Associations between immunological and hormonal parameters during healthy pregnancy in mares.

Cancer-testis antigens (CTAs) in lung cancer.

FBP1/HIF-1α Axis mediates macrophage metabolic reprogramming and serves as diagnostic biomarkers in atherosclerosis.

Siponimod enhances brain-derived neurotrophic factor secretion from immune cells in multiple sclerosis: A longitudinal study.

Impaired kidney function has been linked to altered concentrations of blood biomarkers of Alzheimer disease (AD), but the underlying mechanisms and its potential role in dementia development remain poorly understood. We explored the associations between estimated glomerular filtration rate (eGFR), blood-based biomarkers of AD, and dementia development. Data were extracted from the Swedish National Study on Aging and Care in Kungsholmen, an ongoing longitudinal population-based study. Kidney function was assessed using eGFR based on serum creatinine. AD biomarkers (amyloid beta [Aβ42/40], phosphorylated tau [p-tau181 and p-tau217] and total tau [t-tau] proteins, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) were measured from peripheral blood samples using the Simoa platform. Dementia was diagnosed according to DSM-IV criteria. Quantile regression models assessed the cross-sectional associations between eGFR and AD biomarkers; Cox regression models were used to examine the association of kidney function and biomarkers with incident dementia. At baseline, 2,279 dementia-free participants with available blood samples were included (median age 72 (interquartile range, 61-81) years; 62% female). Lower eGFR was associated with higher median z-score levels of all examined AD blood biomarkers, except Aβ42/40, following a nonlinear relationship. At eGFR = 30 mL/min/1.73 m2, estimated differences were as follows: p-tau181: β, 0.22 [95% CI 0.09-0.35]; p-tau217: β, 0.20 [95% CI 0.10-0.31]; t-tau: β, 0.24 [95% CI 0.05-0.42]; NfL: β, 0.88 [95% CI 0.80-0.95]; GFAP: β, 0.10 [95% CI 0.03-0.16]. During a mean follow-up period of 8.3 (SD, 4.3) years, 362 participants developed dementia. In multivariable-adjusted models, impaired kidney function (eGFR < 60 mL/min/1.73 m2) was not associated with an increased hazard of dementia compared with preserved kidney function (eGFR ≥ 60 mL/min/1.73 m2) (hazard ratio [HR], 0.93 [95% CI 0.72-1.21]). The relationship between increased (high vs low) NfL and dementia was stronger among individuals with impaired (vs preserved) kidney function (HR, 3.85 [95% CI 1.87-7.95] vs HR, 1.84 [95% CI 1.34-2.53], respectively). Impaired kidney function was associated with elevated circulating level of most AD blood biomarkers. However, the presence of impaired kidney function did not independently increase the risk of dementia but rather seemed to accelerate the clinical expression of underlying neurodegenerative pathology.

There is an unmet need to examine antitumor immune responses and predictive biomarkers in the peripheral blood to guide effective combination immunotherapies in classical Hodgkin lymphoma (cHL). We sought to evaluate T-cell specific immune responses as well as cytokine and chemokine profiles including levels of soluble CD30 (sCD30), sCD163, and thymus and activation-regulated chemokine (TARC) in relation to event-free survival in patients with cHL. The Children's Oncology Group (COG) clinical trial AHOD1331 was a randomized phase 3 trial for patients with newly diagnosed high-risk cHL, aged 2 to 21 years, which compared standard chemotherapy and doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) with brentuximab vedotin (Bv) and AVE-PC with response adapted radiation. Our results demonstrate that chemotherapy with or without addition of anti-CD30 antibody-drug conjugate Bv is associated with a favorable cytokine environment for cellular and immunotherapies. Treatment of cHL on both arms increased tumor antigen-specific T-cell responses and resulted in decreased levels of sCD30, sCD163, and TARC. We demonstrate that treatment of cHL on COG AHOD1331 produced an environment that favors antitumor immune response, which may aid in application of further cellular and immunotherapies targeting cHL. This trial was registered at www.ClinicalTrials.gov as #NCT02166463.

Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), which represent distinct inflammatory set points along a shared autoimmune spectrum. Yet, the immunological mechanisms that determine these divergent inflammatory states remain unresolved. We performed single-cell RNA sequencing with paired T and B cell receptor profiling on over 400,000 PBMCs from patients with LADA, newly diagnosed T1D, and individuals acting as healthy controls. PBMC composition was comparable across cohorts, indicating that qualitative rather than quantitative immune differences underlie disease heterogeneity. In T1D, pan-lineage activation of NF-κB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhanced MHC signaling, disrupted adhesion, and promoted systemic inflammation. LADA, by contrast, exhibited global suppression of NF-κB/EGFR activity, retention of moderate JAK/STAT tone, reinforced NK cell inhibitory checkpoints via HLA-C-KIR2DL3/3DL1 interaction, and stabilized CD8+ T cell synapses through HLA-C-CD8 binding, collectively restraining effector activation. Single-cell V(D)J analysis revealed multiclonal, patient-unique adaptive repertoires, emphasizing the primacy of signaling context over receptor convergence. These findings define autoimmune diabetes as an inflammatory-inhibitory set-point continuum, positioning the NF-κB/EGFR-JAK/STAT gradient and HLA-C-KIR axis as potential therapeutic targets to preserve residual β cell function.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome involving dysfunction of multiple immune cell types. This study aimed to comprehensively depict the dynamic trajectory of immune responses throughout the disease course of HBV-related ACLF (HBV-ACLF). Single-cell RNA sequencing and single-cell proteomics were performed on the peripheral blood mononuclear cells of 45 samples from 17 patients who were hospitalised (progressive/stable/recovering course of HBV-ACLF, 6/5/6) and 15 control subjects (liver cirrhosis, chronic hepatitis B and healthy controls, 5/5/5). Functional and mechanistic experiments were validated in vivo and in vitro. Single-cell multiomics analysis revealed specific changes in the peripheral immune response in ACLF. VCAN+CD14+-monocytes with activated interferon-stimulated genes and enhanced inflammatory functions, stimulated by HBV relapse and expanded in ACLF-1, fuelling early inflammatory storm. The subsequent apoptotic hepatocytes predominantly induce hyperinflammatory C-X-C motif chemokine receptor 2 (CXCR2)+-neutrophils and CD163+-monocytes, enriching in patients with progressive ACLF and serving as significant markers of disease deterioration. Cytotoxic T-cells were functionally impaired and significantly decreased in progressive patients. CXCR2+-neutrophils exhibited immunosuppressive activity and induced the exhaustion of cytotoxic T-cells. Pharmacological inhibition of CXCR2 significantly reduced neutrophils infiltration, restored cytotoxic T-cells and showed therapeutic effect in ACLF mice. Six immune cellular modules (CMs) were identified for patient stratification, with CM2 and CM6 showing strong predictive value for disease outcomes, and CM3 indicating a potential early therapeutic window. Our longitudinal multiomics study revealed the dynamic evolution of the immune response in HBV-ACLF and characterised diverse immune patterns for the future precise management and therapeutic intervention.

In malaria-endemic regions, escalating sulfadoxine-pyrimethamine (SP) resistance has raised concerns about the effectiveness of intermittent preventive therapy (IPTp) in pregnant women. Consequently, exploring IPTp alternatives has become an urgent priority in this population. Azithromycin (AZ) has garnered attention in this aspect due to its capability to treat sexually transmitted infections and its established safety profile. A systematic literature search was conducted in the PubMed, Embase, CINAHL, Scopus and Cochrane Library databases as of 14 March 2024. We included randomized controlled trials (RCTs) comparing AZ-containing IPTp regimens with AZ-lacking regimens. Both pairwise and network meta-analyses (NMA) assessed their efficacy and safety. The NMA used a frequentist approach using the Mantel-Haenszel method to determine the optimal regimen for the primary outcome, peripheral blood parasitemia at delivery. Secondary outcomes encompassed adverse pregnancy outcomes (i.e., preterm birth, low birth weight, neonatal death, fetal loss and small for gestational age), maternal anaemia at delivery and safety profiles. We included eight RCTs conducted in moderate SP resistance areas. The meta-analysis revealed that AZ-containing regimens reduced the risk of peripheral parasitemia at delivery compared to AZ-lacking IPTp-SP regimens (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.88). No significant differences were noted between groups for other secondary outcomes. Regarding adverse events, AZ-containing IPTp regimens exhibited a safety profile similar to SP-based IPTp regimens without AZ (OR 1.11, 95% CI 0·76-1·62). AZ-containing IPTp regimens reduce rates of parasitemia at delivery compared to WHO-recommended IPTp-SP regimens or other SP-containing regimens without AZ. Adding AZ to the standard IPTp-SP regimen holds promising potential considering the escalating SP resistance, the safety profile of AZ and its additional coverage of sexually transmitted pathogens.

Postcardiac arrest syndrome is characterized by systemic inflammation that contributes to poor outcomes after resuscitation from sudden cardiac arrest. Mitochondrial DNA (mtDNA) has been implicated as a proinflammatory stimulus in other contexts, but its role in postcardiac arrest syndrome is unclear. We determined if postcardiac arrest syndrome is characterized by a rise in circulating mtDNA, how mtDNA activates immune cells, and if targeting mtDNA-sensing pathways attenuates leukocyte activation. Plasma mtDNA and nuclear DNA levels were measured ~4-hours after return of spontaneous circulation following sudden cardiac arrest in swine (n=8) and humans (n=57). Additionally, porcine peripheral blood mononuclear cells were treated with mtDNA or extracellular vesicles (EVs) isolated from porcine plasma collected after return of spontaneous circulation. Pharmacological agents were used to inhibit TLR9 (toll-like receptor 9)- and cGAS (cyclic GMP-AMP synthase)-mediated mtDNA sensing. A ~250-fold elevation in circulating mtDNA was observed after return of spontaneous circulation in swine despite negligible changes in circulating nuclear DNA, a finding that was corroborated in humans. Circulating mtDNA was largely encapsulated within EVs in both species, suggesting a conserved mechanism of release. Invitro studies demonstrated that peripheral blood mononuclear cell internalization of mtDNA-containing-EVs was required for leukocyte activation. This response was attenuated by EV disruption, DNA degradation, and blockade of TLR9 or cGAS pathways, identifying novel targets to modulate inflammation in postcardiac arrest syndrome. Brief whole-body ischemia and reperfusion in the context of resuscitation from sudden cardiac arrest elicits mtDNA release, primarily within EVs, that triggers leukocyte activation. Targeting mtDNA release or its downstream sensors may offer a new therapeutic strategy to improve outcomes after sudden cardiac arrest.

Inborn errors of immunity (IEI) impairing brain-intrinsic immune defenses can underlie herpes simplex virus encephalitis. By whole-exome sequencing of cohorts of herpesvirus-associated recurrent lymphocytic meningitis and acute retinal necrosis, we identified two patients heterozygous for variants in interferon (IFN) regulatory factor 7 (IRF7). The expression of the Q185X (patient 1, P1) and A86Rfs23X (P2) IRF7 variants in HEK293T cells resulted in truncated IRF7 proteins that lacked IFN-transactivating ability. Peripheral blood mononuclear cells from P1 exhibited reduced type I IFN responses to HSV-2 infection. Genetic knock-in of the IRF7 Q185X variant in THP-1 cells and stem cell-derived plasmacytoid dendritic cells (pDC) confirmed the disrupted IFN expression, resulting in impaired paracrine antiviral protection of meningeal fibroblasts. Strikingly, genetically heterozygous index patient pDC, but not those of healthy carrier family members, showed expression of only the pathogenic IRF7 Q185X allele, resulting in a homozygous transcriptotype. Collectively, this study identifies genetically heterozygous but transcriptionally homozygous IRF7 deficiency as an IEI underlying herpesvirus central nervous system infection.

PRT3789 selectively degrades SMARCA2 and demonstrates activity in SMARCA4-deficient cancers while sparing wild-type models, validating paralog synthetic lethality, and supporting clinical development in SMARCA4-mutated patients, a population with high unmet need.

Tetrahydroxy stilbene glucoside promotes hair regeneration by inducing Th22 cell differentiation.

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells. Minimal residual disease (MRD) assessment holds prognostic significance in both newly diagnosed and relapsed MM patients throughout the disease course. PCR-based targeted next-generation sequencing (NGS) methods face limitations in MRD monitoring due to somatic hypermutation (SHM) in MM. This study compares RNA-seq with the targeted IGH-CDR3-DNA-NGS method to identify more sensitive and convenient MRD monitoring techniques. We analyzed 125 samples from 35 MM patients and compared with 42 B-ALL patients, using MiXCR software for sequencing data processing. RNA-seq detected clonal immunoglobulin (IG) sequences in all bone marrow (BM) and peripheral blood (PB) initial samples with a sensitivity of 10-6, outperforming targeted-NGS, which missed some detections. The SHM rate was higher in targeted-NGS-negative samples (9.98%) compared to positive ones (7.27%). Clonal IG gene expression in MM was significantly higher than in B-ALL. Additionally, MRD-negative PB samples identified via RNA-seq and IG tag sequence correlated with improved survival. In conclusion, RNA-seq surpasses targeted-NGS in MRD monitoring for MM patients, providing comprehensive genetic information that aids in identifying specific IG gene expression patterns. Utilizing RNA-seq for MRD detection in PB samples effectively predicts prognosis.

Characterization of monoclonal antibody against IgM and phagocytic function of IgM+ B cells in snakehead (Channa argus).

Exploring the role of osteoblast-lineage cells in the evolutionary dynamics of acute myeloid leukemia through a stochastic differential equation model.

Application of a novel branched-DNA assay to quantify killer immunoglobulin-like receptor (KIR) mRNA expression identifies tissue compartmentalization in naïve and SIV-infected rhesus macaques.

L-Citrulline inhibits Th2 cell activation via PLAC8 mediated autophagy and L-Citrulline depletion to alleviate pediatric asthma.

The crosstalk between immune cells in skin lesions of numerous immune-mediated diseases such as atopic dermatitis, psoriasis and other T cell mediated is fundamental for understanding the pathogenesis and treating these diseases. The mechanisms by which most activated immune cells such as T cells, mast cells, and neutrophils are shifted from peripheral blood into inflamed skin, and by which they interact, are complex and different in all these diseases. However, once immune cells are infiltrated into the skin, they are polarized to be in close proximity to each other, leading to their further activation and the production of pro-inflammatory cytokines. The immune synapse in patients' skin suffering from chronic spontaneous urticaria (CSU) is fundamental for mast cell activation and degranulation. The role of T cell-mast cell proximity in the pathogenesis of CSU is fairly assessed. A better understanding of this scenario is important for developing beneficial therapies when standard treatment fails to achieve remission.

Triptolide impacts CSF1R expression and reprograms the suppressive function of myeloid-derived suppressor cells via targeting the ER stress pathway.