-
Frontiers in Endocrinology 2023Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure...
OBJECTIVES
Though type 2 diabetes (T2D) has been known as a metabolic disease caused by multiple factors, the etiology remains insufficiently understood. Here, we aimed to figure out whether circulating immune cell profiles causally impact T2D liability.
METHODS
We applied one genome-wide association study (GWAS) summary statistics of blood traits in 563,085 participants from the Blood Cell Consortium and another GWAS of flow cytometric profile of lymphocyte subsets comprising 3,757 Sardinians to identify genetically predicted blood immune cells. We also obtained GWAS summary statistics in 898,130 individuals from the DIAGRAM Consortium to evaluate genetically predicted T2D. We primarily used inverse variance weighted (IVW) and weighted median methods to perform Mendelian randomization analyses and sensitivity analyses to evaluate heterogeneity and pleiotropy.
RESULTS
For circulating blood leukocyte and its subpopulations, the increase of genetically predicted circulating monocyte count was causally correlated with a higher risk of T2D [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, p = 0.0048]. For lymphocyte subsets, CD8 T cell and CD4 CD8 T cell count were identified with causal effect on T2D susceptibility (CD8 T cell: OR = 1.09, 95% CI = 1.03-1.17, p = 0.0053; CD4 CD8 T cell: OR = 1.04, 95% CI = 1.01-1.08, p = 0.0070). No pleiotropy was determined.
CONCLUSIONS
These findings demonstrated that higher circulating monocyte and T-lymphocyte subpopulation predicted increased T2D susceptibility, which confirmed the immunity predisposition for T2D. Our results may have the potential to provide new therapeutic targets for the diagnosis and treatment of T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Mendelian Randomization Analysis; CD8-Positive T-Lymphocytes; Leukocytes
PubMed: 37305035
DOI: 10.3389/fendo.2023.1210415 -
Immunology and Cell Biology Jul 2023Activation-induced marker (AIM) assays have proven to be an accessible and rapid means of antigen-specific T-cell detection. The method typically involves short-term... (Review)
Review
Activation-induced marker (AIM) assays have proven to be an accessible and rapid means of antigen-specific T-cell detection. The method typically involves short-term incubation of whole blood or peripheral blood mononuclear cells with antigens of interest, where autologous antigen-presenting cells process and present peptides in complex with major histocompatibility complex (MHC) molecules. Recognition of peptide-MHC complexes by T-cell receptors then induces upregulation of activation markers on the T cells that can be detected by flow cytometry. In this review, we highlight the most widely used activation markers for assays in the literature while identifying nuances and potential downfalls associated with the technique. We provide a summary of how AIM assays have been used in both discovery science and clinical studies, including studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity. This review primarily focuses on AIM assays using human blood or peripheral blood mononuclear cell samples, with some considerations noted for tissue-derived T cells and nonhuman samples. AIM assays are a powerful tool that enables detailed analysis of antigen-specific T-cell frequency, phenotype and function without needing to know the precise antigenic peptides and their MHC restriction elements, enabling a wider analysis of immunity generated following infection and/or vaccination.
Topics: Humans; Leukocytes, Mononuclear; COVID-19; SARS-CoV-2; T-Lymphocytes; Peptides; Antigens
PubMed: 36825901
DOI: 10.1111/imcb.12636 -
Medicine Sep 2023Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a... (Review)
Review
Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a crescent or sickle shape. This condition affects millions of people worldwide, particularly those of African, Mediterranean, Middle Eastern, and South Asian descent. This paper aims to provide an overview of SCD by exploring its causes, symptoms, and available treatment options. The primary cause of SCD is a mutation in the gene responsible for producing hemoglobin, the protein that carries oxygen in red blood cells. This mutation has abnormal hemoglobin called hemoglobin S, which causes red blood cells to become stiff and sticky, leading to various health complications. Patients with SCD may experience recurrent pain, fatigue, anemia, and increased infection susceptibility. Treatment options for SCD focus on managing symptoms and preventing complications. This includes pain management with analgesics, hydration, and blood transfusions to improve oxygen delivery. Hydroxyurea, a medication that increases the production of fetal hemoglobin, is commonly used to reduce the frequency and severity of pain crises. Additionally, bone marrow or stem cell transplants can cure select individuals with severe SCD. Finally, understanding the causes, symptoms, and treatment options for SCD is crucial for healthcare professionals, patients, and their families. It enables early diagnosis, effective symptom management, and improved quality of life for individuals with this chronic condition.
Topics: Humans; Anemia, Sickle Cell; Causality; Erythrocytes; Quality of Life
PubMed: 37746969
DOI: 10.1097/MD.0000000000035237 -
Immunity Dec 2023Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the...
Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25-85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMKCD8 T cells and HLA-DRCD4 T cells. In contrast to other T cell memory subsets, transcriptionally distinct NKG2CGZMBCD8 T cells counterintuitively decreased with age. Furthermore, we found a concerted age-associated increase in type 2/interleukin (IL)4-expressing memory subpopulations across CD4 and CD8 T cell compartments (CCR4CD8 Tcm and Th2 CD4 Tmem), suggesting a systematic functional shift in immune homeostasis with age. Our work provides novel insights into healthy human aging and a comprehensive annotated resource.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; CD8-Positive T-Lymphocytes; Memory T Cells; T-Lymphocyte Subsets; Aging; Receptors, Antigen, T-Cell; Granzymes
PubMed: 37963457
DOI: 10.1016/j.immuni.2023.10.013 -
Annual Review of Genomics and Human... Aug 2023Sickle cell disease (SCD) is a monogenic blood disease caused by a point mutation in the gene coding for β-globin. The abnormal hemoglobin [sickle hemoglobin (HbS)]... (Review)
Review
Sickle cell disease (SCD) is a monogenic blood disease caused by a point mutation in the gene coding for β-globin. The abnormal hemoglobin [sickle hemoglobin (HbS)] polymerizes under low-oxygen conditions and causes red blood cells to sickle. The clinical presentation varies from very severe (with acute pain, chronic pain, and early mortality) to normal (few complications and a normal life span). The variability of SCD might be due (in part) to various genetic modulators. First, we review the main genetic factors, polymorphisms, and modifier genes that influence the expression of globin or otherwise modulate the severity of SCD. Considering SCD as a complex, multifactorial disorder is important for the development of appropriate pharmacological and genetic treatments. Second, we review the characteristics, advantages, and disadvantages of the latest advances in gene therapy for SCD, from lentiviral-vector-based approaches to gene-editing strategies.
Topics: Humans; Anemia, Sickle Cell; Erythrocytes; Acute Pain; Chronic Pain; Hemoglobins, Abnormal
PubMed: 37624668
DOI: 10.1146/annurev-genom-120122-081037 -
BMJ Sexual & Reproductive Health Jan 2024Heavy menstrual bleeding affects up to one third of menstruating individuals and has a negative impact on quality of life. The diagnosis of heavy menstrual bleeding is...
BACKGROUND
Heavy menstrual bleeding affects up to one third of menstruating individuals and has a negative impact on quality of life. The diagnosis of heavy menstrual bleeding is based primarily on history taking, which is highly dependent on traditional disposable menstrual products such as pads and tampons. Only tampons undergo industry-regulated testing for absorption capacity. As use of alternative menstrual products is increasing, there is a need to understand how the capacity of these products compare to that of standard products.
METHODS
A variety of commercially available menstrual products (tampons, pads, menstrual cups and discs, and period underwear) were tested in the laboratory to determine their maximal capacity to absorb or fill using expired human packed red blood cells. The volume of blood necessary for saturation or filling of the product was recorded.
RESULTS
Of the 21 individual menstrual hygiene products tested, a menstrual disc (Ziggy, Jiangsu, China) held the most blood of any product (80 mL). The perineal ice-activated cold pack and period underwear held the least (<3 mL each). Of the product categories tested, on average, menstrual discs had the greatest capacity (61 mL) and period underwear held the least (2 mL). Tampons, pads (heavy/ultra), and menstrual cups held similar amounts of blood (approximately 20-50 mL).
CONCLUSION
This study found considerable variability in red blood cell volume capacity of menstrual products. This emphasises the importance of asking individuals about the type of menstrual products they use and how they use them. Further understanding of capacity of newer menstrual products can help clinicians better quantify menstrual blood loss, identify individuals who may benefit from additional evaluation, and monitor treatment.
Topics: Female; Humans; Menorrhagia; Menstrual Hygiene Products; Hygiene; Quality of Life; Menstruation; Erythrocytes
PubMed: 37550075
DOI: 10.1136/bmjsrh-2023-201895 -
Journal of Hematology & Oncology Sep 2023Pancreatic cancer lacks effective therapy. Here, we reported two metastatic pancreatic cancer patients administrated with Claudin 18.2 (CLDN 18.2) CART therapy after the...
Pancreatic cancer lacks effective therapy. Here, we reported two metastatic pancreatic cancer patients administrated with Claudin 18.2 (CLDN 18.2) CART therapy after the failure of standard therapy (NCT04581473 and NCT03874897). In case 1, with CLDN 18.2 expression of 2+, 70%, 250 × 10 cells were infused after lymphodepletion. Grade 1 cytokine release syndrome (CRS) occurred on d1 which was later controlled by tocilizumab. Partial response (PR) was achieved according to RECIST v1.1, with great shrinkage of lung metastasis. An increasing CD8+ T cell and Treg cells and declining CD4+ T cell and B cell were observed. In case 2, IHC result of ClDN18.2 showed 3+, 60%. 250 × 10 CLDN18.2 CART cells were subsequently administered. Patient experienced grade 2 CRS, which was controlled with tocilizumab. Target lesions of lung metastasis further achieved complete response. Similar increasing CD8+ T cell and Treg cell was detected from peripheral blood. Elevating IL-8 and declining TGF-β1 were also observed. The tumor is still under well control until the last follow-up on July 18, 2023.
Topics: Humans; Immunotherapy, Adoptive; Pancreatic Neoplasms; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokine Release Syndrome; Claudins
PubMed: 37689733
DOI: 10.1186/s13045-023-01491-9 -
Advances in Therapy Aug 2023The introduction of novel immunotherapies has transformed the treatment landscape in multiple myeloma (MM). The addition of these agents has significantly improved...
The introduction of novel immunotherapies has transformed the treatment landscape in multiple myeloma (MM). The addition of these agents has significantly improved patient outcomes; however, MM remains largely incurable, with heavily pretreated patients suffering from shorter survival times. To address this unmet need, the focus has shifted toward novel mode of action therapies, such as bispecific antibodies (BsAb), which simultaneously bind to immune effector cells and myeloma cells. Currently, there are several T cell-redirecting BsAb being developed that target BCMA, GPRC5D, and FcRH5. These BsAb show impressive clinical activity for the relapsed/refractory population targeted and will likely become an essential part of MM treatment protocols in the future. In this podcast, the authors summarize and highlight some of the T cell-redirecting BsAb currently in development for the treatment of relapsed/refractory MM with a focus on the data reported at the oral session for BsAb at the American Society of Hematology's 2022 meeting from clinical phase 1 and 2 studies. The six presentations reported the latest safety and efficacy data for the BsAb: talquetamab, elranatamab, teclistamab, forimtamig, and alnuctamab.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; T-Lymphocytes; Immunotherapy; Antineoplastic Agents
PubMed: 37328635
DOI: 10.1007/s12325-023-02551-9 -
Cells Feb 2024This Editorial 'Advances in Red Blood Cell Research' is the preface for the special issue with the same title which files 14 contributions listed in Table 1 [...].
This Editorial 'Advances in Red Blood Cell Research' is the preface for the special issue with the same title which files 14 contributions listed in Table 1 [...].
Topics: Erythrocytes
PubMed: 38391972
DOI: 10.3390/cells13040359 -
Blood Advances Nov 2023Red blood cells (RBCs) and platelets contribute to the coagulation capacity in bleeding and thrombotic disorders. The thrombin generation (TG) process is considered to...
Red blood cells (RBCs) and platelets contribute to the coagulation capacity in bleeding and thrombotic disorders. The thrombin generation (TG) process is considered to reflect the interactions between plasma coagulation and the various blood cells. Using a new high-throughput method capturing the complete TG curve, we were able to compare TG in whole blood and autologous platelet-rich and platelet-poor plasma to redefine the blood cell contributions to the clotting process. We report a faster and initially higher generation of thrombin and shorter coagulation time in whole blood than in platelet-rich plasma upon low concentrations of coagulant triggers, including tissue factor, Russell viper venom factor X, factor Xa, factor XIa, and thrombin. The TG was accelerated with increased hematocrit and delayed after prior treatment of RBC with phosphatidylserine-blocking annexin A5. RBC treatment with ionomycin increased phosphatidylserine exposure, confirmed by flow cytometry, and increased the TG process. In reconstituted blood samples, the prior selective blockage of phosphatidylserine on RBC with annexin A5 enhanced glycoprotein VI-induced platelet procoagulant activity. For patients with anemia or erythrocytosis, cluster analysis revealed high or low whole-blood TG profiles in specific cases of anemia. The TG profiles lowered upon annexin A5 addition in the presence of RBCs and thus were determined by the extent of phosphatidylserine exposure of blood cells. Profiles for patients with polycythemia vera undergoing treatment were similar to that of control subjects. We concluded that RBC and platelets, in a phosphatidylserine-dependent way, contribute to the TG process. Determination of the whole-blood hypo- or hyper-coagulant activity may help to characterize a bleeding or thrombosis risk.
Topics: Humans; Thrombin; Phosphatidylserines; Annexin A5; Erythrocytes; Thrombosis; Coagulants; Anemia
PubMed: 37648671
DOI: 10.1182/bloodadvances.2023010027