LILRB4 Checkpoint for Immunotherapy: Structure, Mechanism and Disease Targets.

LILRB4, a myeloid inhibitory receptor belonging to the family of leukocyte immunoglobulin-like receptors (LILRs/LIRs), plays a pivotal role in the regulation of immune tolerance. LILRB4 primarily mediates suppressive immune responses by transmitting inhibitory signals through immunoreceptor tyrosine-based inhibitory motifs (ITIMs). This immune checkpoint molecule has gained considerable attention due to its potent regulatory functions. Its ability to induce effector T cell dysfunction and promote T suppressor cell differentiation has been demonstrated, indicating the therapeutic potential of LILRB4 for modulating excessive immune responses, particularly in autoimmune diseases or the induction of transplant tolerance. Additionally, through intervening with LILRB4 molecules, immune system responsiveness can be adjusted, representing significant value in areas such as cancer treatment. Thus, LILRB4 has emerged as a key player in addressing autoimmune diseases, transplant tolerance induction, and other medical issues. In this review, we provide a comprehensive overview of LILRB4, encompassing its structure, expression, and ligand molecules as well as its role as a tolerance receptor. By exploring the involvement of LILRB4 in various diseases, its significance in disease progression is emphasized. Furthermore, we propose that the manipulation of LILRB4 represents a promising immunotherapeutic strategy and highlight its potential in disease prevention, treatment and diagnosis.

The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy.

Natural killer (NK) cells and CD8+ T cells can clear infected and transformed cells and generate tolerance to themselves, which also prevents autoimmune diseases. Natural killer group 2 member D (NKG2D) is an important activating immune receptor that is expressed on NK cells, CD8+ T cells, γδ T cells, and a very small percentage of CD4+ T cells. In contrast, the NKG2D ligand (NKG2D-L) is generally not expressed on normal cells but is overexpressed under stress. Thus, the inappropriate expression of NKG2D-L leads to the activation of self-reactive effector cells, which can trigger or exacerbate autoimmunity. In this review, we discuss the role of NKG2D and NKG2D-L in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type I diabetes (T1DM), inflammatory bowel disease (IBD), and celiac disease (CeD). The data suggest that NKG2D and NKG2D-L play a pathogenic role in some autoimmune diseases. Therefore, the development of strategies to block the interaction of NKG2D and NKG2D-L may have therapeutic effects in some autoimmune diseases.

Novel role of immune-related non-coding RNAs as potential biomarkers regulating tumour immunoresponse via MICA/NKG2D pathway.

Major histocompatibility complex class I related chain A (MICA) is an important and stress-induced ligand of the natural killer group 2 member D receptor (NKG2D) that is expressed in various tumour cells. Given that the MICA/NKG2D signalling system is critically embedded in the innate and adaptive immune responses, it is particularly involved in the surveillance of cancer and viral infections. Emerging evidence has revealed the important roles of non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in different cancer types. We searched for all relevant publications in the PubMed, Scopus and Web of Science database using the keywords ncRNA, MICA, NKG2D, cancer, and miRNAs. All relevant studies published from 2008 to the 2023 were retrieved and collated. Notably, we found that miRNAs can target to NKG2D mRNA and MICA mRNA 3'-untranslated regions (3'-UTR), leading to translation inhibition of NKG2D and MICA degradation. Several immune-related MICA/NKG2D pathways may be dysregulated in cancer with aberrant miRNA expressions. At the same time, the competitive endogenous RNA (ceRNA) hypothesis holds that circRNAs, lncRNAs, and mRNAs induce an abnormal MICA expression by directly targeting downstream miRNAs to mediate mRNA suppression in cancer. This review summarizes the novel mechanism of immune escape in the ncRNA-related MICA/NKG2D pathway mediated by NK cells and cancer cells. Moreover, we identified the miRNA-NKG2D, miRNA-MICA and circRNA/lncRNA/mRNA-miRNA-mRNA/MICA axis. Thus, we were particularly concerned with the regulation of mediated immune escape in the MICA/NKG2D pathway by ncRNAs as potential therapeutic targets and diagnostic biomarkers of immunity and cancer.

Analysis of Antibodies Induced after SARS-CoV-2 Vaccination Using Antigen Coded Bead Array Luminex Technology.

Objectives. Since the outbreak of SARS-CoV-2 in late 2019, nearly 12.2 billion doses of the COVID-19 vaccine have been administered worldwide; however, the humoral immune responses induced by different types of vaccines are yet to be fully validated. Methods. We analyzed antibody levels in 100 serum samples after vaccination with different types of COVID-19 vaccines and their reactivity against the RBD antigen of Delta and Omicron variants using a bead-based microarray. Results. Elevated levels of anti-wild-type (WT)-RBD IgG and anti-WT-NP IgG were detected in participants who received two doses of the inactivated vaccines (CoronaVac or BBIBP-CorV) and three doses of the recombinant spike protein vaccine (ZF2001), indicating that antibody responses to SARS-CoV-2 were generated regardless of the vaccine administered. We found highly correlated levels of serum anti-RBD IgG and anti-NP IgG (r = 0.432, p < 0.001). We observed that the antibodies produced in vivo after COVID-19 vaccination still reacted with variants of SARS-CoV-2 (p < 0.0001). Conclusions. Our results show that high levels of specific antibodies can be produced after completion of COVID-19 vaccination (two doses of the inactivated vaccines or three doses of ZF2001), with some degree of cross-reactivity to the RBD antigen of Delta and Omicron variants, and provide an accessible and practical experimental method for post-vaccination antibody detection.

Association between HLA-B*27:04 and genetic susceptibility to ankylosing spondylitis in Hunan Province. / 湖南地区携带HLA-B*27꞉04ç­‰ä½åŸºå› äººç¾¤ä¸Žå¼ºç›´æ€§è„ŠæŸ±ç‚Žçš„æ˜“æ„Ÿæ€§å ·æœ‰å¼ºç›¸å ³æ€§ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Human leukocyte antigen (HLA) B27 is a susceptibility allele of ankylosing spondylitis (AS), and HLA-B27 antigen typing is an important indicator for clinical diagnosis of AS, but current typing methods such as sequence specific primer polymerase chain reaction (PCR-SSP) still possess limitation. Therefore, this study aims to analyze the correlation between B27 subtypes and susceptibility to AS in Hunan Province by applying high-resolution polymerase chain reaction-sequence-based typing (PCR-SBT). METHODS: Peripheral blood of 116 patients with suspected AS (suspected AS group) and 121 healthy volunteers (control group) admitted to the Second Xiangya Hospital from January 2020 to December 2020 were collected for HLA-B genotyping by PCR-SBT. Among the patients in the suspected AS group, 23 patients were finally diagnosed with AS (confirmed AS group), and the remaining 93 undiagnosed patients served as the non-confirmed AS group. PCR-SBT and PCR-SSP were used to detect HLA-B27 typing in 116 patients with suspected AS, and the results of the 2 methods were compared. RESULTS: The HLA-B27 allele frequency in the suspected AS group was significantly higher than that in the control group [11.63% vs 2.48%; P<0.001, odds ratio (OR)=5.18, 95% confidence interval (CI) 2.097 to 12.795]. B*27:04, B*27:05, B*27:06, and B*27:07 were detected in the suspected AS group and the control group. The frequency of the B*27:04 allele in the suspected AS group was significantly higher than that in the control group (9.48% vs 1.24%; P<0.001, OR=8.346, 95% CI 2.463 to 28.282). The positive rate of B27 in the suspected AS group and the confirmed AS group (B27+/+ and B27+/-) was significantly higher than that in the control group (χ2=16.579, P<0.001; χ2=94.582, P<0.001, respectively). Among the confirmed AS group, 21 were HLA-B27 carriers, and the B27 positive rate in the confirmed AS group was 91.3%. PCR-SBT could achieve high resolution typing of the HLA-B gene locus, with higher sensitivity, specificity, positive predictive value, negative predictive value, and accuracy than PCR-SSP. CONCLUSIONS: PCR-SBT typing analysis shows a strong correlation between HLA-B * 27:04 and AS in Hunan province. The PCR-SBT method can be used as the preferred option for the auxiliary diagnosis of clinical AS.

Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox.

As an important component of the innate immune system, natural killer (NK) cells have gained increasing attention in adoptive cell therapy for their safety and efficacious tumor-killing effect. Unlike T cells which rely on the interaction between TCRs and specific peptide-MHC complexes, NK cells are more prone to be served as "off-the-shelf" cell therapy products due to their rapid recognition and killing of tumor cells without MHC restriction. In recent years, constantly emerging sources of therapeutic NK cells have provided flexible options for cancer immunotherapy. Advanced genetic engineering techniques, especially chimeric antigen receptor (CAR) modification, have yielded exciting effectiveness in enhancing NK cell specificity and cytotoxicity, improving in vivo persistence, and overcoming immunosuppressive factors derived from tumors. In this review, we highlight current advances in NK-based adoptive cell therapy, including alternative sources of NK cells for adoptive infusion, various CAR modifications that confer different targeting specificity to NK cells, multiple genetic engineering strategies to enhance NK cell function, as well as the latest clinical research on adoptive NK cell therapy.

A Soluble NK-CAR Mediates the Specific Cytotoxicity of NK Cells toward the Target CD20+ Lymphoma Cells.

The structures of chimeric antigen receptors (CARs) currently designed for natural killer (NK) cells are mostly based on knowledge gained about CAR-T cells. Although these CAR-NK cells have shown promising effects, there are still many limitations to their application. In this study, we designed a soluble NK-CAR since the membrane protein NKG2D expressed by NK cells can directly trigger NK cell cytotoxicity by binding with the ligand MICA. This CAR is composed of three segments: the extracellular domain of MICA, an anti-CD20 single-chain variable fragment (anti-CD20 ScFv), and a human IgG Fc component. The nucleotide sequence of the soluble NK-CAR was cloned into a eukaryotic expression vector and expressed in suspension HEK293 cells, and the recombinant NK-CAR protein was then purified in a Staphylococcus aureus protein A column. The novel NK-CAR exhibited bifunctional activity, recognizing both the CD20 antigen of target cells and the NKG2D receptor of NKL cells. The NK-CAR activated the NKG2D receptor signaling pathway, causing NKL cells to express CD107a and secrete interferon-gamma. The soluble NK-CAR mediated the NKL cell killing of CD20+ Daudi cells in vitro, with a 1 µg/mL concentration inducing the maximum killing effect. Moreover, 51.7% (p < 0.01) of Daudi cells were killed at the effector-to-target ratio of 10:1. In the presence of recombinant rMICA and NKG2D-Ig proteins, this killing effect was reduced to 30% (P < 0.01) owing to competitive interference. Our results highlight the clinical application potential of this novel immunotherapy for killing target tumor cells.

Posttransplant-Alloantibodies Against MICA Antigens Associated With Decreased Long-Term Allograft Survival of Kidney Transplant Recipients.

BACKGROUND: Previous evidence showed that antibodies against major histocompatibility complex class I-related chain A (MICA) could lead to antibody-mediated rejection in kidney transplantation in case where the patients had no alloantibodies against HLA. However, the effects of posttransplant anti-MICA antibodies on long-term renal allograft survival and function remained unsettled. We tested the posttransplant anti-MICA antibodies in 150 kidney transplant patients. The aim of this study was to compare the long-term graft survival and function between patients who were MICA positive and those who were negative. METHODS: The posttransplant serum samples from 150 patients receiving kidney transplantation in our center from 2012 to 2013 were tested for MICA antibodies and HLA antibodies by Luminex single antigen array technology. Graft survival and function were followed up for a mean time of 74.2 months. The research was conducted in accordance with the Helsinki Congress and the Declaration of Istanbul. RESULTS: Of the 150 patients, 38 (25.3%) were sensitized against MICA after transplantation. The anti-MICA antibodies-positive (anti-MICA+) group had a worse long-term renal allograft survival than that of anti-MICA-negative (anti-MICA-) group (P = .029), even when stratified by posttransplant HLA sensitization status or donor source. Anti-MICA antibodies also had a detrimental impact on renal allograft function, but only at 1 year posttransplantation (estimated glomerular filtration rates at 1 year: anti-MICA+ 66.6 mL/min/1.73 m2 vs anti-MICA- 78.7 mL/min/1.73 m2; P = .023). CONCLUSION: Posttransplant anti-MICA antibodies were associated with decreased long-term renal allograft survival and short-term renal allograft function.

Diseases association with the polymorphic major histocompatibility complex class I related chain a: MICA gene.

The Major Histocompatibility Complex class I chain-related molecule A (MICA) genes encode a highly polymorphic glycoprotein among the cell surface antigens that trigger an immune response after allograft transplantation. It is encoded by the MICA gene, a member of the glycosylated MIC genes. Discovered in 1994, the MICA gene is located within the MHC class I region. Moreover, its biological function is achieved through the interaction with the NKG2D receptor. Unlike the classical HLA molecules, MICA protein is not associated with ß2- microglobulin nor binds peptides. MICA gene expression may result in a cytotoxic response and IFN-γ secretion through the up-regulation by heat shock proteins in response to infection (Human Cytomegalovirus HCMV), mediated by NKG2D-expressing cells. Anti-MICA antibodies were identified as significant risk factors for antibody mediated rejection after being detected in sera of patients with graft rejection. In addition, soluble MICA proteins (sMICA) has been detected in the serum of transplant recipients with cancers. Furthermore, the association of MICA polymorphisms with infectious diseases, various autoimmune diseases, cancer, and allograft rejection or graft-versus-host disease (GVHD) has been studied. Moreover, numerous advanced disease studies centered on MICA polymorphism are independent of HLA association. In this review, we discussed the up-to-date data about MICA and the association of MICA polymorphism with infections, autoimmune diseases, graft-versus-host disease, and cancer.

Innate lymphoid cells are double-edged swords under the mucosal barrier.

As the direct contacting site for pathogens and allergens, the mucosal barrier plays a vital role in the lungs and intestines. Innate lymphoid cells (ILCs) are particularly resident in the mucosal barrier and participate in several pathophysiological processes, such as maintaining or disrupting barrier integrity, preventing various pathogenic invasions. In the pulmonary mucosae, ILCs sometimes aggravate inflammation and mucus hypersecretion but restore airway epithelial integrity and maintain lung tissue homeostasis at other times. In the intestinal mucosae, ILCs can increase epithelial permeability, leading to severe intestinal inflammation on the one hand, and assist mucosal barrier in resisting bacterial invasion on the other hand. In this review, we will illustrate the positive and negative roles of ILCs in mucosal barrier immunity.

The leukocyte immunoglobulin-like receptor gp49B1, coexpressed with c-Kit, modulates hematopoiesis and B cell leukemia development.

A better understanding of cell-intrinsic factors involved in regulating stem cells and cancer cells will help advance stem cell applications and cancer cell treatment. Previously, we showed that leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog, paired immunoglobulin-like receptor B (PIRB), promote blood stem cell and leukemia development. Another unique mouse paralog to PIRB called gp49B1 was also discovered. However, the roles of gp49B1 in hematopoietic stem cells and leukemia development are largely unknown. Here, we found that gp49B1 is expressed on LSK cells of mouse neonatal hematopoietic organs and is positively correlated with c-Kit expression. However, in noncompetitive and competitive repopulation assays, neonatal splenic gp49B1-positive and c-Kit-highly expressed LSK cells exhibited poor engraftment potential and lymphoid lineage bias. Moreover, in a mouse N-Myc-induced precursor B-acute lymphoblastic leukemia (pre-B ALL) model, we found that gp49B1 deficiency or low levels of c-Kit led to a delay in leukemia development. Together, our results suggest that gp49B1 expressed on hematopoietic progenitor cells supports hematopoietic and leukemia development.

Glycemic deviation index: a novel method of integrating glycemic numerical value and variability.

BACKGROUND: There are many continuous blood glucose monitoring (CGM) data-based indicators, and most of these focus on a single characteristic of abnormal blood glucose. An ideal index that integrates and evaluates multiple characteristics of blood glucose has not yet been established. METHODS: In this study, we proposed the glycemic deviation index (GDI) as a novel integrating characteristic, which mainly incorporates the assessment of the glycemic numerical value and variability. To verify its effectiveness, GDI was applied to the simulated 24 h glycemic profiles and the CGM data of type 2 diabetes (T2D) patients (n = 30). RESULTS: Evaluation of the GDI of the 24 h simulated glycemic profiles showed that the occurrence of hypoglycemia was numerically the same as hyperglycemia in increasing GDI. Meanwhile, glycemic variability was added as an independent factor. One-way ANOVA results showed that the application of GDI showed statistically significant differences in clinical glycemic parameters, average glycemic parameters, and glycemic variability parameters among the T2D groups with different glycemic levels. CONCLUSIONS: In conclusion, GDI integrates the characteristics of the numerical value and the variability in blood glucose levels and may be beneficial for the glycemic management of diabetic patients undergoing CGM treatment.

How to think about severe acute respiratory syndrome coronavirus 2 vaccination for pregnant and lactating women in China. / å¦‚ä½•çœ‹å¾ ä¸­å›½å¦Šå¨ æœŸåŠå“ºä¹³æœŸå¥³æ€§æ–°åž‹å† çŠ¶ç— æ¯’ç–«è‹—æŽ¥ç§ï¼Ÿ.

The coronavirus disease 2019 (COVID-19) continues to spread around the world, and how to build an immune barrier against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the population is the work we need to do for a long time in the future. The vaccination is an important strategy to construct and improve the herd immunity barrier. Therefore, our country is currently actively and extensively implementing the anti-epidemic policy of SARS-CoV-2 vaccination. However, because of insufficient data on the safety of the SARS-CoV-2 vaccine in the population, especially the lack of clinical research in pregnant and lactating women, China has adopted a conservative approach on whether women in this special physiological period receive SARS-CoV-2 vaccine based on the safe consideration. However, with the widespread application of the SARS-CoV-2 vaccine in the prevention and control of the global epidemic, and the emergence of a large number of clinical research evidences at home and abroad, if we still exclude pregnant and lactating women from the vaccinated population, this part of the population will be fully exposed to the SARS-CoV-2 threat, which will weak the national prevention and control policy. Therefore, it is necessary to reconsider the vaccination of people in this special physiological period based on the experience of vaccination at home and abroad.

Airway epithelial integrin ß4 suppresses allergic inflammation by decreasing CCL17 production.

Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin ß4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.

Genomic characterization of MICA gene using multiple next generation sequencing platforms: A validation study.

We have developed a protocol regarding the genomic characterization of the MICA gene by next generation sequencing (NGS). The amplicon includes the full length of the gene and is about 13 kb. A total of 156 samples were included in the study. Ninety-seven of these samples were previously characterized at MICA by legacy methods (Sanger or sequence specific oligonucleotide) and were used to evaluate the accuracy, precision, specificity, and sensitivity of the assay. An additional 59 DNA samples of unknown ethnicity volunteers from the United States were only genotyped by NGS. Samples were chosen to contain a diverse set of alleles. Our NGS approach included a first round of sequencing on the Illumina MiSeq platform and a second round of sequencing on the MinION platform by Oxford Nanopore Technology (ONT), on selected samples for the purpose of either characterizing new alleles or setting phase among multiple polymorphisms to resolve ambiguities or generate complete sequence for alleles that were only partially reported in the IMGT/HLA database. Complete consensus sequences were generated for every allele sequenced with ONT, extending from the 5' untranslated region (UTR) to the 3' UTR of the MICA gene. Thirty-two MICA sequences were submitted to the IMGT/HLA database including either new alleles or filling up the gaps (exonic, intronic and/or UTRs) of already reported alleles. Some of the challenges associated with the characterization of these samples are discussed.

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity.

The natural killer group 2D (NKG2D) receptor and its ligands play important roles in immune surveillance. In this study, we observed that the average serum soluble MICA (sMICA) concentration of 174 hepatocellular carcinoma (HCC) patients was significantly higher than that in 80 healthy subjects (602.17 ± 338.15 vs. 72.26 ± 87.88 pg/ml, t = 3.107, P=0.002). The levels of serum sMICA in 44 HCC patients with initial levels above 400 pg/ml declined significantly after surgical removal of the liver cancer tissue (P<0.001). Moreover, the mean survival time of HCC patients who had sMICA above 400 pg/ml was significantly shorter than that HCC patients with lower sMICA levels (P<0.001). Using the reporter cell line (NKG2D-2B4) in which activation of the NKG2D receptor pathway results in GFP expression based on the stimulation of immobilized rMICA, we showed that the number of GFP-expressing cells decreased sharply in presence of sMICA. Upon adding sMICA, the release of cytokines IFN-γ, TNF-α, and IL-8 by NK cell line (NKL) under stimulation of immobilized rMICA was blocked. Using MICA-expressing cells as the target cells, we observed that about 80% of target cells were killed by NKL at E:T of 10:1, but in presence of sMICAhigh serum of HCC patients, the dead target cells were reduced to 30.8%. Compared in presence of sMICAlow serum from HCC patients, there were 63.7% of target cells dead (p=0.043). Thus, our data suggested that sMICA obstructs the activation of NKG2D pathway to protect tumor cells from NK cell-mediated cytotoxicity.

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response.

Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early-life lung immune responses are far from clear. Our previous study found that integrin ß4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper-responsiveness (AHR) with a house dust mite (HDM)-induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4-deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.

Strategies to achieve immune tolerance in allogeneic solid organ transplantation.

Organ transplantation is an effective way to treat many end-stage diseases. In order to overcome post-transplant rejection, immunosuppressive agents have been widely used, but the long-term survival of transplanted organs still has not been achieved in the clinic. For decades, tolerance is the "holy grail" that transplant immunologists have longed for. The well-known approaches to induce immune tolerance are through adoptively transferred regulatory T cells and achieving chimeric states. In addition, there are a variety of promising potential strategies, including costimulatory blockade, regulating differentiation of immune cell subgroups, adoptive infusion of immunoregulatory cells, using apoptotic cells to induce tolerance, stem cell regenerative medicine to reconstitute tissue and organs, helminthic therapy, using exosomes carrying phagocytic antigen and phagocytic vesicles to induce tolerance, and blocking CD3 and targeted clearance of memory T cells. In this paper, we review the current developments and the potential of these strategies to achieve transplantation tolerance.

Identification of the first case of SFTSV infection in the Hunan Province of China and epidemiological surveillance in the locality.

This study reports the etiological identification, clinical diagnosis, and the results of the local epidemiological surveillance of the first case of severe fever with thrombocytopenia syndrome virus (SFTSV) infection in 2014 in Hunan Province, China. The infected patient was isolated and closely monitored. The virus is a member of the Bunyaviridae sandfly family and is characterized by real-time PCR, electron microscopy, immunofluorescence, and whole-genome sequencing. We also detected IgG and IgM antibodies against SFTSV among the local human population and domestic animals in a serological surveillance. Prevalence of SFTSV-specific antibodies was monitored in the local population for two years after the identification of the first SFTS case. Approximately 5% (4/77) of the people who had direct contact with the patient were seropositive, which is significantly higher than the seropositivity of the general local population [1.57% (44/2800), P < 0.05]. Furthermore, the percentage of the general population who were seropositive was higher in 2015 than in 2014 (χ2 = 7.481, P = 0.006). The epidemiological investigation found that the SFTSV is epidemic in goats, cattle, and chickens in Hunan Province. The risk of infection of domestic animals can be minimized by feeding in pens rather than allowing foraging.

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.