Type I interferon pathway in pediatric systemic lupus erythematosus.

BACKGROUND: The role of type I interferon (IFN-I) signaling in systemic lupus erythematosus (SLE) has been well established. However, unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE. The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE. DATA SOURCES: A literature search was conducted in the PubMed database using the following keywords: "pediatric systemic lupus erythematosus" and "type I interferon". RESULTS: IFN-I signaling is increased in pediatric SLE, largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase 1 and Toll-like receptor (TLR)4/TLR9. Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production. Genetic variants in IFN-I-related genes, such as IFN-regulatory factor 5 and tyrosine kinase 2, are linked to SLE susceptibility in pediatric patients. In addition, type I interferonopathies, characterized by sustained IFN-I activation, can mimic SLE symptoms and are thus important to distinguish. Studies on interferonopathies also contribute to exploring the pathogenesis of SLE. Measuring IFN-I activation is crucial for SLE diagnosis and stratification. Both IFN-stimulated gene expression and serum IFN-α2 levels are common indicators. Flow cytometry markers such as CD169 and galectin-9 are promising alternatives. Anti-IFN therapies, such as sifalimumab and anifrolumab, show promise in adult patients with SLE, but their efficacy in pediatric patients requires further investigation. Janus kinase inhibitors are another treatment option for severe pediatric SLE patients. CONCLUSIONS: This review presents an overview of the IFN-I pathway in pediatric SLE. Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies, paving the way for improved patient care and outcomes.

T-Rex escaped from the cytosolic park: Re-thinking the impact of TREX1 exonuclease deficiencies on genomic stability.

The Three Prime Repair Exonuclease 1 (TREX1) has been implicated in several pathologies characterized by chronic and inborn inflammation. Aberrant innate immunity caused by DNA sensing through the cGAS-STING pathway has been proposed to play a major role in the etiology of these interferonopathies. However, the molecular source of this DNA sensing and the possible involvement of TREX1 in genome (in)stability remains poorly understood. Recent findings reignite the debate about the cellular functions performed by TREX1 nuclease, notably in chromosome biology and stability. Here I put into perspective recent findings that suggest that TREX1 is at the crossroads of DNA damage response and inflammation in different pathological contexts.

Panniculitis: A Cardinal Sign of Autoinflammation.

Panniculitis was first described in the nineteenth century and is characterized by inflammation of the subcutaneous fat. It may be categorized in septal or lobular subtypes, but other histopathological features (e.g., presence of vasculitis, nature of inflammatory infiltrates, characteristics of fat necrosis) are also important for diagnostic purposes. Clinically, panniculitis is characterized by the presence of subcutaneous nodules, and both ulcerative and nonulcerative clinical subtypes have been proposed. In this review, we aimed to describe the occurrence of panniculitis in autoinflammatory disorders (AIDs) and related diseases. Among monogenic AIDs, panniculitis is common in IFN-mediated disorders. Panniculitis is a distinctive feature in proteasome-associated autoinflammatory syndromes (PRAAS), including chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and Nakajo-Nishimura syndrome. On the other hand, erythema nodosum corresponds to the most common clinical form of panniculitis and is common in polygenic AIDs, such as Behçet's syndrome, inflammatory bowel disease, and sarcoidosis. Cytophagic histiocytic panniculitis, lipoatrophic panniculitis of children, and otulipenia are rare disorders that may also present with inflammation of the subcutaneous fat. Therefore, panniculitis can identify a specific subgroup of patients with AIDs and may potentially be regarded as a cardinal sign of autoinflammation.

Aicardi-Goutières Syndrome with Congenital Glaucoma Caused by Novel TREX1 Mutation.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by microcephaly, white matter lesions, numerous intracranial calcifications, chilblain skin lesions and high levels of interferon-α (IFN-α) in the cerebrospinal fluid (CSF). However, ocular involvement is reported significantly less frequently. CASE PRESENTATION: We present a case of a neonate with hypotrophy, microcephaly, frostbite-like skin lesions, thrombocytopenia, elevated liver enzymes and hepatosplenomegaly. Magnetic resonance imaging (MRI) of the brain showed multiple foci of calcification, white matter changes, cerebral atrophy, and atrophic dilatation of the ventricular system. The inflammatory parameters were not elevated, and the infectious etiology was excluded. Instead, elevated levels of IFN-α in the serum were detected. Based on the related clinical symptoms, imaging and test findings, the diagnosis of AGS was suspected. Genetic testing revealed two pathogenic mutations, c.490C>T and c.222del (novel mutation), in the three prime repair exonuclease 1 (TREX1) gene, confirming AGS type 1 (AGS1). An ophthalmologic examination of the child at 10 months of age revealed an impaired pupillary response to light, a corneal haze with Haab lines in the right eye (RE), pale optic nerve discs and neuropathy in both eyes (OU). The intraocular pressure (IOP) was 51 mmHg in the RE and 49 in the left eye (LE). The flash visual evoked potential (FVEP) showed prolonged P2 latencies of up to 125% in the LE and reduced amplitudes of up to approximately 10% OU. This girl was diagnosed with congenital glaucoma, and it was managed with a trabeculectomy with a basal iridectomy of OU, resulting in a reduction and stabilization in the IOP to 12 mmHg in the RE and 10 mmHg in the LE without any hypotensive eyedrops. CONCLUSIONS: We present the clinical characteristics, electrophysiological and imaging findings, as well as the genetic test results of a patient with AGS1. Our case contributes to the extended ophthalmic involvement of the pathogenic c.490C>T and c.222del mutations in TREX1.

A very rare cause of pre-capillary pulmonary hypertension: The PAMI syndrome.

We report the first known case of PAMI syndrome associated with pulmonary arterial hypertension (PAH) with a positive response to cyclophosphamide and pulmonary vasodilators. The patient's history began at 7 months with severe pancytopenia and fever. As time progressed, migrating arthritis, hepatosplenomegaly, and a growth deficit manifested without a plausible explanation. At the age of 17, worsening dyspnea led to a diagnosis of severe pre-capillary pulmonary hypertension and, after a multidisciplinary evaluation, a dual therapy with both vasoactive and immunosuppressive agents led to rapid clinical improvement. After a decade of stability, stopping sildenafil caused deterioration, reversed upon reintroduction. Thirty years after the onset of signs and symptoms, a genetic test identified the underlying condition known as PAMI syndrome. As PAMI syndrome involves intense systemic inflammation similar to PAH related to systemic lupus erythematosus (SLE), parameters and functional autonomy appropriately responded to early immunosuppressive and vasoactive therapy. PAMI syndrome, a rare autoinflammatory disease, is linked to precapillary pulmonary hypertension but the exact cause and optimal treatment approach are not fully understood, requiring further research for clarification and improved treatment options.

Type I Interferonopathies: A Clinical Review.

This review will discuss when clinicians should consider evaluating for Type I interferonopathies, review clinical phenotypes and molecular defects of Type I interferonopathies, and discuss current treatments.

Monogenic autoinflammatory disease-associated cardiac damage.

INTRODUCTION: Autoinflammatory diseases (AIDs) constitute several disorders that are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. Most of them have a strong genetic background, with mutations in single genes involved in inflammation referred to monogenic AIDs. In this article, we will review the cardiac manifestations in various monogenic AIDs. AREAS COVERED: Various cardiac manifestations can be seen in various monogenic AIDs, including pericarditis, valvular diseases, coronary diseases, cardiomyopathies, and pulmonary hypertension, especially in Familial Mediterranean fever (FMF). EXPERT COMMENTARY: Monogenic AIDs can manifest a variety of cardiac lesions, the most common of which is pericardial effusion, which may be local pericardial inflammation secondary to systemic inflammatory responses. While, the pathogenesis and incidence are still unclear. More research is still needed to explore the relationship between monogenic AIDs and cardiac damage for better understanding these diseases.

Síndrome de Aicardi-Goutieres: Diagnóstico genético en una lactante

El Síndrome de Aicardi-Goutieres (SAG) se caracteriza por una encefalopatía genética, progresiva, de inicio temprano, que se asocia a un proceso inflamatorio. Además del SNC, puede afectar a la piel, con erupciones tipo sabañones, y presentar microcefalia, talla baja, disfunción hepática, disfunción tiroidea, reactantes de fase aguda elevados, anticuerpos autoinmunes positivos y asociaciones para enfermedades sistémicas autoinmunes como él LES. El SAG presenta locus heterogénicos, con mutaciones identificadas en los genes que codifican el exonucleasa TREX1 3´â†’5´ y las tres subunidades del complejo de endonucleasa RNASEH2. Se presenta el caso de una paciente de 2 años de edad, con retraso del desarrollo psicomotor, sin otras manifestaciones sistémicas, diagnosticada como SAG, con variante c.529G(A (p.Ala177Thr) con efecto patogénico en homocigosis en el gen RNASEH2B.

Aicardi-Goutieres Syndrome (AGS) is characterized by an early-onset, progressive, genetic encephalopathy associated with an inflammatory process. In addition to the CNS, it can affect the skin, with chilblain-like eruptions, and present with microcephaly, short stature, liver dysfunction, thyroid dysfunction, elevated acute phase reactants, positive autoimmune antibodies, and associations for autoimmune systemic diseases such as SLE. SAG presents heterogeneous loci, with mutations identified in the genes encoding the TREX1 3'→5' exonuclease and the three subunits of the RNASEH2 endonuclease complex. We present the case of a female 2-year-old patient, with delayed psychomotor development, without other systemic manifestations, diagnosed as SAG, with variant c.529G>A (p.Ala177Thr) with a pathogenic effect in homozygosis in the RNASEH2B gene.

Efficacy and safety of baricitinib in Japanese patients with autoinflammatory type I interferonopathies (NNS/CANDLE, SAVI, And AGS).

BACKGROUND: This study evaluated the efficacy and safety of baricitinib (Janus kinase-1/2 inhibitor), in adult and pediatric Japanese patients with Nakajo-Nishimura syndrome/chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (NNS/CANDLE), stimulator of interferon genes-associated vasculopathy with onset during infancy (SAVI), or Aicardi-Goutières syndrome (AGS). METHODS: A Phase 2/3, multicenter, open-label study (NCT04517253) was conducted across 52 weeks. Primary efficacy endpoint assessed the change in mean daily diary score (DDS) from baseline to the end of primary treatment period. Other efficacy endpoints included change in mean DDS to the end of maintenance period, daily corticosteroid use, Physician's Global Assessment of Disease Activity (PGA) scores, and daily symptom-specific score (DSSS) from baseline to primary and maintenance treatment periods. All treatment-emergent adverse events (TEAEs) that occurred postdosing were recorded. RESULTS: Overall, 9 patients (5 with NNS, 3 with SAVI, and 1 with AGS) were enrolled; 55.6% were females, mean age was 26 years, and mean corticosteroid use/weight was 0.2 mg/kg. At the end of primary treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.22) and SAVI (0.21) and increased in the patient with AGS (0.07). At the end of maintenance treatment period, mean DDS decreased from baseline in patients with NNS/CANDLE (0.18) and SAVI (0.27) and increased in the patient with AGS (0.04). Mean percent corticosteroid use decreased by 18.4% in 3 out of 5 patients with NNS/CANDLE and 62.9% in 1 out of 3 patients with SAVI. Mean PGA score decreased from baseline in patients with NNS/CANDLE (1.60), SAVI (1.33), and AGS (1.0), and mean DSSS improved from baseline. All patients reported ≥ 1 TEAE. Frequently reported AEs included BK polyomavirus detection (3; 33.3%), increased blood creatine phosphokinase (2; 22.2%), anemia (2; 22.2%), and upper respiratory tract infection (2; 22.2%). Three (33.3%) patients reported serious adverse events, 1 of which was related to study drug. One patient with SAVI died due to intracranial hemorrhage, which was not related to study drug. CONCLUSION: Baricitinib may offer a potential therapeutic option for patients with NNS/CANDLE, SAVI, and AGS, with a positive benefit/risk profile in a vulnerable patient population with multiple comorbidities. TRIAL REGISTRATION: NLM clinicaltrials.gov, NCT04517253 . Registered 18 August 2020.

Breaking down the cellular responses to type I interferon neurotoxicity in the brain.

Since their original discovery, type I interferons (IFN-Is) have been closely associated with antiviral immune responses. However, their biological functions go far beyond this role, with balanced IFN-I activity being critical to maintain cellular and tissue homeostasis. Recent findings have uncovered a darker side of IFN-Is whereby chronically elevated levels induce devastating neuroinflammatory and neurodegenerative pathologies. The underlying causes of these 'interferonopathies' are diverse and include monogenetic syndromes, autoimmune disorders, as well as chronic infections. The prominent involvement of the CNS in these disorders indicates a particular susceptibility of brain cells to IFN-I toxicity. Here we will discuss the current knowledge of how IFN-Is mediate neurotoxicity in the brain by analyzing the cell-type specific responses to IFN-Is in the CNS, and secondly, by exploring the spectrum of neurological disorders arising from increased IFN-Is. Understanding the nature of IFN-I neurotoxicity is a crucial and fundamental step towards development of new therapeutic strategies for interferonopathies.

Interferon in systemic lupus erythematosus-A halfway between monogenic autoinflammatory and autoimmune disease.

Although perceived as an adaptative immune disorder, mainly related to Lymphocyte B and T, last years focus on Systemic Lupus Erythematosus (SLE) pathogeny emphasised the important role of innate immunity. This should not take us by surprise since the lupus cell described by Hargraves and colleagues in 1948 was a neutrophil or macrophage with specific aspect after coloration with haematoxylin related to cell detritus engulfment (Hargraves et al., 1948) [1] (Presentation of two bone marrow elements; the tart. Hargraves M, Ricmond H, Morton R. 1948, Proc Staff Meet Mayo Clinic, pp. 23:25-28). Normal immune system maintains homeostasis through innate and adaptative response that are working together to prevent both infection and autoimmunity. Failure of the immune mechanisms to preserve the balance between these two will initiate and propagate autoinflammation and/or autoimmunity. It is well known now that autoinflammation and autoimmunity are the two extremes of different pathologic conditions marked with multiple overlaps in many diseases. Recent findings in SLE demonstrated that innate immune system initiates the abnormal autoimmunity and starts the continuous inflammatory reaction after that, interferon being one of the key cytokines in innate immunity and SLE. Understanding this mechanism might offer a better clue for an efficient treatment in SLE patients. The purpose of this review is to highlight the enormous impact of innate immunity and mostly interferons in SLE.

The role of type I IFN in autoimmune and autoinflammatory diseases with CNS involvement.

Type I interferons (IFNs) are major mediators of innate immunity, with well-known antiviral, antiproliferative, and immunomodulatory properties. A growing body of evidence suggests the involvement of type I IFNs in the pathogenesis of central nervous system (CNS) manifestations in the setting of chronic autoimmune and autoinflammatory disorders, while IFN-ß has been for years, a well-established therapeutic modality for multiple sclerosis (MS). In the present review, we summarize the current evidence on the mechanisms of type I IFN production by CNS cellular populations as well as its local effects on the CNS. Additionally, the beneficial effects of IFN-ß in the pathophysiology of MS are discussed, along with the contributory role of type I IFNs in the pathogenesis of neuropsychiatric lupus erythematosus and type I interferonopathies.

Phenotypic spectrum in recessive STING-associated vasculopathy with onset in infancy: Four novel cases and analysis of previously reported cases.

Gain-of-function variants in the stimulator of interferon response cGAMP interactor 1 (STING1) gene cause STING-Associated Vasculopathy with onset in Infancy (SAVI). Previously, only heterozygous and mostly de novo STING1 variants have been reported to cause SAVI. Interestingly, one variant that only leads to SAVI when homozygous, namely c.841C>T p.(Arg281Trp), has recently been described. However, there are no entries in public databases regarding an autosomal recessive pattern of inheritance. Here, we report four additional unrelated SAVI patients carrying c.841C>T in homozygous state. All patients had interstitial lung disease and displayed typical interferon activation patterns. Only one child displayed cutaneous vasculitis, while three other patients presented with a relatively mild SAVI phenotype. Steroid and baricitinib treatment had a mitigating effect on the disease phenotype in two cases, but failed to halt disease progression. Heterozygous c.841C>T carriers in our analysis were healthy and showed normal interferon activation. Literature review identified eight additional cases with autosomal recessive SAVI caused by c.841C>T homozygosity. In summary, we present four novel and eight historic cases of autosomal recessive SAVI. We provide comprehensive clinical data and show treatment regimens and clinical responses. To date, SAVI has been listed as an exclusively autosomal dominant inherited trait in relevant databases. With this report, we aim to raise awareness for autosomal recessive inheritance in this rare, severe disease which may aid in early diagnosis and development of optimized treatment strategies.

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations.

In this article we revised the literature on Inborn Errors of Immunity (IEI) keeping our focus on those diseases presenting with intrauterine or perinatal clinical manifestations. We opted to describe our findings according to the IEI categories established by the International Union of Immunological Societies, predominantly addressing the immunological features of each condition or group of diseases. The main finding is that such precocious manifestations are largely concentrated in the group of primary immune regulatory disorders (PIRDs) and not in the group of classical immunodeficiencies. The IEI categories with higher number of immunological manifestations in utero or in perinatal period are: (i) diseases of immune dysregulation (HLH, IPEX and other Tregopathies, autosomal recessive ALPS with complete lack of FAS protein expression) and (ii) autoinflammatory diseases (NOMID/CINCA, DIRA and some interferonopathies, such as Aicardi-Goutières syndrome, AGS, and USP18 deficiency). Regarding the other IEI categories, some patients with Omenn syndrome (an atypical form of SCID), and a few X-linked CGD patients present with clinical manifestations at birth associated to immune dysregulation. The most frequent clinical features were hydrops fetalis, intrauterine growth retardation leading to fetal loss, stillbirths, and prematurity, as in HLH and IPEX. Additionally, pseudo-TORCH syndrome was observed in AGS and in USP18 deficiency. The main goal of our review was to contribute to increasing the medical awareness of IEI with intrauterine and perinatal onset, which has obvious implications for diagnosis, treatment, and genetic counseling.

Hereditary Systemic Autoinflammatory Diseases: Therapeutic Stratification.

Hereditary systemic autoinflammatory diseases (SAIDs) are rare, often severe conditions characterised by mutations in the key regulators of innate immune responses. Dramatic advances in the molecular genetics and next-generation sequencing in the past decade enabled identification of novel mutations that play a pivotal role in the mechanistic pathways of inflammation. Although genetic testing may not always provide straightforward guidance in diagnosis and clinical decision making, through translational research, it sheds light into molecular immunopathogenesis, particularly in IL-1 inflammasome and cytokine signalling pathways. These remarkable insights provided a better understanding of autoinflammatory conditions and their association with the innate and adaptive immune systems, as well as leading to development of cytokine-targetted biologic treatments. Use of targetted therapeutics not only helps control disease flares, reduce acute-phase responses and prevent devastating complications such as amyloidosis, but also improves health-related quality of lives and support patients to pursue almost a normal life. Herein, we discuss the commonest monogenic SAIDs, describe their immunopathology, and summarise the approaches in the management and targetted treatment of these conditions, including presentation of novel data based on a cohort of children with these rare diseases from a single quaternary referral centre in London.

Janus Kinase Inhibitors in the Treatment of Type I Interferonopathies: A Case Series From a Single Center in China.

Objective: This study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD). Methods: A total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR. Results: Three patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25-4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections. Conclusion: The JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety.

[Autoinflammation-differences between children and adults]. / Autoinflammation ­ Unterschiede bei Kindern und Erwachsenen.

Autoinflammatory diseases present as multisystemic inflammation and often manifest in early childhood. In contrast, in a few diseases, e.g., the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) syndrome, the first symptoms occur exclusively in adulthood. This article describes how the phenotypic expression and severity of individual autoinflammatory diseases differ depending on age. Furthermore, differences in the development of organ damage in children and adults are pointed out. In addition to the hereditary periodic fever syndromes, the clinical picture of deficiency of adenosine deaminase 2, the interferonopathies, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome as well as VEXAS and Schnitzler syndromes are highlighted.

Pathogenic insights from genetic causes of autoinflammatory inflammasomopathies and interferonopathies.

A number of systemic autoinflammatory diseases arise from gain-of-function mutations in genes encoding IL-1-activating inflammasomes or cytoplasmic nucleic acid sensors including the receptor and sensor STING and result in increased IL-1 and type I interferon production, respectively. Blocking these pathways in human diseases has provided proof-of-concept, confirming the prominent roles of these cytokines in disease pathogenesis. Recent insights into the multilayered regulation of these sensor pathways and insights into their role in amplifying the disease pathogenesis of monogenic and complex genetic diseases spurred new drug development targeting the sensors. This review provides insights into the pathogenesis and genetic causes of these "prototypic" diseases caused by gain-of function mutations in IL-1-activating inflammasomes (inflammasomopathies) and in interferon-activating pathways (interferonopathies) including STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and proteasome-associated autoinflammatory syndromes that link activation of the viral sensors STING, "self" nucleic acid metabolism, and the ubiquitin-proteasome system to "type I interferon production" and human diseases. Clinical responses and biomarker changes to Janus kinase inhibitors confirm a role of interferons, and a growing number of diseases with "interferon signatures" unveil extensive cross-talk between major inflammatory pathways. Understanding these interactions promises new tools in tackling the significant clinical challenges in treating patients with these conditions.