乳児発症 STING 関連血管炎

Type I interferonopathies (TI-IFN) represent a heterogeneous group of autoinflammatory disorders characterized by upregulated type I interferon (IFN) signaling. Among them, STING-associated vasculopathy with onset in infancy (SAVI) is a rare, severe autoinflammatory disease caused by gain-of-function mutations in the STING1 gene. Mechanistically, these mutations lead to a constitutive activation of the STING protein, resulting in excessive type I interferon production, which drives chronic inflammation and damage to various organs, primarily as cutaneous vasculopathy and progressive interstitial lung disease (ILD). Emerging clinical data indicate that current therapeutic options - including Janus kinase inhibitors (JAKi), biological agents as anifrolumab and solid organ transplantation - for SAVI face limited and often inconsistent long-term efficacy, highlighting a significant unmet need. Consistently, preclinical models highlight that SAVI pathogenesis is not only driven by the interferon storm, but relies also on non-canonical IFN-independent cellular pathways across distinct hematopoietic and non-hematopoietic compartments. This review provides a comprehensive overview of SAVI pathogenesis, from mutational mechanisms and comparative phenotypes to the clinical challenges of advanced interventions. Finally, we discuss future therapeutic prospects and clinical implications, exploring next-generation frontiers such as patient-derived induced pluripotent stem cell (iPSCs) models, hematopoietic stem cell transplantation (allo-HSCT) and gene editing (GE) technologies. The transition from immune - to a mutational-perspective, provides a foundational framework to optimize diagnostic and therapeutic strategies for precision medicine in SAVI patients.

Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been increasingly recognized as a key driver of autoimmune and inflammatory diseases. In recent years, accumulating evidence has highlighted the close association between cGAS-STING signaling and the pathogenesis of these disorders, suggesting that pharmacological targeting of this pathway may represent a promising therapeutic strategy. This review provides a comprehensive overview of the molecular mechanisms underlying cGAS-STING hyperactivation and its pathological roles across diverse diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH), STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, Niemann-Pick disease type C (NPC), neurodegenerative diseases and cancer. We critically evaluate current and emerging pharmacological strategies targeting the cGAS-STING pathway, encompassing direct cGAS and STING inhibitors, protein degradation technologies, epigenetic modulation, regulation of biomolecular phase separation, and artificial intelligence (AI)-enabled drug discovery approaches. By integrating disease-specific pathogenic mechanisms with therapeutic opportunities, this review highlights key challenges and future directions in the development of cGAS-STING-targeted therapies. Collectively, these insights provide a translational perspective for precision targeting of pathological cGAS-STING activation.

STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by mutations in TMEM173 gene encoding STING (stimulator of interferon genes). It typically presents in infancy and is mainly characterized by interstitial lung disease, skin rash, and systemic inflammation. This report presents the case of adult-onset SAVI:A 28-year-old male patient was admitted with recurrent episode of cough, expectoration, chest tightness with shortness of breath and erythematous rashes on the extremities, chest, and back.His CT revealed bilateral diffuse fine reticular opacities and irregular reticular shadows, with focal areas of honeycombing. Further inquiry into the family history revealed that the patient's mother had been diagnosed with interstitial lung disease (ILD).Thus, a genetic etiology should be highly suspected.Later, whole-exome sequencing identified a heterozygous mutation in the STING1 gene: c.842G>A (p.R281Q), establishing the diagnosis of SAVI. The patient was subsequently referred to a tertiary care hospital for specialized management. During one year of follow-up, the patient underwent lung transplantation in August 2025 and had since received long-term immunosuppressive therapy for rejection prophylaxis. Cough and expectoration improved markedly, although exertional dyspnea persisted; the cutaneous rash had resolved completely.

We report the case of an 18-year-old previously healthy female who developed acute liver and kidney injuries with cytopenia and hyperinflammatory markers following cytomegalovirus (CMV) infection. Despite not meeting the hemophagocytic lymphohistiocytosis (HLH)-2004 or H-score criteria, her clinical and biochemical profiles suggested an HLH-like syndrome. Whole-exome sequencing revealed a heterozygous dominant stimulator of interferon genes (STING1) (c.841C>T; p. Arg281Trp) mutation. Although the patient lacked classic STING-associated vasculopathy with onset in infancy (SAVI)-associated skin or lung manifestations, immunological profiling revealed an inverted cluster of differentiation (CD)4/CD8 ratio and absolute CD4+ lymphopenia, supporting a state of underlying immune dysregulation that likely predisposed the patient to severe CMV infection. The patient showed partial clinical and biochemical improvements following antiviral and corticosteroid therapy, supporting our hypothesis of a genetically primed infection-triggered hyper-inflammatory response. This case broadens the STING1 disease spectrum and emphasizes the importance of genomic evaluation of unexplained hyperinflammation, even in apparently immunocompetent hosts. Conclusion: This case highlights a novel STING1 (p. Arg281Trp) gain-of-function mutation with a previously unreported autosomal dominant inheritance pattern identified in both the patient and her asymptomatic father, suggesting incomplete penetrance and variable expression rather than a fully penetrant autosomal dominant pattern. The patient's presentation was atypical compared with classical SAVI, manifesting as a CMV-triggered HLH-like syndrome with acute renal and liver cell injury in an adolescent with no prior evidence of immune deficiency or family history of genetic disease. Notably, this presentation lacked the characteristic cutaneous and pulmonary involvement. This case highlights a distinct phenotypic spectrum and expands our understanding of STING1-related interferonopathies.

Identification of the genetic mutations underlying the ultrarare monogenic conditions STING-associated vasculopathy with onset in infancy (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome revealed a role for the stimulator of interferon genes (STING) immune pathway in the pathogenesis of interstitial lung disease (ILD) in these conditions. STING-focused therapeutics could be a potential avenue for the treatment of SAVI and COPA syndrome in the future, yet the relevance of STING to more common types of ILD is not clear. Here, we provide an overview of SAVI and COPA syndrome, the nature of ILD in these conditions, and current evidence regarding STING activity in their pathogenesis. We discuss data from studies of a variety of other ILDs and model systems and explore the potential role for STING in more common forms of ILD.