Imagine Institute for Genetic Diseases

Uncontrolled kallikrein-related peptidase (KLK) activity underlies Netherton syndrome (NS). However, whether KLK expression and activity vary between lesional and nonlesional skin, or across NS clinical subtypes, remains unclear, which could be crucial for treatment optimization. Using noninvasive skin sampling and skin biopsies, we profiled the expression and activity of five NS-relevant KLKs (the trypsin-like KLK5, KLK6, KLK13, and KLK14, and the chymotrypsin-like KLK7) in lesional and nonlesional skin from 20 patients with NS with the two clinical subtypes. We found that KLK5 and KLK7 were strongly expressed in the upper epidermis of healthy controls and patients with NS, regardless of lesion status. In contrast, KLK6 and KLK13 were predominantly increased in NS lesional skin. KLK14 showed weak expression in NS epidermis and healthy control skin, but was more strongly expressed in nonepithelial cells, including neutrophils and mast cells. Regarding protease activity, total trypsin-like serine protease activity (comprising KLK5, KLK6, KLK13, and KLK14 activities) and KLK7-like activity in lesional and nonlesional NS skin, regardless of clinical subtype, were higher as compared with healthy controls. Notably, within each clinical subtype, lesional and nonlesional skin displayed similar protease activity levels. However, patients with scaly erythroderma (SE) subtype showed higher KLK7-like protease activity in lesional superficial skin than patients with ichthyosis linearis circumflexa subtype. In one patient with NS-SE undergoing partially effective secukinumab therapy, superficial skin protease activity showed no significant change. Measurement of KLK activity from tape strips revealed distinct proteolytic patterns among patients with NS and represents a noninvasive tool for evaluating treatment efficacy in NS clinical trials.NEW & NOTEWORTHY This study identifies differences in kallikrein-related peptidase (KLK) expression and activity between healthy skin and Netherton syndrome (NS) skin, distinguishing lesional and nonlesional areas in the two major clinical subtypes. Increased expression of KLK6 and KLK13 is characteristic of the epidermis in NS lesional skin. KLK14 can be expressed by both keratinocytes and immune cells. Patients with scaly erythroderma subtype NS show higher KLK7-like activity in lesional skin, highlighting subtype-specific differences.

More than 500 primary immunodeficiencies (PIDs) or inborn errors of immunity (IEIs) have been reported. In general, IEIs are caused by monogenic germinal variants resulting in immunodeficiency and immune dysregulation symptoms. These "in natura" experiments have highlighted selective factors and pathways required for the immune control of a given pathogen, including Epstein-Barr virus (EBV). Several IEIs predominantly predispose to develop severe EBV infections and associated diseases including infectious mononucleosis (IM), hemophagocytic lymphohistiocytosis (HLH) and nonmalignant or malignant B cell lymphoproliferative disorders (B-LPD). Identification of these IEIs revealed critical components/molecules of the immune response to EBV. Notably, these elements differ depending on the type of the EBV viral disease. On one hand, defects in factors involved in the cytotoxic responses of lymphocytes preferentially underlie HLH, whereas, on the other hand, factors implicated in the expansion of EBV-specific T cells are mostly responsible for B-LPD when impaired. IEIs also inform on mechanisms underlying rare EBV viral diseases such as EBV+ smooth muscle tumors(EBV+SMT) and the "atypical" T/NK cell lymphoproliferative disorders (NK/T-LPD) including chronic active EBV infections (CAEBV). Finally, IEIs not predisposing to EBV provide information on immune components not necessary or redundant for EBV immunity. All these aspects are discussed in this chapter.

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. Here, we dissected the mechanisms of scoliosis onset in a zebrafish mutant for the rpgrip1l gene encoding a ciliary transition zone protein. rpgrip1l mutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles. Taking advantage of this asynchrony, we found that curvature onset was preceded by ventricle dilations and was concomitant to the perturbation of Reissner fiber polymerization and to the loss of multiciliated tufts around the subcommissural organ. Rescue experiments showed that Rpgrip1l was exclusively required in foxj1a-expressing cells to prevent axis curvature. Genetic interactions investigations ruled out Urp1/2 levels as a main driver of scoliosis in rpgrip1 mutants. Transcriptomic and proteomic studies identified neuroinflammation associated with increased Annexin levels as a potential mechanism of scoliosis development in rpgrip1l juveniles. Investigating the cell types associated with annexin2 over-expression, we uncovered astrogliosis, arising in glial cells surrounding the diencephalic and rhombencephalic ventricles just before scoliosis onset and increasing with time in severity. Anti-inflammatory drug treatment reduced scoliosis penetrance and severity and this correlated with reduced astrogliosis and macrophage/microglia enrichment around the diencephalic ventricle. Mutation of the cep290 gene encoding another transition zone protein also associated astrogliosis with scoliosis. Thus, we propose astrogliosis induced by perturbed ventricular homeostasis and associated with immune cell activation as a novel pathogenic mechanism of zebrafish scoliosis caused by cilia dysfunction.

BackgroundCollection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes.MethodsThe Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes.ResultsA range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments.ConclusionsLong-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)−6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.

In this article, the author name Kenneth McElreavey was incorrectly written as Kenneth MacElreavey. The original article has been corrected.