Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease.

TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel mutations in TLR7, F507S and L528I. While the L528I substitution arose de novo, the F507S mutation was present in three individuals from the same family, including a severely affected male, notably given that the TLR7 gene is situated on the X chromosome and that all other cases so far described have been female. The observation of mutations at residues 507 and 528 of TLR7 indicates the importance of the TLR7 dimerization interface in maintaining immune homeostasis, where we predict that altered homo-dimerization enhances TLR7 signaling. Finally, while mutations in TLR7 can result in SLE-like disease, our data suggest a broader phenotypic spectrum associated with TLR7 gain-of-function, including significant neurological involvement.

Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort.

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a new condition that first appeared in children and adolescents during the COVID-19 pandemic. We aimed to describe the diagnostic course, clinical and biological manifestations, and treatment of MIS-C during the first three COVID-19 waves. Methods: We extracted patient data from the Juvenile Inflammatory Rheumatism (JIR) cohort. We analyzed data for patients meeting the World Health Organization diagnostic criteria for MIS-C from the start of the COVID-19 pandemic from March 2020 to June 30, 2021. We then compared data for patients in wave one to those in waves two and three. Results: We identified 136 patients with MIS-C. The median age decreased but not significantly during the waves, from 9.9 years to 7.3 years (p = 0.105). Boys represented 52.2% (n = 71) of patients, and 46% (n = 41) of patients originated from sub-Saharan Africa (p < 0.001). Patients presented less diarrhea (p = 0.004), respiratory distress (p < 0.001), and myocarditis (p < 0.001) with progressive waves. Biological inflammation also decreased, namely, C-reactive protein level (p < 0.001), neutrophil count (p = 0.004), and albumin level (p < 0.001). Patients received more corticosteroids (p < 0.001) and required less ventilation support (p < 0.01) and less inotrope treatment (p < 0.001) in the later waves. The duration of hospitalization gradually decreased (p < 0.001), as did critical care unit admissions (p = 0.002). Conclusion: Over the three COVID-19 waves, with a change in the management of MIS-C, children in the JIR cohort in France showed a less severe disease course, in particular, a greater use of corticosteroids. This observation may reflect the impact of both improved management and different SARS-CoV-2 variant.