ブラウ症候群

OBJECTIVE AND DESIGN: This narrative review synthesizes current evidence on the immunopathogenesis of autoimmune uveitis(AU), with particular emphasis on genetic susceptibility, immunometabolic dysregulation, tissue-resident immunity, and the proposed gut-spleen-eye immunometabolic axis. MATERIAL AND SUBJECTS: Published genetic, clinical, experimental, and in vitro studies addressing immune-mediated uveitis and related mechanistic pathways were summarized. TREATMENT: Not applicable. METHODS: We summarized evidence on subtype-associated genetic factors, Th17-centered immunometabolic reprogramming, retinal microglial and myeloid responses, innate-adaptive immune interactions, and gut-derived metabolic regulation, with attention to evidence level and translational relevance. RESULTS: Genetic susceptibility showed the clearest subtype specificity, including HLA-B27/ERAP1-associated acute anterior uveitis, IL23R-C1orf141-associated Vogt-Koyanagi-Harada disease, HLA-B51-ERAP1-associated Behçet disease, and NOD2-associated Blau syndrome. Experimental and clinical evidence further links Th17 dysregulation to AU, whereas most pathway-specific metabolic, microglial, macrophage, retinal vascular, and gut-derived mechanisms remain supported mainly by experimental autoimmune uveitis or in vitro studies. The proposed HDCA-red pulp macrophage-oleic acid pathway may integrate systemic metabolic and immune regulation, but its relevance to defined human AU subtypes remains uncertain. CONCLUSIONS: AU is mechanistically heterogeneous, and current evidence supports phenotype-stratified validation of candidate pathways before translation into targeted therapeutic strategies.

OBJECTIVE: Mosaicism is a recognized cause of systemic autoinflammatory diseases (SAIDs). Initially described in cryopyrin-associated periodic syndromes (CAPS), it has since been reported in several dominantly inherited SAIDs, including Blau syndrome, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), stimulator of interferon genes-associated vasculopathy with onset in infancy, NLRC4 inflammasomopathies, and familial Mediterranean fever. Recently, somatic variants underlying vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) have extended this to late-onset disease. This study aimed to characterize the prevalence, spectrum, and clinical significance of acquired variants in SAIDs. METHODS: A total of 5,530 patients referred to a national SAIDs reference center between 2017 and 2025 underwent deep next-generation sequencing autoinflammatory gene panel testing to detect low-level mosaicism. Results underwent multidisciplinary review and correlation with clinical data from electronic medical records. RESULTS: SAID diagnoses were made in 403 of 5,530 patients (7.3%, 95% confidence interval [CI] 6.6%-8.0%). Among these, mosaic variants were identified in 83 patients (20.6%, 95% CI 16.9%-24.8%), including patients with VEXAS syndrome (69%), CAPS (24%), TRAPS (5%), Blau syndrome (1%), and NLRC4 inflammasomopathies (1%). Twenty-three distinct mosaic variants were identified across different SAIDs genes; in eight, the minor allele frequency was ≤5%. We report the first case of vertical transmission of TRAPS due to gonosomal mosaicism. AA amyloidosis complicated the disease course in 20% of patients diagnosed with late-onset mosaic CAPS. CONCLUSION: Somatic mosaicism is a frequent mechanism underlying late-onset SAIDs, which are often diagnosed late and carry a high risk of AA amyloidosis. To our knowledge, this represents the largest genetically heterogeneous single-center cohort of individuals with mosaic SAIDs reported to date.

Juvenile idiopathic arthritis is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage and genome-wide association studies have identified genes that contribute to the risk of developing juvenile idiopathic arthritis but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of juvenile idiopathic arthritis. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as juvenile idiopathic arthritis. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein pathway, are found to be associated with juvenile idiopathic arthritis. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

PURPOSE: Childhood-onset sarcoidosis (COS) is a rare granulomatous autoinflammatory condition characterised by arthritis, dermatitis, and uveitis which includes early-onset forms (sporadic or Blau syndrome) and a later-onset form resembling adult sarcoidosis. Ocular involvement often occurs early and may be a prominent, sight-threatening feature. Despite this, COS is sparsely described in the literature. This case series aims to characterise the ocular manifestations, complications, and outcomes in COS. METHODS: A review of patients diagnosed with COS under a tertiary paediatric uveitis service. Data collected included age at onset, clinical findings, diagnostic methods, treatments, ocular complications, and visual acuity (VA) at presentation and last follow-up. RESULTS: Six patients were identified, all of whom presented with granulomatous uveitis. Four had posterior segment involvement including choroiditis and optic disc swelling. The mean age of ocular disease onset was 7 years. Diagnosis was supported by elevated serum angiotensin converting enzyme (ACE) followed by lymph node biopsy (n = 3), skin biopsy (n = 2), and/or NOD2 mutation (n = 3). All received systemic immunosuppression: methotrexate (n = 6), adalimumab (n = 5), mycophenolate (n = 2), oral corticosteroids (n = 3), and infliximab (n = 1). Complications included uveitic glaucoma (n = 2), cataract (n = 3), and chorioretinal scarring (n = 1). VA improved or remained stable in most, with one case of persistent visual impairment. CONCLUSION: COS-related uveitis demonstrates an aggressive, chronic course with early onset, bilateral involvement, and frequent complications with potential to cause visual loss. Careful ophthalmic screening in children with known or suspected sarcoidosis is critical.