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Large-scale analysis of the genetic basis of pediatric systemic lupus erythematosus Abstract Background Systemic lupus erythematosus (SLE) is a rare immunological disorder where genetic factors are important in causation. Mendelian forms of lupus have been described in the context of almost 30 genotypes in humans, and more than 60 in mice. Murine susceptibility models and genome-wide association studies (GWAS) also highlight the role of genetic variants in pathogenesis. The overall genetic contribution to pediatric SLE is unknown. Methods We designed a next-generation sequencing panel comprising 147 genes, including all known Mendelian lupus causing (KLC) genes in humans, and lupus associated genes identified through GWAS and animal models (potentially lupus causing, PLC, genes). Using this panel we screened 117 probands fulfilling American College of Rheumatology criteria for SLE, ascertained through two cohorts of pediatric SLE in the UK and France, and 791 ethnically matched controls from the 1000 Genomes Project. Results Mendelian genotypes were present in 6.8% of probands. Beyond these cases, rare, predicted damaging variants were significantly enriched in the SLE cohort compared to controls, with an odds ratio of 14.09 and 3.99 in KLC and PLC genes respectively. Overall, 27% of SLE probands versus 4.6% of controls were identified with at least one rare, predicted damaging variant amongst our selected gene panel (p = 4.14×10 −15). Conclusion Rare and predicted damaging variants in KLC and PLC genes were highly enriched in a population of pediatric onset lupus, with 1 in 15 probands demonstrating clear Mendelian causation. Germline defects of innate immunity represent the main genetic contribution to SLE in children.

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Background Food allergy is a potentially life‐threatening disease, affecting up to 10% of the pediatric population. Objective The aim of our study was to assess the health‐related quality of life (HRQL) of food‐allergic patients compared with the general population and patients with other chronic diseases with dietary or allergic burden, in a cross‐sectional study. Methods We recruited patients aged 8–17 years diagnosed with food allergy and matched healthy controls recruited in schools. We also included patients with asthma, inflammatory bowel disease, celiac disease, diabetes, obesity, and eating disorders. We used the CHQ‐CF87 questionnaire for generic HRQL assessment. Food allergy HRQL was also assessed using specific questionnaires: Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM). Results One hundred and thirty‐five food‐allergic children, 255 children with chronic diseases, and 463 healthy controls were included in the analyses. Food‐allergic patients had a better HRQL than healthy controls in the Behavior (BE), Bodily Pain (BP), Family Activities (FA), and Mental Health (MH) domains and a worse HRQL in the General Health Perception (GH) domain (p = .048). Food‐allergic patients exhibited a better HRQL than patients affected by other chronic diseases, notably diabetes. Although an epinephrine autoinjector had been prescribed to 87.4% of the food‐allergic children, only 54.2% of them carried it at all times. Conclusion Food‐allergic patients display overall good HRQL compared with the general population and those with other diseases with daily symptoms and treatments, in line with recent improvements in food allergy management.

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