Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti–calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

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.

Kawasaki disease is an acute self-limited vasculitis of unknown aetiology. The prognosis depends mainly on coronary damage. There is no consensus regarding optimal adjunctive therapeutics for refractory forms to treatment by intravenous immunoglobulins and corticosteroids. We report the case of an 18-month-old infant with refractory Kawasaki disease complicated by diffuse aneurysms of coronary arteries and successfully treated by anakinra with partial regression of coronary aneurysms.

Objectives Excessive and inappropriate production of pro-inflammatory cytokines plays a key role in Still’s disease. JAK inhibitor (JAKi) agents mainly block pro-inflammatory cytokine pathways, notably IL-6 and IFN. The objective was to assess the efficacy and safety of JAKi agents in difficult-to-treat systemic juvenile idiopathic arthritis (SJIA) or adult-onset Still's disease (AOSD). Methods This retrospective study was based on a national survey conducted in the departments of rheumatology, paediatric rheumatology and internal medicine of French hospitals regarding SJIA and AOSD patients who received JAKi agents. The data were collected with a standardised questionnaire and analysed at different times (treatment initiation, months 1, 3, and 6 and the end of follow-up). Results Nine patients (7 adults) were included. All patients showed inadequate response to corticosteroids or conventional synthetic or biologic disease-modifying anti-rheumatic drugs. Baricitinib was used in 5 patients, ruxolitinib in 2, tofacitinib in 2, and upadacitinib in 1. A JAKi was used combined with corticosteroids in all but 2 patients. A JAKi was associated with anakinra and corticosteroids in one patient, and with methotrexate, anakinra and corticosteroids in another. The median follow-up was 16 [1–33] months. Two cases out 9 showed complete remission, 3/9 partial response and 4/9 treatment failure. At the last visit, corticosteroids could be decreased but not stopped. Tolerance of the JAKi was acceptable (no severe adverse events). Conclusion JAKi agents may be a therapeutic option for some patients with difficult-to-treat Still’s disease, especially those with partial response to medium- or high-dose corticosteroids or biologics.