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Epstein–Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RAthat underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RAencodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA–IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA–IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

Supplemental Digital Content is available in the text.Laparoscopic transhiatal approach to esophagectomy with mediastinal lymphadenectomy usually involves hand-assisted laparoscopic surgery. However, a totally laparoscopic approach can decrease the size of the abdominal wound and curtail the impact on respiration. We present a novel, totally laparoscopic transhiatal technique that may reduce respiratory complications following thoracoscopic esophagectomy. We performed a series of combined, thoracoscopic and laparoscopic, McKeown esophagectomies via a neck-abdominal first approach. Middle and lower mediastinal lymphadenectomy, subtracheal lymph node removal, and esophageal mobilization were performed via a totally laparoscopic transhiatal approach. Subsequently, upper mediastinal lymph nodes were dissected using a thoracoscopic approach. Finally, an esophagogastric anastomosis was constructed in the neck. For the 36 patients in this series, the median values of the total operative duration and the thoracoscopic portion were 499 minutes (range, 315 to 678 min) and 106 minutes (range, 67 to 243 min), respectively. Postoperative pneumonia occurred in 3 (8.3%) patients. Totally laparoscopic transhiatal approach is feasible for esophageal surgery with acceptable short-term outcomes.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment.

X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurologic complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.

Introduction:Germline gain-of-function variants in PIK3CDand PIK3R1cause activated PI3K delta syndrome (APDS) types 1 and 2, respectively. Lymphoproliferative disorder (LPD) and susceptibility to various infections, including Epstein-Barr virus (EBV), are well-known features of APDS. EBV-associated LPDs are frequently observed in patients with APDS, and oligoclonal LPD might transform malignant lymphoma (ML). However, somatic molecular alterations in LPD and ML are not fully elucidated. Here, we report clinical characteristics and somatic mutational landscape and transcriptomic profiles of LPDs with EBV infection in APDS.

Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. IKBKB encodes IKK2, which activates NF-κB signaling. IKK2V203I results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2V203 is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in Ikbkb using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes arising from de novo germline mutations and yield insight into pathogenesis.

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs.

Biomimetic epoxide-opening cascade cyclizations of polyepoxides enable the efficient and rapid construction of polyether skeletons. In this study, we discovered a method for switching the cyclization mode from tetrahydrofuran to tetrahydropyran (THP) formation in epoxide-opening cascades of polyepoxides. The THP formation proceeded via an epoxonium-ion intermediate by simple heating in neutral water. Next, by expanding the switching reaction, we successfully established a “ring-size-divergent” synthetic strategy that enabled the synthesis of the five-, six-, and seven-membered ether rings from identical diepoxide cyclization precursors under simple acidic or neutral conditions. The “ring-size-divergent” synthetic strategy was applied to the short divergent synthesis of nerolidol-type sesquiterpenoids and feroniellins, resulting in the revision of the proposed stereochemistry of certain natural products and the determination of all of the absolute configurations. Additionally, the anti-inflammatory activities of the synthetic samples were evaluated.

Epstein–Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137–CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.

Aims. In order to determine the indications of transoral surgery for a tumor located at the pharyngoesophageal junction, the trumpet maneuver with transnasal endoscopy was used. Its efficacy is reported here. Material and Methods. An 88-year-old woman complaining of dysphagia, diagnosed with cervical esophageal cancer, and hoping to preserve her voice and swallowing function was admitted to our hospital. Conventional endoscopy showed that the tumor had invaded the hypopharynx. When inspecting the hypopharynx and the orifice of the esophagus, we asked the patient to blow hard and puff her cheeks with her mouth closed (trumpet maneuver). After the trumpet maneuver, the pharyngeal mucosa was stretched out. The pedicle of the tumor arose from the left-anterior wall of the pharyngoesophageal junction, so we decided to perform endoscopic resection. Result. Under general anesthesia, the curved laryngoscope made it possible to view the whole hypopharynx, including the apex of the piriform sinus and the orifice of the esophagus. The cervical esophageal cancer was pulled up to the hypopharynx. Under collaboration between a head and neck surgeon and an endoscopist, the tumor was resected en bloc by endoscopic laryngopharyngeal surgery combined with endoscopic submucosal dissection. Conclusion. Transnasal endoscopy using the trumpet maneuver is useful for a precise diagnosis of the pharyngoesophageal junction. Close collaboration between head and neck surgeons and endoscopists can provide good results in treating tumors of the pharyngoesophageal junction.

No relevant conflicts of interest to declare.

ALPS is characterized by chronic lymphoproliferation in combination with autoimmunity; mutations of molecules involved in FAS-dependent pathways play causative roles in this syndrome. The hallmarks of ALPS are an elevated CD4/CD8 double-negative T (DNT) cell count and attenuated induction of apoptosis by FAS stimulation. Autoimmune thrombocytopenia and/or hemolytic anemia are common in cases of ALPS; the combination of autoimmune thrombocytopenia and hemolytic anemia is referred to as Evans syndrome. ALPS is diagnosed in 47% of patients who present with Evans syndrome. Some patients with ALPS-like syndromes harbor mutations in RASor PRKCD.

The characteristics of KrF and XeCl laser media pumped by e-beam controlled discharge have been studied. A glow discharge easily turns into an arc in the KrF laser medium, in which Ar is used as a buffer gas, and a maximum enhancement ratio of 3 only was obtained. A glow discharge is much more stable in the XeCl laser medium, in which Ne buffer gas is used, and a maximum enhancement ratio of 6 was obtained by maintaining stable glow discharge for as long as the electron beam of 150 ns FWHM duration was injected into the medium. The amplification characteristics of the XeCl medium were studied, and a small-signal gain of 1.5%/cm, an absorption coefficient of 0.2%/cm, a saturation intensity of 1.2 MW/cm2and an internal conversion efficiency of ?4% were obtained at a pumping density of 0.2 MW/cm3. Thus, e-beam controlled discharge has been found to be useful in the low-pumping-density and long-pulse operation of XeCl lasers.