Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi–ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon–driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered.We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics.All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy.COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.

The adaptive immune system in vertebrates relies on an enormous repertoire of antigen receptors. The variable domains of antigen receptors are encoded by extensive arrays of variety, diversity and joining (V, D, and J) gene segments flanked by conserved recombination signal sequences (RSSs) [1]. During the early lymphoid-specific process known as V(D)J recombination, RAG1 and RAG2 recognize and pair two RSSs based on the 12/23 rule and introduce a pair of double-strand breaks (DSB) between each RSS and its adjoining coding segment [2]. The non-homologous DNA end-joining pathway then rejoins the coding segments together and generates functional receptors [3].Murine RAG1 contains 1 040 amino acids, and RAG2 contains 527 amino acids. Biochemical studies have confirmed that the core regions of RAG1 (aa 384-1 008) and RAG2 (aa 1-387) are fundamental for the cleavage reaction in vitro [4]. Core RAG1 is capable of recognizing RSSs and can form tetramers with RAG2 in which the DDE triad is responsible for the DNA cleavage activity [5]. Core RAG2 contains Kelch motifs that assist RAG1 binding and cutting of the RSSs [6]. The plant homology domain within the RAG2 non-core region has recently been shown to bind histone H3K4Me3 and activate the recombination reaction [7,8]. Regarding the non-core region, especially the N-terminal region of RAG1 (aa 1-383), several conserved clusters of basic residues have been identified within residues 1-264 [9]. This region is thought to bind to a zinc ion and associate with KPNA1 and SRP1 [10][11][12]. A recently defined WW-like domain (aa 179-205) might mediate protein-protein interactions [13]. Residues 265-383 of RAG1 contain a C3HC4 ring-finger domain harboring E3 ubiquitin ligase activity [14]. However, the roles of these domains or motifs in V(D)J recombination have not been fully elucidated.The impaired V(D)J recombination in core RAG1 knock-in mice suggests that non-core RAG1 increases the efficiency and accuracy of recombination, yet quite a number of lymphocytes can mature, indicating that non-core RAG1 is dispensable for basic recombination activity [15]. Nevertheless, in some Omenn syndrome Cell Research (2015) 25:181-192.

COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit a (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a Copa E241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from Copa E241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.

A series of lanthanide sulfates coordination complexes, Ln 2 (SO 4 ) 3 (H 2 O) 8 (Ln = Pr (1), Nd (2), Tb (3), Sm (4), Dy (5), Gd (7), Ho (8)), and EuK(SO 4 ) 2 (6), were constructed by the reaction in situ of lanthanide ions (Ln 3+ ) with flexible dodecanedioic acid and rigid aromatic 5-sulfosalicylic acid under hydrothermal conditions. All of them were characterized by elemental analysis, IR spectroscopy, and single-crystal X-ray diffraction. The crystal structures and coordination modes of metal centers and sulfate ions, as well as the novel reaction mechanism and different conditions of lanthanide ions and 5-sulfosalicylic acid to form the series of lanthanide sulfate complexes, were discussed in detail. Solid-state properties for these crystalline materials, such as thermal stability and powder X-ray diffraction have been investigated. Additionally, the photoluminescent characterizations of the complexes 3, 4, 5 and 6, and the catalytic properties of all the complexes about cyclohexane being oxidized into cyclohexanone/cyclohexanol were investigated and compared.

15 † equal contribution 16 2 Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation 17 with elevated type I interferon signaling 1,2 . COPA is a subunit of coat protein complex I 18 (COPI) that mediates Golgi to ER transport 3 . Missense mutations that disrupt the COPA 19 WD40 domain impair binding and sorting of proteins targeted for retrieval to the ER but 20 how this causes disease remains unknown 1,4 . Given the importance of COPA in Golgi-ER 21 transport, we speculated that type I interferon signaling in COPA syndrome involves 22

Disseminated intravascular coagulation (DIC) is a complication of sepsis currently lacking effective therapeutic options. Excessive inflammatory responses are emerging triggers of coagulopathy during sepsis, but the interplay between the immune system and coagulation are not fully understood. Here we utilize a murine model of intraperitoneal lipopolysaccharide stimulation and show neutrophils in the circulation mitigate the occurrence of DIC, preventing subsequent septic death. We show circulating neutrophils release extracellular vesicles containing mitochondria, which contain superoxide dismutase 2 upon exposure to lipopolysaccharide. Extracellular superoxide dismutase 2 is necessary to induce neutrophils’ antithrombotic function by preventing endothelial reactive oxygen species accumulation and alleviating endothelial dysfunction. Intervening endothelial reactive oxygen species accumulation by antioxidants significantly ameliorates disseminated intravascular coagulation improving survival in this murine model of lipopolysaccharide challenge. These findings reveal an interaction between neutrophils and vascular endothelium which critically regulate coagulation in a model of sepsis and may have potential implications for the management of disseminated intravascular coagulation.

One Sentence Summary:A new mouse model of COPA syndrome develops lung pathology that recapitulates patients and reveals that T cells are important drivers of the disease. Abstract:COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the Coatomer protein complex subunit alpha (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or 2 interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis that requires life-saving measures such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a Copa E241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokinesecreting T cells. Here we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from Copa E241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.