Muscle Spatial Transcriptomic Reveals Heterogeneous Profiles in Juvenile Dermatomyositis and Persistence of Abnormal Signature After Remission.

This study aimed to investigate the spatial heterogeneity of molecular signature in the muscle of juvenile dermatomyositis (JDM) patients before and after treatment. Unsupervised reference-free deconvolution of spatial transcriptomics and standardized morphometry were performed in two JDM muscle biopsies with different clinical severity at disease onset and compared to healthy muscle. Identified signatures were scored in two additional JDM muscle biopsies from the same patient before and after remission.

Myositis specific autoantibody subtypes are associated with response to Janus kinase inhibitors in patients with juvenile dermatomyositis.

Objectives: To evaluate the efficacy and safety of Janus kinase inhibitors (JAKi) in a monocentric series of patients with juvenile dermatomyositis (JDM) and to identify factors associated with the achievement of clinically inactive disease (CID).

Methods: Single-centre retrospective study of 39 JDM patients treated with JAKi fot at least 6 months. The proportion of patients achieving CID within 6 months after initiation of JAKi was assessed using the PRINTO criteria and the Skin Disease Activity Score.

Targeting interferon responses in juvenile dermatomyositis: Siglec-1 as an in vitro biomarker for JAK inhibitor efficacy.

Objectives: For IFN-driven diseases, such as juvenile dermatomyositis (JDM), there is a critical need for targeted therapies. We aimed to develop an in vitro model, using Siglec-1 as read-out, to evaluate inhibition of IFN-mediated responses with different JAK inhibitors (JAKi).

Methods: Healthy donor (HD) PBMCs were cultured with type I and II IFNs, TLR agonists and plasma or serum from patients (JDM, DM, JSLE, COVID-19) and HDs.

Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series.

Background: Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease.

Methods: In this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel.

Implication of the LRR Domain in the Regulation and Activation of the NLRP3 Inflammasome.

The NLRP3 inflammasome is a critical component of the innate immune response. NLRP3 activation is a tightly controlled process involving an initial priming to express NLRP3, pro-IL-1 β, and pro-IL-18, followed by an activation signal. The precise mechanism of activation is not fully understood due to the diverse range of activators, yet it effectively orchestrates the activation of caspase-1, which subsequently triggers the release of proinflammatory cytokines IL-1β and IL-18.

ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling.

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport.

pSTAT5 is associated with improved survival in patients with thick or ulcerated primary cutaneous melanoma.

Identifying prognostic biomarkers to predict clinical outcomes in stage I and II cutaneous melanomas could guide the clinical application of adjuvant and neoadjuvant therapies. We aimed to investigate the prognostic value of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) as a biomarker in early-stage melanoma. This study evaluated all initially staged Ib and II melanoma patients undergoing sentinel node biopsy at a tertiary centre in Brisbane, Australia between 1994 and 2007, with survival data collected from the Queensland Cancer Registry.

Heterogeneity and functions of the 13 IFN-α subtypes - lucky for some?

Type I IFNs are critical for host responses to viral infection and are also implicated in the pathogenesis of multiple autoimmune diseases. Multiple subtypes exist within the type I IFN family, in particular 13 distinct IFN-α genes, which signal through the same heterodimer receptor that is ubiquitously expressed by mammalian cells. Both evolutionary genetic studies and functional antiviral assays strongly suggest differential functions and activity between the 13 IFN-α subtypes, yet we still lack a clear understanding of these different roles.

Successful treatment of JAK1-associated inflammatory disease.

Background: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.

Objectives: This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition.

Methods: The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients.

Efficacy and tolerance of corticosteroids and methotrexate in patients with juvenile dermatomyositis: a retrospective cohort study.

Objectives: To assess the efficacy and tolerance of the conventional first-line treatment by MTX and CS in patients with JDM regardless of severity.

Methods: We conducted a monocentric retrospective study of patients with newly diagnosed JDM treated with MTX and CS from 2012 to 2020. The proportion of clinically inactive disease (CID) within 6 months of MTX initiation was evaluated using both Paediatric Rheumatology International Trials Organisation (PRINTO) criteria (evaluating muscle inactive disease) and DAS (evaluating skin inactive disease).

Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis.

mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function.

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A).

Differential levels of IFNα subtypes in autoimmunity and viral infection.

Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease.

JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study.

Objective: To evaluate the efficacy and safety of Janus kinase inhibitors (JAKis) in JDM.

Methods: We conducted a single-centre retrospective study of patients with JDM treated by JAKi with a follow-up of at least 6 months. Proportion of clinically inactive disease (CID) within 6 months of JAKi initiation was evaluated using PRINTO criteria and skin Disease Activity Score.

From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies.

Objective: Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology.

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry.