CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

After germinal center B cells undergo somatic mutation and antigen selection, they become either memory B cells or plasma cells, but the signal requirements that control entry into either pathway have been unclear. When purified human germinal center cells were cultured with interleukin-2, interleukin-10, and cells expressing CD40 ligand, cells with characteristics of memory B cells were generated. Removal of CD40 ligand from the system resulted in terminal differentiation of germinal center B cells into cells with the characteristics of plasma cells. These results indicate that CD40 ligand directs the differentiation of germinal center B cells toward memory B cells rather than toward plasma cells.

No abstract

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day

The ability of human ␥␦ T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of V␦2 ؊ ␥␦ T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. V␦2 ؊ ␥␦ T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas V␦2 ؊ ␥␦ T cells were found as naive cells in CMV ؊ patients, they virtually all exhibited the cytotoxic effector/ memory phenotype in CMV ؉ patients, which is also observed in transplanted patients challenged with CMV. This longterm complete remodeling of the V␦2 ؊ ␥␦ T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster ␥␦ T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effectormemory V␦2 ؊ IntroductionHuman cytomegalovirus (CMV) is a widespread ␤-herpesvirus that establishes a lifelong viral persistence without detectable symptoms in immunocompetent patients but with life-threatening consequences in immunologically immature or compromised patients. Many studies have been reported that support an important role for adaptive T lymphocytes in the control of CMV infection. [1][2][3][4] In addition, we have demonstrated that the ␥␦ T-cell subpopulation contributes to the anti-CMV immune responses. 5,6 These unconventional T cells are generally considered to be intermediates between innate and adaptive immunity because of their rapid and massive responses to very diverse immune challenges.Compelling data exist that demonstrate the importance of ␥␦ T cells in various microbial infections in humans. They exhibit in vitro reactivity against cells infected by viruses, bacteria, or parasites and are selectively expanded in the peripheral blood of infected patients. [7][8][9][10] The majority of human circulating ␥␦ T cells express a T-cell receptor (TCR) encoded by the V␥9 and V␦2 gene segments. These cells are activated after interaction with nonpeptidic phosphorylated compounds, collectively called phosphoantigens, which are metabolic intermediates of the isoprenoid biosynthetic pathway. 11,12 These phosphoantigens are expressed by a variety of bacteria and parasites and are also present in some tumors. The other ␥␦ T cells are known as V␦2 Ϫ ␥␦ T cells, are largely located in mucosal epithelia and in the spleen, and represent approximately 20% of all circulating ␥␦ T cells. These cells predominantly express a TCR containing the V␦1 region. Their repertoire in the peripheral blood of most healthy adults is restricted, whereas it is polyclonal in the thymus and in cord blood. [13][14][15] This observation suggests that unknown environmental factors encou...