Background Heterozygous loss-of-function mutations in the TNFAIP3 gene cause an early-onset autoinflammatory disease named haploinsufficiency of A20 (HA20). Here we described three unrelated patients with autoimmune lupus nephritis (LN) phenotypes carrying three novel mutations in the TNFAIP3 gene. Methods Whole-exome sequencing (WES) was used to identify the causative mutations in three biopsy-proven LN patients. Sanger sequencing and quantitative PCR (qPCR) were used to validate the mutations identified by WES. RNA sequencing, qPCR, Cytometric Bead Array was used to detect inflammatory signature in the patients. Results The patients predominantly presented with autoimmune phenotype, including autoimmune haemolytic anaemia, multipositive autoantibodies, and LN. Additionally, novel phenotypes of allergy, and pericardial effusion were first reported. WES identified three novel heterozygous mutations in the TNFAIP3 gene, including a novel splicing mutation located in the canonical splicing site (c.634 + 2T > C) resulting in an intron4 insertion containing a premature stop codon, a de novo novel copy number variation (exons7-8 deletion), and a novel nonsense mutation c.1300_1301delinsTA causing a premature stop codon. We further identified hyperactivation signatures of NF-κB and type-I IFN signalling and overproduction of pro-inflammatory cytokines in blood. This report expand the phenotype to later age, as two girls were diagnosed at age 3 years and one man at age 29 years. Conclusions Kidney involvement may be the main feature of the clinical spectrum of HA20, even in adults. Genetic screening should be considered for early-onset LN patients.
Background:Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus, with heterogeneous phenotypes and different responses to therapy. Identifying genetic causes of LN can facilitate more individual treatment strategies.Methods:We performed whole-exome sequencing in a cohort of Chinese patients with LN, and identified variants of a disease-causing gene. Extensive biochemical, immunologic, and functional analyses assessed the impact of the variant on type I interferon (IFN) signaling. We further investigated the effectiveness of targeted therapy using single-cell RNA sequencing.Results:We identified a novelDDX58pathogenic variant, R109C, in five unrelated families with LN. TheDDX58R109C variant is a gain-of-function mutation, elevating type I IFN signaling due to reduced autoinhibition, which leads to RIG-I hyperactivation, increased RIG-I K63 ubiquitination, and MAVS aggregation. Transcriptome analysis revealed an increased IFN signature in patient monocytes. Initiation of JAK inhibitor therapy (baricitinib 2 mg per day) effectively suppressed the IFN signal in one patient.Conclusions:A novelDDX58R109C variant that can cause LN, connects IFNopathy and LN, suggesting targeted therapy based on pathogenicity.
Background: Autoinflammatory diseases (AIDs) were first proposed 20 years ago and caused by dysregulation of the innate immune system leading to episodes of systemic inflammation. Advances in next-generation sequencing and biological technology have resulted in the identification of new monogenic diseases and the corresponding signaling pathways that may guide us in targeted therapy. The kidney is a major target organ of various inflammatory process. Summary: During systemic inflammation, increased proinflammatory cytokines, such as IL-6, IL-1β and TNF, lead to over transcription and release of acute phase reactant serum amyloid A (SAA). Sustained high SAA levels promote a cascade of pathophysiological events, including protein misfolding, protein fragmentation and aggregation into highly ordered amyloid fibrils. Amyloid fibrils deposition in kidney cause progressive glomerular and vascular damage. Renal AA amyloidosis is a common and severe complication of AIDs, including FMF, CAPS, TRAPS, MKD/HIDS, and DADA2. Amyloidosis may even be the first clinical manifestation in some patients, presenting with asymtomatic proteinuria, nephritic syndrome, progressive renal insufficiency or end-stage kidney disease. In addition, major dysregulated pathways in different AIDs lead to endogenous inflammation, which is due to direct endothelial cytotoxicity caused by IL-1β, type I interferon, or possibly immune complexes. The kidney is frequently affected by various vasculitis and renal involvement is a major determinant of treatment options and outcomes. The renal vasculitis involved in AIDs includes renal artery Takayasu vasculitis, polyarteritis nodosa, and IgA vasculitis. Moreover, other kidney diseases, such as glomerulonephritis, lupus nephritis, and renal tubular dysfunction were also reported in AIDs. Key Messages: Kidney manifestations can be a coexisting disease seen with AIDs. They may also be one of the characteristics of AIDs. Clinicians should be aware of the possibility that amyloidosis, vasculitis or other renal diseases may be associated with AIDs in order to make appropriate diagnosis and treatment. Renal biopsy may be of great significance. Biologics, which switch off the underlying cytokine mediated inflammatory process, have the potential to restore organ damage and improve the outcome in the very early stage of the disease.
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