Abstract Peginterferon‑α is useful to treat myeloproliferative neoplasms (MPNs) but can precipitate broad autoimmunity. By promoting beta‐cell, thyroid, and systemic immune injury, it can lead to Type 1 diabetes, autoimmune thyroiditis, systemic lupus erythematosus, or Sjögren's syndrome. Onset typically occurs within the first months but may be delayed until after treatment cessation. Type 1 diabetes is usually irreversible and requires lifelong therapy, whereas thyroiditis and lupus more often improve after interferon withdrawal, though autoantibodies frequently persist. In this narrative review, we provide an overview of how peginterferon can induce autoimmunity in genetically susceptible individuals with pre‐existing subclinical autoimmunity. Pre‐treatment risk assessment, including personal/family history of autoimmune disease and consideration of baseline thyroid function and anti‐GAD antibodies in high‐risk patients, may identify those at elevated risk for irreversible complications, particularly Type 1 diabetes. Targeted clinical and laboratory monitoring throughout therapy and for 12–24 months post‐cessation can enable early detection and appropriate intervention.

Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that lacks effective targeted therapies. T cell and neutrophil activation are associated with tissue lesions in ANCA-associated vasculitis responsible for the necrotizing vasculitis of small blood vessels. Although the aberrant release of reactive oxygen species (ROS) by neutrophils contribute to the disruption of the endothelial barrier, the underlying molecular mechanisms of this oxidative burst remain unclear. Here, we observe that blood vessels in the inflamed organs of patients with AAV express CD95L, which is cleaved by metalloproteases to release soluble CD95L (sCD95L). sCD95L stimulates ROS production in AAV neutrophils via a caspase-driven mechanism. Proteomic analysis reveals that the deubiquitinase OTULIN is a caspase substrate in sCD95L-exposed neutrophils. Caspase-10 cleaves OTULIN after its aspartates at positions 31 and 54 to unleash the activity of E3 ligase complex LUBAC and trigger mitochondrion-dependent ROS production in AAV neutrophils. Inhibition of the CD95-mediated non-apoptotic signaling abrogates ROS production in AAV neutrophils and alleviates clinical symptoms in AAV and crescentic glomerulonephritis mouse models, indicating that CD95 and CD95L represent attractive molecular targets for patients with AAV.

Introduction ANCA-associated vasculitis with glomerulonephritis (AAV-GN) is classically considered pauci-immune, yet complement activation is a central pathogenic mechanism. Whether intrarenal complement-related transcriptional programs are reflected by conventional serum or immunofluorescence markers, and whether they are clinically informative, remains unclear. Methods In 369 AAV-GN patients from two independent retrospective cohorts, complement was assessed across circulating, histopathological, and transcriptomic layers (serum C3/C4, glomerular C1q/C3 deposition, targeted kidney transcriptomics). Predefined classical and alternative pathway–related expression scores were derived from intrarenal gene expression. Associations with severity and outcomes were evaluated using multivariable Cox models. Public spatial transcriptomic datasets provided validation and localization. Results Below-normal serum C3/C4 levels were uncommon. Low serum C3, but not C4, was associated with more severe kidney involvement, kidney failure (adjusted HR 2.0 [1.1–3.7]) and mortality (adjusted HR 2.3 [1.3–4.0]). Glomerular C3 (47%) and C1q (11%) deposition both identified more severe pathology and adverse outcomes. Compared with controls, AAV-GN kidneys showed increased complement-related expression involving classical pathway components, proximal alternative pathway genes, C3, C5AR1, and regulatory transcripts, only weakly concordant with serum or deposition markers. Low alternative pathway–related expression was independently associated with better kidney (adjusted HR 0.3 [0.1–0.7]) and overall (adjusted HR 0.4 [0.2–0.9]) survival. Spatial transcriptomics validated these signatures and suggested contributions from both immune and resident kidney compartments. Conclusion AAV-GN displays a reproducible intrarenal complement-related transcriptional program, only weakly captured by serum levels or routine immunofluorescence, associated with renal severity and outcomes. These findings support prospective studies integrating tissue complement transcriptomics for stratification and therapeutic hypothesis generation.

INTRODUCTION:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) causes severe multisystemic organ damage. The main phenotypes, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), share similarities but differ in clinical presentation and outcome. To uncover their molecular differences, we performed transcriptomic profiling of kidney tissue, then focused on type I interferon (IFN-I) pathway activation in kidney and blood and its clinical implications. METHODS:We analyzed two independent cohorts (Maine-Anjou and RENVAS registries) totaling 193 patients with AAV and glomerulonephritis. NanoString nCounter transcriptomic profiling, and serum inflammatory molecules quantification were conducted. Comparative analyses of MPA vs. GPA (and MPO-AAV vs. PR3-AAV) were validated using independent public datasets (including kidney spatial transcriptomic datasets, European cDNA Renal Biobank and blood from the RAVE trial). RESULTS:The kidney IFN-I signature found in AAV-GN is upregulated in MPA/MPO-AAV compared to GPA/PR3-AAV and controls. Quantitative PCR, MxA immunohistochemistry, and analysis of external datasets confirmed these findings. This IFN-I signature, close to the one found in lupus nephritis, is linked to the extent of pDC infiltration. Kidney IFN-I activation correlated with increased kidney fibrosis, independently of kidney function. High kidney IFN-I signatures were linked to lower kidney survival, independently of kidney function and pathological scores. MPA kidneys also exhibited higher mast cell and T-cell infiltration. Systemic analyses showed elevated IFNα and interferon related inflammatory molecules in all patients with AAV, but a stronger IFN-I gene signature was found in immune cells from MPA. CONCLUSIONS:Our study identifies an IFN-I signature in AAV, especially in MPA/MPO-AAV, underscoring its potential role in disease heterogeneity and kidney pathology. IFN-I emerges as a potential prognostic biomarker and therapeutic target in AAV, particularly for MPA. Further studies are needed to clarify its mechanisms and explore IFN-I modulation in clinical trials.

Evaluation of CMV-specific cell-mediated immunity (CMI) has improved strategies to prevent post-transplant CMV disease. This study assessed the association between CMV disease and absolute count of TEMRA γδ T cells at the end of universal prophylaxis in kidney transplant recipients (KTR). We retrospectively analyzed 262 R⁺ and 82 D⁺/R⁻ KTRs who received antiviral prophylaxis and had TEMRA γδ T cells quantified at the end of prophylaxis. The primary endpoint was CMV disease within two years post-transplant. Post-prophylaxis CMV disease occurred in 43/344 (12.5%) patients. A threshold of 4.65/mm³ for TEMRA γδ T-cell count was identified by ROC analysis; higher counts were associated with reduced CMV disease incidence. While no significant association was found in the overall cohort, in R⁺ patients, a count >4.65/mm³ was associated with a 97.7% positive predictive value for protection against CMV disease. Multivariate analysis confirmed its independent association with disease-free survival [HR: 0.27 (95% CI: 0.09–0.85), p = 0.0252]. Measuring TEMRA γδ T-cell counts at the end of prophylaxis may serve as a useful, accessible immune marker to guide CMV prevention strategies in R⁺ kidney transplant recipients.

Paediatric-onset anti-nuclear antibody-associated immune thrombocytopenic purpura (ITP-ANA+) is a pre-lupus condition. Interferon signature (IS) is a reliable method to measure interferon-stimulated gene expression which is commonly raised in systemic lupus erythematosus (SLE) and in adult pre-lupus cases. Between 2022 and 2024, IS analysis was performed on 61 children, 17 with ITP-ANA+, 15 with ITP-ANA-, 15 with SLE and 14 with juvenile idiopathic arthritis. IS was positive in 14/17 children (82%), with a median score of 17 (1.2-143). This median IS was significantly higher than in the ITP-ANA- group (2.8, 1-41, p = 0.03) and lower than in the SLE group (37.5, 2.1-129, p = 0.04). Among ITP-ANA+ children, IS elevation was associated with age >10 years at ITP diagnosis, newly diagnosed or persistent ITP, positive anti-extractable nuclear antigen antibodies and the absence of hydroxychloroquine treatment. Hydroxychloroquine significantly reduced IS values in three children with pre- and post-treatment scores available. The involvement of type I interferon signalling in childhood ITP-ANA+ highlights a distinct pathogenic pathway and IS appears as a pertinent biomarker to identify patients at risk of progression to SLE. The introduction of hydroxychloroquine in these patients could help prevent the high morbidity of SLE at adult age.

INTRODUCTION:Pregnancy in women with systemic lupus erythematosus presents significant clinical challenges due to heightened risks of complications for both mother and fetus. Therapeutic management must be carefully tailored to safeguard maternal health while ensuring optimal fetal development. AREAS COVERED:This review explores pharmacological treatments used during pregnancy in women with lupus, focusing on medication safety profiles, risk-benefit analyses of available therapeutic options, and specific challenges posed by comorbidities such as antiphospholipid syndrome and vaccination considerations. EXPERT OPINION:Although significant advances have been made in managing lupus during pregnancy, many treatments, particularly biologic therapies, still lack sufficient evidence for unrestricted use. This underscores the necessity for vigilant monitoring and individualized treatment protocols. Preconception consultation remains crucial for optimizing therapeutic strategies, ensuring appropriate medication adjustments prior to conception. A coordinated multidisciplinary approach is essential to navigate these complexities and achieve favorable outcomes for both mother and child.

Crystalline silica (the most abundant form of silicon dioxide) is a natural element that is ubiquitous in the Earth's crust. Chronic personal or professional exposure has been implicated in various pathologies, including silicosis and autoimmune diseases since the early 20th century. More recently, a specific pathogenic role for crystalline silica has been identified through its impact on lung epithelial cells as well as immune cells present at this organism barrier. This review summarizes the current in vitro and in vivo knowledge regarding the physiopathology of crystalline silica at the lung-environment interface, discusses its effects on innate and adaptive immune cells and epithelial cells, and reviews current therapeutic perspectives explored in mouse models to alleviate its impact, especially on autoimmune phenotypes.

Key PointsLarge-scale kidney transcriptomics identifies a 12-gene signature, including and , predicting kidney failure in ANCA-associated vasculitis.CLUC3This molecular signature outperformed Berden, renal risk score, and ANCA kidney risk score clinicopathologic classifications.ANCA-associated vasculitis with GN kidneys show broad immune dysregulation, notably in complement, TGF beta, and immunometabolism pathways.BackgroundANCA-associated vasculitis with GN (AAV-GN) frequently progresses to kidney failure. However, tools for risk stratification of kidney outcomes remain limited. Existing approaches inadequately capture the molecular complexity underlying kidney injury, despite its potential value to tailor therapeutic management. We explored whether kidney transcriptomics could identify molecular signatures linked to kidney outcomes. MethodsWe included 199 patients with AAV-GN from two multicenter biobanks, and 23 controls. Kidney biopsies were profiled using NanoString nCounter to assess the expression of 750 immune-related genes. We conducted differential gene expression analysis, pathway enrichment analysis, and immune cell infiltration estimation to explore associations with kidney function and survival. A 12-gene prognostic signature was developed through least absolute shrinkage and selection operator-penalized Cox regression and compared with established histologic classifications (Berden classification, renal risk score, and ANCA kidney risk score) with robust internal validation. ResultsAAV-GN demonstrated extensive immune dysregulation with 150 differentially expressed genes versus controls, highlighting complement activation, immune cell recruitment and activation, TGF beta signaling, and immunometabolism pathways. Immune cell infiltration was marked by increased macrophages, dendritic cells, neutrophils, and T-cell subsets, reflecting broad immune activation. Initial eGFR correlated with the expression of 319 genes. A 12-gene signature (CLU, C3, LTF, FLT1, PLCG2, FES, PRKCD, TXNIP, SLC7A5, PTEN, NRBF2, and NFATC1) was significantly more strongly associated with kidney survival than were established histologic classifications (adjusted P value < 0.0001). Both high expression and low expression of several immune pathways (especially lymphocyte trafficking) were associated with better outcomes compared with intermediate expression. ConclusionsTranscriptomic analysis of kidney biopsies in AAV-GN identified 150 differentially expressed immune-related genes and led to the development of a 12-gene signature that correlated strongly with kidney survival, outperforming established histologic classifications.

Abstract Background and Aims Kidney involvement in ANCA-associated vasculitis (AAV-GN) predicts poor patient and kidney survival. Deciphering the transcriptomic landscape in AAV-GN may provide insights into pathogenic mechanisms or identify biomarkers for refining diagnosis and/or prognosis, which would help stratify risk and tailor therapeutic management. We aimed to investigate the potential prognostic value of kidney transcripts associated with kidney survival. Method This study included adult patients with AAV-GN from the French Maine-Anjou Registry. Immune gene transcript analysis was performed on RNA extracted from 97 AAV-GN kidney biopsies using NanoString technology. Transcripts of interest were selected, and their prognostic performance was assessed with respect to current histological-based classifications. Following the identification of a possible role for clusterin (CLU), the relationship between serum CLU and prognosis was assessed. Results Among the 750 evaluated transcripts, we identified a 4-gene signature (XRCC6, PRKCD, TEK, and CLU) that was strongly associated with kidney survival (Fig. 1A). This signature predicted kidney survival better than histological-based classifications (global C-Index 0.87 vs. 0.65 for Berden classification or 0.81 for Renal Risk Score, with better time-dependent AUC and Brier scores, especially beyond 1 year after diagnosis) (Fig. 1B). Among these 4 transcripts, the expression level of the CLU transcript had the highest correlation with glomerular involvement, kidney function at diagnosis, and kidney survival. Serum CLU levels were associated with kidney survival, especially when assessed at 6 months from diagnosis (Fig. 1C, P = .023). Conclusion Transcriptomic analysis of kidney biopsies of AAV-GN identified potential transcripts that may improve prediction of kidney survival. This transcriptomic signature may help us gain a deeper understanding of the AAV-GN pathogenesis and provide insights for developing new therapeutic options.

Purpose About 25% of patients with common variable immunodeficiency disease (CVID) have splenomegaly, necessitating sometimes splenectomy whom consequences on the immunological profile of CVID patients have never been studied. We analyzed 11 CVID patients’ comprehensive blood immune cell phenotypes pre- and post-splenectomy. Methods Flow cytometry analyses of immune cell populations. Results Among 89 CVID cohort patients, 41 with splenomegaly, splenomegaly was strongly associated with granulomatous disease, autoimmune disorders, lymphoid hyperplasia, and/or portal hypertension. CVID patients with splenomegaly have significant peripheral lymphopenia ( p = 0.001), and significantly fewer peripheral class-switched memory B cells (smBs) ( p = 0.001), CD4 + T lymphocytes ( p = 0.001), NK ( p = 0.0001) and dendritic cells ( p ≤ 0.01), and significantly more circulating CD4 + and CD8 + ( p = 0.00001) T cell subset activation ( p = 0.00005), than CVID patients without splenomegaly. Examination of splenectomy impact on circulating lymphocyte subset distributions demonstrated the drastically enhanced total circulating lymphocyte count post-splenectomy, predominantly B lymphocytes and CD8 + T cells. However, splenectomy did not change B cell distribution, with smBs remaining persistently low, in contrast to complete inversion of the circulating T cell composition, with reversal of the CD4 + /CD8 + ratio suggesting that amplification of the CD8 + T cell compartment is a CVID characteristic in patients with splenomegaly. Our results highlight this CD8 + amplification in CVID–splenomegaly patients that might be explained by a homing effect to the spleen and/or possible chronic virus replication, which in turn could induce T cell expansions. Conclusion Splenectomizing CVID patients with splenomegaly restores the absolute circulating lymphocyte count, suggesting that the decreased T cell count in the presence of splenomegaly cannot be used as an exclusive criterion for combined immunodeficiency.

Background: Myocarditis is commonly diagnosed in the intensive care cardiology unit (ICCU). No current recommendation nor guideline aids exist for aetiological assessments. Methods: From September 2021 to October 2023, 84 patients with acute myocarditis underwent thorough and systematic serum and blood cell panel evaluations to determine the most common causes of myocarditis. Results: Of the 84 patients (median age 34 years, range 22–41 years, 79% male), 16 presented with complicated myocarditis. The systematic aetiological assessment revealed that 36% of patients were positive for lupus anticoagulant, 12% for antinuclear antibodies, 8% for anti-heart antibodies, and 12% for anti-striated muscle antibodies. Viral serology did not yield any significant results. After the aetiological assessment, one patient was diagnosed with an autoimmune inflammatory disorder (Still’s disease). T-cell subset analyses indicated that myocarditis severity tended to increase with the T-cell lymphopenia status. Conclusions: A comprehensive, systematic aetiological assessment was of limited value in terms of predicting the clinical or therapeutic outcomes in myocarditis patients presenting to the ICCU.

IntroductionType 1 interferons (IFNs) play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE) and various type I IFNs targeting therapeutic approaches have been developed. Anifrolumab, a monoclonal antibody that binds to the subunit 1 of the type I IFN receptor, has acquired considerable interest and has entered different clinical human trials willing to evaluate its efficacy and safety.Areas coveredThis review summarizes the data obtained in phases 1, 2, and 3 clinical trials of anifrolumab for SLE patients. A focus is made on data of clinical efficacy and safety obtained in MUSE, TULIP-1 and TULIP-2 trials.Expert opinion/CommentaryAnifrolumab is a promising therapeutic option for patients with SLE, currently authorized for moderate-to-severe SLE. Extensive real-world use is now going to generate data required to gain experience on the type of patients who benefit the most from the drug, and the exact positioning of anifrolumab in the therapeutic plan.

We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis.