molecular mechanisms triggered by extranuclear nucleic that distinguish monogenic SLE from the autoinflammatory interferonopathies.
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Monogenic inborn errors of immunity caused by NF-κB dysregulation, mitochondrial dysfunction or impaired DNA damage responses unravel sources of interferogenic nucleic acids that drive type I interferon production in the context of complex developmental and/or immune-dysregulation.
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Treatments that block interferon signalling and interferon-stimulated genes continue to elucidate the role of type I interferon in driving systemic and organ-specific inflammation.
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Novel drugs targeting cytoplasmic sensors in autoinflammatory interferonopathies and endosomal TLRs in paediatric-onset SLE provide new treatment opportunities for a broader spectrum of diseases with presumed interferon-mediated pathology.
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Advances in modelling tissue and organ inflammation start to unravel the effect of disease-causing mutations on critical tissues. These insights herald a new era of precision medicine in rare monogenic diseases.
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Acknowledgements
The authors of this Review were supported by the Intramural Research Program of the NIH.
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R.G.M. has a government funded Cooperative Research and Development Agreement that supports translational research with STING inhibitors. S.A. and A.A.D.J. have no relevant competing interests to report.
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Nature Reviews Rheumatology thanks Alexandre Belot, who co-reviewed with Anne-Laure Mathieu; Min Ae Lee-Kirsch; Ryuta Nishikomori, who co-reviewed with Kazushi Izawa; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Autosomal-dominant mutation
-
A mutation that is present on one allele (copy) of a given gene.
- Autosomal-recessive mutation
-
A mutation that is present on both alleles (copies) of a given gene.
- Biallelic variants
-
Variants that occur in both copies of a gene; these variants can be homozygous or compound heterozygous.
- Chilblain-like lesions
-
Skin lesions that mimic chilblains or pernio lesions, which are erythematous violaceous lesions, typically macules, papules, or nodules that develop in response to exposure to cold environments and affect mainly the acral areas, particularly toes and fingers.
- Deleterious frameshift mutation
-
A damaging or pathogenic mutation caused by the insertion or deletion of nucleotide bases in numbers that are not multiples of three that disrupt the expected translated amino acid sequence.
- Deleterious null mutation
-
A damaging or pathogenic mutation that leads to the gene not being transcribed into RNA and/or translated into a functional protein product; null mutation is also known as amorphic mutation.
- Digenic mutations
-
Mutations that occur in two genes to manifest a particular phenotype or disease.
- Dominant negative mutation
-
A heterozygous mutation that results in a protein that interferes with the normal function of the wild type protein.
- Heterozygous missense mutation
-
A single nucleotide change in one allele that results in a different amino acid being encoded at a particular position in the resulting protein.
- Hypomorphic X-linked mutation
-
A mutation on a gene on the X chromosome that results in a partial loss of gene function because of a reduction in the expression of RNA or protein, or by a reduction in the functional performance of the gene product; a hypomorphic mutation is also known as a leaky mutation.
- Inborn errors of immunity
-
A group of rare genetically defined immunological disorders with increased susceptibility to immunodeficiency and infections, autoinflammation, autoimmunity, allergy and/or predisposition to lymphomas and other malignancies, mostly because of damaging germline variants in single genes.
- Interferogenic
-
An element or molecule, such as nucleic acids, which triggers an interferon response or induces the expression of interferon stimulated genes.
- Interferon score
-
The quantification of an interferon signature by the sum of z-scores of specific interferon-stimulated gene expression measured by RT–qPCR, NanoString or RNA-sequencing.
- Nonsense mutations
-
Single-nucleotide changes that result in a stop codon rather than in a codon specifying an amino acid, thus leading to the production of a shortened protein.
- Pseudo-TORCH syndromes
-
An inherited neurological disorder with clinical and neuroradiological features that mimic intrauterine toxoplasmosis, others (syphilis, hepatitis B), rubella, cytomegalovirus, herpes simplex (TORCH) infections in the absence of evidence of infection.
- Warm antibodies
-
Autoantibodies that are active only at body temperatures of 37 °C or higher and attach to and prematurely destroy red blood cells.
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Goldbach-Mansky, R., Alehashemi, S. & de Jesus, A.A. Emerging concepts and treatments in autoinflammatory interferonopathies and monogenic systemic lupus erythematosus. Nat Rev Rheumatol 21, 22–45 (2025). https://doi.org/10.1038/s41584-024-01184-8
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DOI: https://doi.org/10.1038/s41584-024-01184-8
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