UNASSIGNED: Despite surgical resection, chemoradiation, and targeted therapy, brain tumors remain a leading cause of cancer-related death in children. Immunotherapy has shown some promise and is actively being investigated for treating childhood brain tumors. However, a critical step in advancing immunotherapy for these patients is to uncover targets that can be effectively translated into therapeutic interventions.
UNASSIGNED: In this study, our team performed a transcriptomic analysis across pediatric brain tumor types to identify potential targets for immunotherapy. Additionally, we assessed components that may impact patient response to immunotherapy, including the expression of genes essential for antigen processing and presentation, inhibitory ligands and receptors, interferon signature, and overall predicted T cell infiltration.
UNASSIGNED: We observed distinct expression patterns across tumor types. These included elevated expression of antigen genes and antigen processing machinery in some tumor types while other tumors had elevated inhibitory checkpoint receptors, known to be associated with response to checkpoint inhibitor immunotherapy.
UNASSIGNED: These findings suggest that pediatric brain tumors exhibit distinct potential for specific immunotherapies. We believe our findings can guide investigators in their assessment of appropriate immunotherapy classes and targets in pediatric brain tumors.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which poses significant challenges due to its chronic nature and complex clinical manifestations. For patients with moderate-to-severe SLE, anifrolumab, a monoclonal antibody that targets the type 1 interferon receptor (IFNAR), has emerged as a cutting-edge treatment option that can reduce disease activity, prevent organ damage from the illness or side effects resulting from medications, and enhance the quality of life for those living with SLE. Consequently, this drug has received approval from major regulatory agencies. Anifrolumab\'s safety, effectiveness, and long-term results are assessed in this systematic review using information from clinical trials, real-world research, and retrospective analysis. In particular, clinical investigations, such as the MUSE Phase II and TULIP Phase III trials, showed that anifrolumab significantly improved important outcomes compared to placebo, including the SLE Responder Index, major clinical response, and disease activity ratings. During extended use, anifrolumab demonstrated significant sustained efficacy and a tolerable safety profile, with controllable side events mostly associated with viral infections. Moreover, subgroup analyses, demonstrating that Asian patients and individuals with a strong interferon gene profile are particularly responsive to anifrolumab, underscore the importance of customized treatment methods. Anifrolumab\'s safety and effectiveness were further validated by real-world data, particularly in patients who reached the Lupus Low Disease Activity State (LLDAS), where the drug decreased glucocorticoid consumption and disease activity. Overall, anifrolumab shows great promise as a treatment for moderate-to-severe SLE, providing significant efficacy together with a manageable safety profile. To fully explore its therapeutic potential and optimize therapy approaches for the management of SLE, further research is necessary, especially in lupus nephritis and other disease subsets.

UNASSIGNED: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.
UNASSIGNED: We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.
UNASSIGNED: We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = -0.530; p = 0.007) and anti-PmScl100 (r = -0.445; p = 0.03).
UNASSIGNED: We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.

Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8+GZMH+ cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials.

While the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets.
A total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated.
An overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS (p < 0.010) and SLE patients (p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets (p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted (p = 0.002).
IFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization.

The exact pathogenesis of IgA nephropathy (IgAN) is complex and so far, not well defined. Since it has been shown that microbial infections could induce high levels of type I interferon (IFN-I) and there is an evident link between mucosal infection and gross hematuria in IgAN, we hypothesized that IFN-I may play a role in the pathogenic process. In this study, we investigated the type I interferon status in IgAN based on the expression of 17 IFN-regulated genes (IRGs) in whole blood from 59 IgAN patients in a cross-sectional study, of which 34 patients followed longitudinally. Analysis of the IFN-score showed that there was a significant elevated IFN-score in the IgAN patients compared with healthy controls (n = 28, p = 9.80 × 10-3), and we observed an elevated IFN-score in the group with less tubular atrophy/interstitial fibrosis (p = 1.07 × 10-2) and with a lower proportion of mesangial hypercellularity (p = 1.23 × 10-2). In the longitudinal analysis, Cox regression analysis revealed that a higher IFN level was associated with a better renal outcome in IgAN after adjustments for gender and age (hazard ratio, 0.90; 95 % confidence interval, 0.81 to 0.97; p = 4.20 × 10-2). In conclusion, our finding suggested that IFN score may represent a novel type of biomarker in IgAN, which requires further exploration on its mechanism and therapeutic targeting.

Dermatomyositis (DM) is a rare autoimmune disease with involvement of skin and muscle that is classified as an idiopathic inflammatory myopathy. In addition to cutaneous lesions as well as weakness and atrophy of muscles, the heart and lungs are the major affected organs. DM occurs in association with malignant tumors in 20% of affected adults. The pathogenesis of the disease is not completely understood. DM is a multifactorial disease influenced by genetic, environmental and immunological factors. The immune response is characterized by activation of innate and adaptive immune mechanisms and a strong activation of the type I interferon pathway. Myositis-specific antibodies are characteristic of DM and allow differential diagnosis. Therapies include corticosteroids, antimalarials, immunoglobulins, biologics such as rituximab or JAK inhibitors. Early diagnosis and treatment are essential for the prognosis.
UNASSIGNED: Dermatomyositis (DM) ist eine seltene Autoimmunerkrankung mit Haut- und Muskelsymptomen, die den idiopathisch inflammatorischen Myopathien zugeordnet wird. Neben Hautveränderungen und einer typischen Muskelschwäche und -atrophie können ebenfalls Herz und Lunge als wesentliche Organe betroffen sein. In 20 % der Fälle findet sich bei Erwachsenen eine Assoziation zu malignen Tumoren. Die Pathogenese der Erkrankung ist unvollständig verstanden. Sie basiert auf multifaktoriellen Ursachen, die genetische, umweltbezogene und immunologische Faktoren einschließen. Es resultiert eine Aktivierung angeborener und adaptiver Immunmechanismen, die durch eine Stimulation des Typ-I-Interferon-Signalweges und Immunantwort gegen körpereigene Strukturen charakterisiert ist. Myositis-spezifische Antikörper sind charakteristisch für DM und ermöglichen eine differenzierende Diagnose. Therapien umfassen Kortikosteroide, Antimalariamittel, Immunglobuline, Biologika wie Rituximab oder JAK(Januskinase)-Inhibitoren. Eine frühzeitige Diagnose und Behandlung sind entscheidend für eine bessere Prognose.

UNASSIGNED: The 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for systemic lupus erythematosus (SLE) rely on clinical and routine immunological items. The criteria have anti-nuclear antibodies (ANA) as an obligatory entry criterion; items are weighted and ordered in domains. While demonstrating good sensitivity and specificity, the lack of a more molecular approach to some came as a disappointment.
UNASSIGNED: Based on a non-systematic literature search, this review covers items investigated in the EULAR/ACR classification criteria project, but not included in the set of criteria. It demonstrates data on the importance of the criteria and analyses implications of multiomics studies started around the same time as the criteria project. We also discuss data on the type-I interferon signature and on other cytokines, as well as on complement proteins and their split products. The final part deals with the variability in disease and the apparently random pattern of autoantibodies and organ manifestations in individual patients.
UNASSIGNED: We believe that the EULAR/ACR criteria are a relevant step toward the right direction. A more uniform molecular approach will not be feasible as long as the molecular mechanisms underlying the tendency toward producing multiple autoantibodies are not better understood.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system and is characterized by extensive brain damage and neurodegeneration. Immunological, genetic, and histological analyses of MS patients provide data in support of the concept that autoimmunity plays a crucial role in the condition\'s course. It has been proposed that MS may be treated with interferon (IFN)-β and other members of the type I family.
OBJECTIVE: Low levels of type I IFN in MS patients may affect immunological control, establish the threshold for an IFN therapeutic response, and be\"primed\" or \"fixed\" by IFN therapy.
METHODS: This study was conducted as a cross-sectional study. qRT-PCR was used to examine the expression of two critical IFN regulatory genes, IFI44 and MX1, in MS patients receiving IFN-β treatment.
RESULTS: The findings demonstrated a considerable rise in the expression of both genes in MS patients treated with IFN-β compared to those newly diagnosed with the illness. In addition, IFI44 and MX1 might be positively associated with their expression after IFN-β therapy and be regarded as IFN-β responsiveness indicators.
CONCLUSIONS: The IFI44/MX1 axis could act as one of the crucial regulators of the disease following IFN-β treatment.

Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, human leucocyte (HLA) haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between 1 January 2014 and 31 December 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurological syndromes; HLA haplotypes; blood type I-IFN signature [RNA quantification of 6 or 28 IFN-response genes (IRG)] and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in Cohort B. Thirty-nine (42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis and behavioural-psychiatric) showed a high (≥95% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A*02 (4/21, 19%) than those who did not develop AE (42/65, 65%, P = 0.0003) or the Spanish general population (2005/4335, 46%, P = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19/21 (91%) and 18/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At Day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE [median Zs-6-IRG 1.4 (0.6; 2.0) versus 0.2 (-0.4; 0.8), P = 0.03]. However, a very high median Zs-6-IRG (>4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE [3/37 (8%) versus 2/57 (4%), P = 0.379]. Multivariate logistic regression showed that a moderate increase of the blood IFN signature at Day 21 (median Zs-6-IRG >1.5 but <4) was the most important predictor of AE post-HSE [odds ratio 34.8, interquartile ratio (1.7-691.9)]. Altogether, these findings show that most AE post-HSE manifest with three distinct syndromes, and HLA-A*02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.