Chen et al. report single-cell transcriptomic characteristics of IgA nephropathy across species and identify key cell types and molecular pathways associated with disease progression. The cover art sho ws the recruitment of bone marrow–derived immune cells, especially macrophages, that infiltrate into kidney tissue through blood vessels and secrete immune factors to activate mesangial cells, thereby promoting IgA nephropathy immune injury. Image credit: Yiyao Deng.
Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation responsible for impaired hepatic metabolism and muscle weakness. To date, there is no curative treatment for GSDIII. We previously reported that two distinct dual AAV vectors encoding for GDE were needed to correct liver and muscle in a GSDIII mouse model. Here, we evaluated the efficacy of rapamycin in combination with AAV gene therapy. Simultaneous treatment with rapamycin and a novel dual AAV vector expressing GDE in the liver and muscle resulted in a synergic effect demonstrated at biochemical and functional levels. Transcriptomic analysis confirmed synergy and suggested a putative mechanism based on the correction of lysosomal impairment. In GSDIII mice liver, dual AAV gene therapy combined with rapamycin reduced the impact of the immune response to AAV observed in this disease model. These data provide proof of concept of an approach exploiting the combination of gene therapy and rapamycin to improve efficacy and safety and support clinical translation.
Louisa Jauze, Mallaury Vie, Quentin Miagoux, Lucille Rossiaud, Patrice Vidal, Valle Montalvo-Romeral, Hanadi Saliba, Margot Jarrige, Helene Polveche, Justine Nozi, Pierre-Romain Le Brun, Luca Bocchialini, Amandine Francois, Jeremie Cosette, Jérémy Rouillon, Fanny Collaud, Fanny Bordier, Emilie Bertil-Froidevaux, Christophe Georger, Laetitia Van Wittenberghe, Adeline Miranda, Nathalie Daniele, David Gross, Lucile Hoch, Xavier Nissan, Giuseppe Ronzitti
Diabetes increases the risk of both cardiovascular disease and kidney disease. Notably, most of the excess cardiovascular risk in people with diabetes is in those with kidney disease. Apolipoprotein C3 (APOC3) is a key regulator of plasma triglycerides, and it has recently been suggested to play a role in both type 1 diabetes-accelerated atherosclerosis and kidney disease progression. To investigate if APOC3 plays a role in kidney disease in people with type 2 diabetes, we analyzed plasma levels of APOC3 from the Veterans Affairs Diabetes Trial (VADT). Elevated baseline APOC3 levels predicted a greater loss of renal function. To mechanistically test if APOC3 plays a role in diabetic kidney disease and associated atherosclerosis, we treated BTBR wildtype (WT) and leptin-deficient (OB; diabetic) mice, a model of type 2 diabetes, with an antisense oligonucleotide (ASO) to APOC3 or a control ASO (cASO), all in the setting of human-like dyslipidemia. Silencing APOC3 prevented diabetes-augmented albuminuria, renal glomerular hypertrophy, monocyte recruitment, and macrophage accumulation, partly driven by reduced ICAM1 expression. Furthermore, reduced levels of APOC3 suppressed atherosclerosis associated with diabetes. This suggests that targeting APOC3 might benefit both diabetes-accelerated atherosclerosis and kidney disease.
Jocelyn Cervantes, Juraj Koska, Farah Kramer, Shreeram Akilesh, Charles E. Alpers, Adam E. Mullick, Peter Reaven, Jenny E. Kanter
Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM at diagnosis. Furthermore, we find that these changes in B cells are paralleled by T cell signatures suggestive of Th2-mediated inflammation that persist despite disease quiescence. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with previously masked cell states including dysfunctional protein processing in CD4+ T cells and regulation of cell death programming in NK, CD8+ T cells and gdT cells. Together, these findings unveil the coordinated immune dysregulation underpinning JDM and provide insight into strategies for restoring balance in immune function.
Gabrielle Rabadam, Camilla Wibrand, Emily Flynn, George C. Hartoularos, Yang Sun, Chioma Madubata, Gabriela K. Fragiadakis, Jimmie Ye, Susan Kim, Zev J. Gartner, Marina Sirota, Jessica Neely
Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single cell RNA sequencing and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell-mediated depletion of B cells in SLE patients. The resulting datasets do not only confirm a selective CAR T cell-mediated reset of the B cell response, but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type 1 interferon signaling. Our current data thus provide evidence for a causal relationship between the B cell response and the increased interferon signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and novel analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.
Artur Wilhelm, David Chambers, Fabian Müller, Aline Bozec, Ricardo Grieshaber-Bouyer, Thomas Winkler, Dimitrios Mougiakakos, Andreas Mackensen, Georg Schett, Gerhard Krönke
Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and non-canonical effects on non-immune cells. The adipsin/C3a/C3aR1 pathway stimulates insulin secretion and sustains pancreatic beta cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that male Adipsin/Cfd knockout mice exhibit increased energy expenditure and white adipose tissue (WAT) browning. In addition, male adipocyte-specific C3aR1 knockout mice exhibit enhanced WAT thermogenesis and increased respiration. In stark contrast, female adipocyte-specific C3aR1 knockout mice display decreased brown fat thermogenesis and are cold intolerant. Female mice express lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 is also lower in female subcutaneous adipose tissue than males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis and defense against cold stress. Our findings establish a newly discovered role of the alternative complement pathway in adaptive thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.
Lunkun Ma, Ankit Gilani, Alfonso Rubio-Navarro, Eric Cortada, Ang Li, Shannon M. Reilly, Liling Tang, James C. Lo