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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 Angiotensin-converting enzyme 2 (ACE2) is known as a tumor suppressor and lowly expressed in most cancers. The expression pattern and role of ACE2 in breast cancer (BC) have not been deeply elucidated. Methods A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). The correlation of ACE2 expression and immunological characteristics in the BC tumor microenvironment (TME) was evaluated. The role of ACE2 in predicting the response to therapeutic options was estimated. Moreover, the pharmacodynamic effect of angiotensin-(1–7) (Ang-1–7), the product of ACE2, on chemotherapy and immunotherapy was evaluated on the BALB/c mouse BC model. In addition, the plasma samples from BC patients receiving neoadjuvant chemotherapy were collected and subjected to the correlation analysis of the expression level of Ang-1–7 and the response to neoadjuvant chemotherapy. Results ACE2 was lowly expressed in BC tissues compared with that in adjacent tissues. Interestingly, ACE2 was shown the highest correlation with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB) in BC. In addition, a high level of ACE2 indicated a low response to endocrine therapy and a high response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. In the mouse model, Ang-1–7 sensitized mouse BC to the chemotherapy and anti-PD-1 immunotherapy, which revealed its significant anti-tumor effect. Moreover, a high plasma level of Ang-1–7 was associated with a better response to neoadjuvant chemotherapy. Conclusions ACE2 identifies immuno-hot tumors in BC, and its enzymatic product Ang-1–7 sensitizes BC to the chemotherapy and immunotherapy by remodeling the TME.