Explore the vast range of titles available.

T-cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disease and bone marrow failure syndrome which responds to immunosuppressive therapies. We show single-cell TCR coupled with RNA sequencing of CD3 + T cells from 13 patients, sampled before and after alemtuzumab treatments. Effector memory T cells and loss of T cell receptor (TCR) repertoire diversity are prevalent in T-LGLL. Shared TCRA and TCRB clonotypes are absent. Deregulation of cell survival and apoptosis gene programs, and marked downregulation of apoptosis genes in CD8 + clones, are prominent features of T-LGLL cells. Apoptosis genes are upregulated after alemtuzumab treatment, especially in responders than non-responders; baseline expression levels of apoptosis genes are predictive of hematologic response. Alemtuzumab does not attenuate TCR clonality, and TCR diversity is further skewed after treatment. Inferences made from analysis of single cell data inform understanding of the pathophysiologic mechanisms of clonal expansion and persistence in T-LGLL. T cell large granular lymphocyte leukemia (T-LGLL) and the cellular phenotype underlying response to therapy is not well understood. Here the authors use single cell sequencing to better understand changes in T cell clonal frequency and gene expression before and after therapy in T-LGLL.

In a phase 2 clinical trial, eltrombopag plus standard immunosuppression resulted in a 6-month complete-response rate of 58% among patients receiving eltrombopag for 6 months. Immunosuppression alone has induced complete responses in approximately 10% of patients historically. In patients with aplastic anemia, the “empty” bone marrow does not produce blood cells, and when pancytopenia is severe and untreated, almost all patients die within 1 year after diagnosis. 1 Acquired aplastic anemia has immune pathophysiological features, as inferred from numerous laboratory studies and animal models. 2 Patients are cured by the replacement of both the hematopoietic and immune systems in a stem-cell transplant, but immunosuppressive therapy alone is also effective. Approximately two thirds of patients have increased blood-cell production after a single course of horse antithymocyte globulin and cyclosporine. 3 – 5 Hematologic response is strongly correlated with long-term survival. 6 Many efforts . . .

A phase 2 study showed a 44% response rate with eltrombopag, an oral thrombopoietin mimetic, among 25 patients with refractory aplastic anemia. Severe aplastic anemia is an acquired bone marrow disease characterized by trilineage marrow hypoplasia and a paucity of hematopoietic stem and progenitor cells due to an autoimmune attack on the bone marrow. 1 The standard treatment for aplastic anemia is immunosuppressive therapy with horse antithymocyte globulin (ATG) and cyclosporine, and hematologic responses are observed in about two thirds of patients. 2 Patients with disease that is refractory to immunosuppression and those who have a relapse after treatment may undergo allogeneic hematopoietic stem-cell transplantation (HSCT). However, 20 to 40% of patients without a suitable donor for HSCT continue to have severe cytopenias and . . .

Immune aplastic anemia (AA) results from T cell attack on hematopoietic cells, resulting in bone marrow hypocellularity and pancytopenia. Animal models have been successfully developed to study pathophysiological mechanisms in AA. While we have systemically defined the critical components of the adaptive immune response in the pathogenesis of immune marrow failure using this model, the role of innate immunity has not been fully investigated. Here, we demonstrate that lymph node (LN) cells from B6-based donor mice carrying IL-6, TLR2, or TLR4 gene deletions were fully functional in inducing severe pancytopenia and bone marrow failure (BMF) when infused into MHC-mismatched CByB6F1 recipients. Conversely, B6-based recipient mice with IL-6, TLR2, and TLR4 deletion backgrounds were all susceptible to immune-mediated BMF relative to wild-type B6 recipients following infusion of MHC-mismatched LN cells from FVB donors, but the disease appeared more severe in IL-6 deficient mice. We conclude that IL-6, TLR2, and TLR4, molecular elements important in maintenance of normal innate immunity, have limited roles in a murine model of immune-mediated BMF. Rather, adaptive immunity appears to be the major contributor to the animal disease.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is caused by inactivating somatic mutations in the UBA1 gene. Here, we characterize the immunological landscape of VEXAS syndrome by performing multi-omics single-cell RNA analysis, cytokine multiplex assays, and in vitro functional assays on patients’ peripheral blood. Our data reveals a broad immune system activation with upregulation of multiple inflammatory response pathways and proinflammatory cytokines. Unexpectedly, we find that monocytes have dysfunctional features irrespective of UBA1 mutation status, exhibiting impaired efferocytosis and blunted cytokine production in vitro. In contrast, UBA1 -mutated NK cells show an upregulation of the inflammation pathways and enhanced cytotoxicity. Within the lymphocyte subsets, predominantly UBA1 wild-type, we identify clonal expansion of effector memory CD8 + T cells and skewed B cell differentiation with loss of transitional B cells and expansion of plasmablasts. Thus, our analysis indicates that VEXAS syndrome is characterized by profound alterations in both adaptive and innate immune systems, accounting for the complex pathophysiology of the disease, and provides a basis to understand the marked clinical heterogeneity and variable disease course. VEXAS syndrome is a clinically heterogeneous inflammatory condition caused by mutations in the UBA1 gene. Here, by single cell transcriptomics on peripheral blood cells from VEXAS patients, the authors reveal innate and adaptive immune dysregulations irrespective of UBA1 mutations, including the presence of functionally impaired monocytes and clonal expansion of UBA1 wild-type effector memory B cells and plasmablasts.

Hematopoietic chimerism is known to promote donor-specific organ allograft tolerance; however, clinical translation has been impeded by the requirement for toxic immunosuppression and large doses of donor bone marrow (BM) cells. Here, we investigated in mice whether durable chimerism might be enhanced by pre-treatment of the recipient with liposomal clodronate, a macrophage depleting agent, with the goal of vacating BM niches for preferential reoccupation by donor hematopoietic stem cells (HSC). We found that liposomal clodronate pretreatment of C57BL/6 mice permitted establishment of durable hematopoietic chimerism when the mice were given a low dose of donor BM cells and transient immunosuppression. Moreover, clodronate pre-treatment increased durable donor-specific BALB/c skin allograft tolerance. These results provide proof-of-principle that clodronate is effective at sparing the number of donor BM cells required to achieve durable hematopoietic chimerism and donor-specific skin allograft tolerance and justify further development of a tolerance protocol based on this principle.

Severe immune aplastic anemia is a fatal disease due to the destruction of marrow hematopoietic cells by cytotoxic lymphocytes, serving as a paradigm for marrow failure syndromes and autoimmune diseases. To better understand its pathophysiology, we apply advanced single cell methodologies, including mass cytometry, single-cell RNA, and TCR/BCR sequencing, to patient samples from a clinical trial of immunosuppression and growth factor stimulation. We observe opposing changes in the abundance of myeloid cells and T cells, with T cell clonal expansion dominated by effector memory cells. Therapy reduces and suppresses cytotoxic T cells, but new T cell clones emerge hindering robust hematopoietic recovery. Enhanced cell-cell interactions including between hematopoietic cells and immune cells, in particular evolving IFNG and IFNGR, are noted in patients and are suppressed post-therapy. Hematologic recovery occurs with increases in the progenitor rather than stem cells. Genetic predispositions linked to immune activation genes enhances cytotoxic T cell activity and crosstalk with target cells. The transcriptional phenotype of immune cells associated with severe aplastic anaemia (SAA) may change post immunotherapy. Here the authors analyse single cell transcriptomics of hematopoietic and immune cells from SAA patients and assess how these phenotypes change after treatment showing alterations in myeloid cells and TCR clonal abundance correlate with robustness of hematopoietic response.

To improve the passive safety of the collision process, we designed a kind of energy absorption device based on cutting shear rings (CSR). It can be installed in a limited space, overcoming the characteristic of traditional energy absorption devices that cannot play their advantages in a narrow space, and it will not be accompanied by the splashing of chips in the process of energy absorption. The impact energy absorption characteristics of the shear rings outside the energy absorption rods are analyzed. The feasibility of the finite element method to study the device’s characteristics is demonstrated through the combination of the drop hammer test and numerical simulation. At the same time, the device’s responses under nine different working cases are simulated, and the impact energy absorption characteristics of the shear rings are analyzed. Moreover, the effects of shear ring thickness and spacing on the device are also analyzed. The results show that there are several peak forces during the energy absorption process, and each peak force is accompanied by the failure of the shear ring. The shear rings’ thickness correlates positively with energy absorption and peak force. But the spacing of shear rings only affects the number of peak forces. There is a linear trend between the shear rings’ spacing and energy absorption, and the slope of the trend increases with the increase in thickness.

Background Presently, there is no comprehensive analysis of the transcription regulation network in hematopoiesis. Comparison of networks arising from gene co-expression across species can facilitate an understanding of the conservation of functional gene modules in hematopoiesis. Results We used single-cell RNA sequencing to profile bone marrow from human and mouse, and inferred transcription regulatory networks in each species in order to characterize transcriptional programs governing hematopoietic stem cell differentiation. We designed an algorithm for network reconstruction to conduct comparative transcriptomic analysis of hematopoietic gene co-expression and transcription regulation in human and mouse bone marrow cells. Co-expression network connectivity of hematopoiesis-related genes was found to be well conserved between mouse and human. The co-expression network showed “small-world” and “scale-free” architecture. The gene regulatory network formed a hierarchical structure, and hematopoiesis transcription factors localized to the hierarchy’s middle level. Conclusions Transcriptional regulatory networks are well conserved between human and mouse. The hierarchical organization of transcription factors may provide insights into hematopoietic cell lineage commitment, and to signal processing, cell survival and disease initiation.

Background. Semen is the main carrier of sexually transmitted viruses, including human immunodeficiency virus type 1 (HIV-1). However, semen is not just a mere passive transporter of virions but also plays an active role in HIV-1 transmission through cytokines and other biological factors. Methods. To study the relationship between viruses and the chemokine-cytokine network in the male genital tract, we measured the concentrations of 21 cytokines/chemokines and the loads of HIV-1 and of 6 herpesviruses in seminal and blood plasma from HIV-1-infected and HIV-uninfected men. Results. We found that (1) semen is enriched in cytokines and chemokines that play key roles in HIV-1 infection or transmission; (2) HIV-1 infection changes the chemokine-cytokine network in semen, further enriching it in cytokines that modulate its replication; (3) HIV-1 infection is associated with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) compartmentalized seminal reactivation; (4) CMV and EBV concomitant seminal shedding is associated with higher HIV-1 loads in blood and seminal plasma; and (5) CMV seminal reactivation increases the seminal levels of the CCR5 ligands RANTES and eotaxin, and of the CXCR3 ligand monokine induced by gamma interferon (MIG). Conclusions. HIV-1 infection results in an aberrant production of cytokines and reactivation of EBV and CMV that further changes the seminal cytokine network. The altered seminal milieu in HIV-1 infection may be a determinant of HIV-1 sexual transmission.