Laureline Berteloot

SAVI is a rare STING1 gain-of-function disorder causing systemic inflammation, vasculopathy, and interstitial lung disease. JAK inhibitors are first-line therapy. We report a SAVI patient on prolonged JAK inhibitors who developed opportunistic infections, including fatal Aspergillus endocarditis, underscoring therapeutic challenges.

Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.

The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis and dysregulated B cell receptor signaling. CBL deficiency impairs humoral immunity by limiting memory B cell formation and reducing class switching and somatic hypermutation. Consequently, antigen-specific B cell generation and adaptive immune memory are disrupted, predisposing individuals to infection. Human CBL is critical for B cell development and function but redundant for T cell biology.

Objectives: Severe forms of systemic JIA (sJIA), also called paediatric-onset Still’s disease are associated with two major life-threatening complications: macrophage activation syndrome (MAS) and severe lung disease. Patients are usually resistant to conventional synthetic (cs) DMARDs, biologic (b) DMARDs, and targeted synthetic (ts) DMARDs. Recently, allogeneic haematopoietic stem cell transplantation (HSCT) has been performed in a small number of patients with refractory and life-threatening disease. We aimed to report outcomes and complications of allogeneic HSCT in patients with severe, refractory sJIA treated at our centre. Methods: We conducted a retrospective, observational, single-centre study in a tertiary paediatric immunology care centre (Necker Hospital, Paris, France). Results: We report three sJIA patients who underwent allogeneic HSCT at a median age of 3.5 years. All had recurrent MAS; two had lung disease and the HLA-DRB1*15 haplotype, associated with severe delayed hypersensitivity to IL-1/IL-6 inhibitors. Donors were matched sibling donors for the first and third patient, and matched unrelated donor for the second patient. They presented multiple post-graft complications: graft-vs-host disease, infections, thrombotic microangiopathy and severe inflammatory complications on previously affected organs, such as skin and lungs. At a median follow-up of 22 months (20–33) after transplantation, they were all in remission with full-donor chimerism and were off immunosuppressive treatment. Conclusion: Allogeneic HSCT can be an effective salvage therapy in patients with refractory sJIA. However, the risk of post-transplant endothelial complications and severe inflammation in previously affected organs, such as joints, skin and lungs deserves particular attention.

Anorectal malformations (ARMs) are congenital anomalies of the distal part of the hindgut often associated with sacral and/or spinal anomalies. We investigated anatomical and microstructural properties of the lumbosacral plexus of ARM patients from imaging data. Twenty-five patients (16 males), median age 4 months (2–49), 13 high and 12 low ARM, underwent 3 Tesla magnetic resonance imaging with diffusion tensor sequences (dMRI) before repair. A 3D model was built from manual segmentation and used to guide novel AI algorithms for the segmentation of the nervous pelvic network. Volume and diffusion parameters were obtained for each root (L5 to S4) and compared among patients with high and low ARMs using a nonparametric Wilcoxon test. Comparison was also made between the groups with (n = 9) or without (n = 16) sacral and/or spinal cord anomalies. When compared with low ARMS, high ARMs exhibited the following: a smaller volume of S1, S2, and S3 roots and of S1 and S3 for patients without sacral and/or spinal cord abnormalities; an overall significant alteration of the roots micro-architecture reflected by a diminution of the fractional anisotropy and an increase of the axial diffusivity and radial diffusivity measures. This first analysis of the lumbosacral plexus from dMRI in children with ARMs shows differences in the development and microarchitecture of the lumbosacral nerve roots between high and low ARMs. This observation supports the hypothesis that high ARMs may result from a more regional developmental abnormality than low ARMs and open new ways to visualize and assess the lumbosacral plexus in children and adults.

IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay–Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding, and suggesting IKKα’s role in canonical NF-κB target gene expression in humans.

The main monogenic causes of pulmonary fibrosis in adults are mutations in telomere-related genes. These mutations may be associated with extrapulmonary signs (hepatic, haematological and dermatological) and typically present radiologically as usual interstitial pneumonia or unclassifiable fibrosis. In children, the monogenic causes of pulmonary fibrosis are dominated by mutations in surfactant-related genes. These mutations are not associated with extrapulmonary signs and often manifest radiologically as unclassifiable fibrosis with cysts that can lead to chest wall deformities in adults. This review discusses these mutations, along with most of the monogenic causes of interstitial lung disease, including interferon-related genes, mutations in genes causing cystic lung disease, Hermansky–Pudlak syndrome, pulmonary alveolar proteinosis, lysinuric protein intolerance and lysosomal storage disorders, and their pulmonary and extrapulmonary manifestations.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Computed tomography (CT) is commonly used for paediatric thoracic diseases but involves radiation exposure and often requires intravenous contrast. We evaluated the performance of a magnetic resonance imaging (MRI) protocol including a 3D zero echo time (3D-ZTE) sequence for radiation-free and contrast-free imaging of the paediatric chest. In this prospective, single-centre study, children aged 6–16 years underwent chest CT and MRI within 48 h. CT and MRI exams were independently assessed by two paediatric radiologists. The primary outcome was the image quality of the 3D-ZTE sequence using a scoring system based on the acceptability of the images obtained and visibility of bronchial structures, vessels and fissures. Secondary outcomes included radiologists’ ability to detect lung lesions on 3D-ZTE MRI images compared with CT images. Seventy-two children were included. Overall, the image quality achieved with the 3D-ZTE MRI sequence was inferior to that of CT for visualising pulmonary structures, with satisfactory lung image quality observed for 81.9% (59/72) and 100% (72/72) of patients, respectively. However, MRI sensitivity was excellent (above 90%) for the detection of certain lesions such as lung consolidation, proximal mucoid impactions, pulmonary cysts, ground glass opacities and honeycombing. Intermodality agreement (MRI versus CT) was consistently higher for the senior reader compared to the junior reader. Conclusion: Despite its overall lower image quality compared to CT, and the additional years of experience required for accurate interpretation, the 3D-ZTE MRI sequence demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications. What is Known: • Chest radiography and CT are the main imaging modalities for paediatric thoracic diseases but involve radiation exposure and CT often requires IV contrast. • MRI is promising for radiation-free lung imaging in children but faces challenges of low signal-to-noise ratio and motion artefacts. What is New: • An MRI protocol including a 3D zero echo time (ZTE) sequence allows satisfactory visualisation of lung parenchyma in 82% of children. • Despite overall inferior image quality compared to CT, MRI demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications.