Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double-stranded RNA (mt-dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi-Goutières syndrome (AGS). We describe a 7-month-old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off-label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN-driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment-limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a "mitochondrial interferonopathy" and suggests that IFN-signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.

Background and objectives. Rheumatoid arthritis (RA) is a progressive systemic autoimmune disorder that mainly targets the joints, causing inflammation and destruction of affected joints. The main therapeutic goal is to prevent joint destruction, preserve function, and maintain a better quality of life. The type I interferon (IFN-I) signature, characterized by increased expression of interferon-response genes, is present in a subset of RA patients and may serve as a potential biomarker for disease activity and prognosis. The purpose of this study was to shed light on the role of the IFN-I signature in patients with RA. Materials and methods. The study included 100 participants: 50 RA patients and 50 healthy controls. History taking, clinical assessment, and disease activity scoring were performed in all patients, along with anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) measurements. Whole blood samples were obtained, and quantitative real-time polymerase chain reaction (qPCR) was performed to assess the mRNA expression levels of IFI44L, IFNAR1, and IFNAR2. Results. IFI44L, IFNAR1, and IFNAR2 were significantly upregulated in RA patients and showed significant positive correlations with DAS28, anti-CCP, and RF (all p < 0.001). The strongest correlation was observed between IFI44L and anti-CCP (r = 0.671). ROC analysis showed high discriminatory performance within the studied cohort, with AUC values of 0.974 for IFI44L, 0.982 for IFNAR1, and 0.984 for IFNAR2. Conclusions. Patients with RA showed a high IFN-I signature, supporting its role in disease pathogenesis and activity.

Adult-onset dermatomyositis (DM) is an autoimmune inflammatory myopathy with distinct cutaneous manifestations and a strong association with malignancy. Through comparative analysis with cutaneous lupus erythematosus (CLE), our integrated spatial and single-cell transcriptomics analysis reveals unique immune and stromal niches associated with DM subtypes. We find that cancer-associated DM skin lesions are distinguished by the presence of dispersed immune infiltrates enriched with macrophages or organized lymphoid aggregates with dense B cell cores surrounded by CD4 + /CD8 + T cells, accompanied by preserved vascular architecture. In contrast, non-cancer-associated DM skin is characterized by dense myeloid cell infiltrates, harbouring elevated expression of IL1B and CXCL10 localizing near injured vascular endothelia. Cytokines produced by these myeloid infiltrates, together with local tissue hypoxia, trigger dramatic stromal remodelling, leading to loss of vascular-associated fibroblasts. In addition to the CXCL10+ myeloid signature, non-cancer-associated DM skin is characterized by specific cellular pairs: PD-L1-expressing mature dendritic cells enriched in immunoregulatory molecules (mregDC) and activated regulatory T cells (Treg) expressing NFKB2 and TNF receptors. While both DM and CLE show strong interferon signatures, DM uniquely displays IFNβ expression. Together, our study provides a comprehensive spatial mapping of immune and stromal cells in adult-onset DM.

Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is accompanied by profound remodeling of the bone marrow microenvironment (BME), yet the contribution of its non-immune compartment remains unclear. Using single-cell RNA sequencing in genetically engineered mouse models that recapitulate disease evolution, we transcriptionally profile endothelial cells (EC) and mesenchymal stem cells (MSC). EC adopt a stress-associated program at MGUS that precedes angiogenesis in MM, while MSC undergo early and sustained loss of differentiation capacity. We identify a coordinated interferon (IFN)-driven program across EC and MSC that defines MM in the BIcγ1 model but is absent in the more aggressive MIcγ1 model. Treatment with bortezomib, lenalidomide, and dexamethasone suppresses this IFN signature, promotes endothelial adaptation, and restores osteogenic potential in MSC. Validation in patient samples reveals enrichment of this IFN-signature across disease stages. These findings define dynamic and targetable alterations in the non-immune BME during myeloma progression.

Type I interferonopathies are heterogeneous diseases driven by dysregulated IFN-I signaling. Diagnosis is challenging due to clinical/molecular variability and the need for IFN-I quantification. To characterize the clinical, immunological, genetic, molecular profiles of patients with suspected enhanced IFN-I signaling, and assess diagnostic utility of IFN signature, CXCL10 levels, antiviral activity. Forty-six patients with clinical or genetic findings consistent with type I interferonopathies were included. The IFN signature, CXCL9 and IFNG were assessed using RT-qPCR (n=34 each). Serum CXCL10 and CXCL9 were measured by ELISA (n=37 each). WES was performed for molecular diagnosis (n=46). Antiviral activity was evaluated using rVSV-GFP (n=5). Two groups were defined: genetically confirmed and undifferentiated interferonopathies. Molecular diagnosis was established in 37/46 (80%) of the patients. IFN signature was evaluable in 34/46 and positive in 31/34 (91%); median IFN score was higher in patients (p<0.0001). CXCL10 levels were higher in patients and correlated with IFN scores (rs=0.4994, p=0.0026). Both IFN score and CXCL10 showed strong discriminative capacity. Autoantibodies were detected in 67%. Antiviral activity varied across phenotype. Our findings highlight the clinical and molecular diversity of interferonopathies and underscore the possible diagnostic utility of CXCL10 levels. We define a group of patients with consistent clinical features and clear interferon signatures as undifferentiated interferonopathies. Variable antiviral responses indicate differential IFN pathway modulation. These results support the integration of molecular and functional IFN profiling into the diagnostic workup and monitoring of suspected interferonopathies, which may aid in precision medicine.

Systemic lupus erythematosus (SLE) is a disease with considerable unmet treatment needs. Endosomal nucleic acid sensing by Toll-like receptor 7 (TLR7) is emerging as a key pathogenic pathway. Gain-of-function mutations in the genes encoding TLR7 and its chaperone UNC93B1 can cause monogenic childhood-onset SLE; rare variants in proteins that regulate ligand availability or downstream signalling proteins also contribute to disease. TLR7 variants can increase the affinity of this receptor for its ligands and can alter binding to endogenous antagonists. Both self RNA-protein complexes and viruses have been implicated in TLR7 activation. Key pathogenic mechanisms include breakdown in B cell tolerance and autoantibody production and type I interferon secretion. Although current therapies such as B cell-depleting chimeric antigen receptor(CAR) T cells and anifrolumab (anti-type I interferon receptor) offer benefit, they are limited by high costs and lack of oral options. In this context, TLR7 has emerged as a promising therapeutic target. Phase II trials of an oral dual TLR7-TLR8 antagonist show durable suppression of the interferon signature in all patients, indicating that TLR7 and TLR8 drive this signature in SLE. This treatment has shown clinical benefit for SLE and cutaneous lupus erythematosus, although the primary endpoint (a dose-response effect) was only met in cutaneous lupus erythematosus. Thus, TLR7-TLR8 antagonists might reshape SLE treatment, alone or in combination with other drugs.

One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many patients, highlighting the need for strategies to overcome resistance. Most efforts have focused on promoting immune cell infiltration into refractory tumors to improve ICI efficacy. In this work, we mobilize this approach by focusing on Argonaute 2 (Ago2), a pivotal member of the RNA interference pathway. Using two murine models of immunorefractory NSCLC, we demonstrate that tumoral Ago2 suppresses interferon signaling, leading to poor immunogenicity and failure of ICI therapy. Genetic deletion of Ago2 in cancer cells restores interferon signaling and supports immune infiltration of the tumor. Consequently, whereas wild-type tumors are resistant to ICI, tumors devoid of Ago2 become sensitive to treatment. In NSCLC patients treated with ICI, high Ago2 expression and a low interferon signature in tumors correlates with reduced survival. Ago2 is thus a driver of the immunorefractory phenotype observed in NSCLC and may represent a therapeutic target when aiming to sensitize patients to ICI.

Type I interferons (IFN-I), including IFN-α, IFN-β, and IFN-ω, are central to antiviral defence and immune regulation. Autoantibodies targeting IFN-I (anti-IFN-I AAbs) have emerged as key pathogenic factors in severe coronavirus disease 2019 (COVID-19) and are detectable in systemic lupus erythematosus (SLE), a prototypic IFN-driven autoimmune disease. Here we compare the prevalence and clinical impact of anti-IFN-I autoantibodies (Aabs) in COVID-19 and SLE based on a structured review of 53 studies from 2014 to 2025 and highlight the clinical associations and therapeutic opportunities presented by these autoantibodies. In COVID-19, neutralising anti-IFN-α and/or anti-IFN-ω AAbs were consistently associated with severe disease and impaired antiviral responses, particularly in older male populations. In SLE, anti-IFN-α AAbs were variably detected; neutralising antibodies were associated with reduced interferon gene signatures in some cohorts but inconsistent correlations with disease activity. Therapeutically, anti-IFN-I AAbs in COVID-19 may inform risk stratification and early antiviral strategies, whereas in SLE, IFN-α blockade, including IFN-α kinoid vaccination, demonstrates modulation of IFN signatures but variable clinical benefit. Notably, these findings reveal an immunological paradox: the same neutralising mechanism that impairs antiviral defence in COVID-19 may attenuate chronic IFN-driven inflammation in SLE. Taken together, anti-IFN-I AAbs exert context-dependent effects: pathogenic in acute viral infection yet potentially modulatory in chronic IFN-driven autoimmunity. Prospective longitudinal studies are required to further clarify their translational utility and long-term clinical impact.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death within this decade. Here, we show that its major driver oncogene KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response that primes PDAC cells for necroptosis. Using genetically engineered mouse models, we find that cancer cell-specific deletion of caspase-8 is sufficient to trigger necroptotic cell death, eliminating most pancreatic precursor lesions. Mechanistically, KRAS-driven IFN signalling induces ISGF3-dependent expression of necroptosis-related interferon-stimulated genes, including MLKL. This renders PDAC cells selectively vulnerable to necroptosis upon caspase-8 inhibition. Therapeutically, pharmacologic caspase inhibition reduces tumour burden in aggressive PDAC models and human patient-derived organoids. A pan-cancer transcriptomic analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumour types. These findings reveal a KRAS-induced IFN program that sensitises tumour cells to necroptosis, highlighting a therapeutic vulnerability in PDAC with broader relevance across IFN-activated cancers.

Oral potentially malignant disorders (OPMDs) are precursor lesions with variable risk of progressing to oral squamous cell carcinoma (OSCC). Reliable biomarkers to predict malignant transformation (MT) risk are urgently needed. RNA sequencing and pathway analyses were performed on 18 progressive and 22 non-progressive OPMDs. A prospective, multicenter cohort study (TWOPMD) analysed 1313 saliva samples from eight Taiwan healthcare centers: 356 healthy controls, 860 OPMD patients and 97 OSCC patients. Eight inflammation-related cytokines were quantified using Bio-Plex immunoassay. Cox regression models evaluated 749 OPMD cases with longitudinal follow-up to identify cytokine predictors of malignant transformation. Interferon (IFN) signalling was significantly enriched in progressive OPMDs, with IFN signatures correlating strongly with inflammation-related cytokine expression. IL-1β, IL-6, IL-8, TNF-α and IL-10 were significantly dysregulated across the OPMD, OSCC and control groups. Cox regression identified IL-6, IL-6/IL-1Ra ratio, and composite index (IL-6×IL-8)/IL-1Ra as significant MT predictors. Kaplan-Meier analyses confirmed elevated cytokine biomarkers were associated with significantly higher cancer risk (p = 0.02, p = 0.00001, p = 0.002). Incorporation of betel nut chewing status into the cytokine-based models further improved prognostic performance. Salivary cytokines, particularly IL-6/IL-1Ra ratio, are promising noninvasive biomarkers for predicting oral cancer risk in OPMD patients.

Systematic dysregulation of immune-related alternative polyadenylation in systemic lupus erythematosus contributes to patient stratification

Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatosis characterized by skin blistering and erosions in intertriginous regions, frequently complicated by secondary infections leading to substantial impairment in quality of life. No targeted mechanism-based therapies are currently available. Here, we applied a multiomics approach to define the molecular and cellular landscape of HHD. Bulk transcriptomics and proteomics uncovered a striking interferon (IFN) signature in HHD skin lesions. Single cell and spatial transcriptomics analyses revealed inflammatory niches, where immune, epithelial, vascular and stromal cells create a multi-compartment IFN-driven signaling network, that sustains a feed-forward amplification loop essential for chronic inflammation. Crucially, in nine patients with refractory HHD, topical treatment with the JAK1/2 inhibitor ruxolitinib led to rapid and durable re-epithelialization with drastic reduction in pain, itching, oozing and skin inflammation, significantly improving patient quality of life. Collectively, our findings identify IFN signaling as a key pathogenic driver in HHD and support topical JAK inhibition as an effective therapy, redefining the standard of care for individuals living with HHD.

This study aims to evaluate the safety, biological activity, and exploratory clinical effects of CD19-directed T-cell engagement with blinatumomab in patients with severe, treatment-refractory antitopoisomerase I-positive systemic sclerosis (SSc). We conducted an exploratory case series of 5 patients with refractory SSc who received a 14-day continuous intravenous infusion of blinatumomab (9 µg/d for 7 days, escalated to 28 µg/d for 7 days) in 2 tertiary hospitals. Safety assessments included cytokine release syndrome (CRS), neurotoxicity, infections, and serum immunoglobulin levels. Exploratory efficacy outcomes comprised modified Rodnan skin score (mRSS), pulmonary function tests, and patient-reported outcomes. Immunologic endpoints included serial peripheral CD19⁺ B-cell counts, B-cell subset phenotyping, and a 6-gene type I interferon signature. Patients' follow-up was a median of 8 months (range: 6-12). Blinatumomab administration was generally well tolerated. Three patients experienced low-grade CRS (grade 1, n = 2; grade 2, n = 1), managed conservatively; no neurotoxicity or severe infections occurred. Rapid peripheral CD19⁺ B-cell depletion was achieved in all patients. B-cell repopulation occurred by 1 month in all but 1 patient and was dominated by naïve and transitional subsets. At 3 months, modest clinical improvements were observed, including a median mRSS change of -4 points (range: +1 to -8) from a baseline of 16 (range: 0-25) and a transient improvement in lung function and patient-reported outcomes. However, all patients experienced clinical relapse between months 3 and 6, leading to resumption of immunosuppressive therapy in most cases. CD19-directed T-cell engagement with blinatumomab induces rapid B-cell depletion and short-term clinical improvement in refractory SSc but lacks durability after a single treatment cycle.

Single-cell RNA-seq reveals a persistent interferon signature in immune cells from systemic lupus erythematosus patients with high versus low polygenic risk scores despite antimalarial treatment.

Immunologic links between cutaneous lupus and internal organ involvement in SLE: A systematic review and meta-analysis.

Breast cancer (BC) is the most common type of cancer among women worldwide and underlies relapse, disease progression, and metastasis. Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects BC therapy success and remains a major challenge. Although necroptosis, a lytic, and via damage-associated molecular patterns (DAMP) release, highly immunogenic mode of PCD, might overcome apoptosis resistance, there is an urgent need for physiological and translational human models to model necroptosis and PCD resistance in BC. Here, we apply 3D patient-derived, metastatic human mammary organoids (hMOs) to model apoptosis resistance, necroptosis, and inflammatory signaling using single-cell CITE-sequencing, time-lapse live cell brightfield, and immunofluorescent confocal microscopy, as well as biochemical approaches. Smac mimetic-triggered apoptosis could be confirmed in a panel of BC hMOs. Upon inducing apoptosis resistance with caspase inhibition, BC hMOs rapidly undergo necroptosis with profound MLKL phosphorylation. Necroptotic cell death was preceded by prominent transcriptional upregulation of inflammatory cyto- and chemokines, including interferons, that activate natural killer cells. Finally, necroptosis and the expression and release of inflammatory messengers in metastatic BC hMOs could be attenuated upon the inhibition of linear ubiquitination. We describe a novel experimental platform to model PCD, inflammation, and necroptosis that allows therapeutic screening to overcome chemotherapy resistance in patient-derived metastatic BC hMOs. With this platform, we identified necroptosis-induced interferon signaling, suggesting Smac mimetics and necroptosis as a potential immunotherapy strategy against metastatic BC.

Immune checkpoint inhibitor-induced lichen planus (ICI-LP) is a cutaneous immune related adverse event (irAE) that shares key clinicopathologic features with spontaneous lichen planus (LP) but differs histologically and in the sex distribution of its incidence, and may therefore reflect a distinct tissue inflammatory state. To define the cellular programs that distinguish ICI-LP from LP, we profiled lesional skin by single cell and spatial transcriptomic approaches. We found few differences in the T cell and keratinocyte compartments between ICI-LP and LP, which shared similar inflammatory signatures. Rather, the dominant transcriptional features differentiating these two eruptions occurred within the fibroblast and myeloid cell compartments. Fibroblasts in ICI-LP were enriched for IGF1, FGF7, and androgen-response-associated programs, whereas myeloid cells exhibited amplified JAK-STAT and interferon-responsive states spanning both type I and type II interferon signatures. The potential role of androgen response in shaping lichenoid inflammation was supported by a striking loss of androgen receptor expression in lesional keratinocytes by immunohistochemistry. Furthermore, using spatial RNA and transcriptomic approaches, we identified anatomically segregated IFNG, IL17A , and IL13 niches within lesional skin, suggesting that regional immune compartmentalization with differences in local immunoregulation may explain the mixed inflammatory features reported in both ICI-LP and LP. Collectively, these data indicate that ICI-LP is not simply a more inflamed form of LP, but a distinct form of the disease with more prominent inflammatory perturbations within stromal and innate immune cell populations.

Maternal-fetal type I interferon signaling drives TREM2 dysregulation and synaptic dysfunction in neurodevelopmental disorders.

Type I interferon (IFN-I) is a proinflammatory cytokine that activates signalling pathways crucial for antiviral defence in innate immunity. The IFN-I system is a self-preserving mechanism that normally responds to exogenous nucleic acids derived from pathogens, but not to endogenous nucleic acids from host cells. However, genetic defects that constitutively activate this pathway can lead to aberrant IFN-I production (the "IFN signature") and sterile inflammation (autoinflammation), giving rise to a group of monogenic disorders collectively termed "autoinflammatory interferonopathies." This emerging perspective was initially prompted by the phenotypic similarities between Aicardi-Goutières syndrome and congenital toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex (TORCH) infection. Autoinflammatory interferonopathies can manifest with variable combinations of cutaneous changes, encephalopathy, vasculopathy, interstitial lung disease, and other features (e.g., skeletal changes), and are commonly accompanied by autoimmunity. More recently, the IFN signature has also attracted attention in autoimmune diseases such as systemic lupus erythematosus and dermatomyositis, which have been increasingly referred to as "autoimmune interferonopathies." Collectively, interferonopathies provide a novel framework for immune-mediated diseases spanning an autoinflammatory-autoimmune continuum. Here, we outline the clinical, imaging, and pathogenic features of paediatric interferonopathies. While each disorder has distinctive imaging findings, many share common patterns reflecting common underlying pathophysiology.

Interleukin-1 receptor-associated kinase 2 (IRAK2) is essential for the Myddosome complex formation downstream of Toll-like receptors. We identify twelve patients with a homozygous loss-of-function copy number variant in IRAK2, designated IRAK2-∆ex2. Most patients present with recurrent infections, autoantibody production, and gastrointestinal ulceration. Two patients were clinically diagnosed with primary immunodeficiency, while the majority fulfill diagnostic criteria for autoimmune or autoinflammatory diseases. The IRAK2-∆ex2 protein fails to interact with IRAK4, leading to impaired activation of nuclear factor kappa B signaling via the Myddosome complex. An elevated type I interferon signature is observed in the patients, which is confirmed in bone marrow-derived macrophages from knock-in mice and knockout cell lines. Mechanistically, our data are consistent with engagement of a TRIF-dependent interferon pathway. Baricitinib attenuates the elevated interferon signature in patient-derived cells ex vivo and cell lines. Here, we show IRAK2 deficiency as a monogenic immune dysregulation disorder.