Role of H-2 LD and CD antigens in induction of in vitro unresponsiveness.
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Animals↗
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HLA CD antigen crossmatching--the pool cell-mediated lympholysis test.
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HLA Antigens↗
Antigenic requirements for the generation of secondary cytotoxicity.
The in vitro role of products of the H-2 complex in restimulation of secondary proliferative and cytotoxic responses has been studied. In this paper we have studied in particular the role of CD antigens, the target antigens for cytotoxic T lymphocytes. We have used UV-treated cells that express their CD antigens but no LD. Like others, we demonstrate that CD antigens alone are able to generate a secondary cytotoxic response and furthermore that these CD antigens must be the same as those used for primary sensitization. However, in contrast to the results of others, in some cases UV-treated cells were unable to restimulate such a response even when appropriate controls showed that the CD antigens on UV-treated cells were functional. Furthermore, in these cases the addition of an LD stimulus in the presence of UV-treated cells results in a secondary cytotoxic response that is significantly greater than that elicited by LD restimulation alone. Such potentiation is not observed if the CD antigens used for restimulation are different from those used for the primary sensitization. In addition, a non-H 2 differences(s), presumably the M1s locus, appears to be able to generate a secondary response. The implication of these results are discussed in terms of "memory" T lymphocytes in cell-mediated immunity.
Animals↗
Jarid2 is induced by TCR signalling and controls iNKT cell maturation.
Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.
Animals↗
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.
Adaptor Proteins, Signal Transducing↗
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
ATP-Binding Cassette Transporters↗
Anifrolumab Treatment Leads to Rapid Reduction in Urinary Biomarkers of Intrarenal Inflammation in Lupus Nephritis: Results From the Phase 2 Randomized Trial.
OBJECTIVE: Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE) and is partially driven by type I interferon signaling. Anifrolumab, an approved treatment for patients with SLE, has been investigated in a phase 2 trial in patients with LN receiving standard therapy (TULIP-LN, ClinicalTrials.gov identifier NCT02547922). We studied the impact of anifrolumab treatment on urinary biomarker expression in patients with LN through proteomic analysis of samples from TULIP-LN. METHODS: Urine samples were collected at weeks 0, 12, and 48 from patients treated with the anifrolumab basic regimen (n = 35), intensified regimen (n = 42), or placebo (n = 35), in addition to standard therapy, and analyzed for the presence of 197 proteins. The impact of anifrolumab relative to placebo on prespecified biomarkers linked to histologic activity was assessed, and a comparison of responders versus nonresponders was conducted on proteins detected in ≥75% of samples. RESULTS: Anifrolumab treatment significantly reduced urinary CD163 and monocyte chemoattractant protein 1 expression at week 12 versus placebo, including in patients classified as proteinuric nonresponders across all regimens. By week 48, biomarker levels declined in all groups, indicating that standard therapy alone can eventually suppress intrarenal inflammation but with slower kinetics. Proteomic analyses further revealed that anifrolumab was superior to placebo in reducing the proteomic inflammatory signature, regardless of responder status. CONCLUSION: Compared with placebo, anifrolumab treatment significantly reduced urinary biomarkers of renal histologic activity in patients with LN, which may accelerate the resolution of intrarenal inflammation, potentially preventing damage accrual.
Humans↗
Biomimetic mesoporous silica nanosphere ameliorate experimental autoimmune uveitis by delivering sCD83.
Autoimmune uveitis (AU) is an autoimmune disease that may lead to blindness, but there are currently no precise targeted therapies for its prevention and treatment. Dendritic cell (DC) is key cell involved in the pathogenesis of AU, and specific regulation of their state can help improve AU. In this work, mesoporous silica nanospheres were loaded with the immunomodulator soluble CD83 (sCD83) and subsequently camouflaged with dendritic cell (DC) membranes to fabricate the nanocarrier DCM@MSN/sCD83 for treating experimental autoimmune uveitis (EAU). Research results show that DCM@MSN/sCD83 effectively alleviated the symptoms of uveitis in EAU, reduced the proportion of CD4+CD25-T cell/CD4+CD25+T cell and the percentage of DC in the eyes and cervical lymph nodes. It also decreased the expression of STING in Müller cell. Furthermore, the efficacy of DCM@MSN/sCD83 was found to be primarily targeting DC, and promoted the expression of IL-10 and TGF-β1 in DC by activating the phosphorylated HIF/STAT3 pathway, to induce the production of CD4+CD25+ T. This effect is superior to nanomedicine loaded with dexamethasone. Moreover，DCM enabled the nanocarriers to efficiently cross the blood-eye barrier and reach cervical lymph nodes, thereby regulating peripheral immunity. This research indicate that cell membrane-modified nanoparticles targeting homologous cells can effectively improve treatment efficiency and duration, which is potential therapy strategy for uveitis.
Animals↗
Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.
Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.
Animals↗
Longitudinal clinical proteomics reveals pneumonia type-specific protein biomarkers and autoantibodies.
Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined, and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza, and SARS-CoV-2-driven pneumonia. Our analysis revealed highly pneumonia type-specific proteomic signatures, including COVID-19-specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V-domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry-driven autoantibody profiling in 2 independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.
Humans↗
Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity.
Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4+ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4+ and CD8+ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.
Animals↗
Bovine meat and milk factor protein expression in tumor-free mucosa of colorectal cancer patients coincides with macrophages and might interfere with patient survival.
Bovine milk and meat factors (BMMFs) are plasmid-like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co-markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor-adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low-/high-grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co-immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor-adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD-adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC-specific death were increased for higher Rep expression (TMA), with high tumor-adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF-specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC.
Humans↗
A comparison of challenge with Trypanosoma cruzi blood-stream trypomastigotes and metacyclic trypomastigotes from Rhodnius prolixus in mice immunized with killed antigens.
Groups of CD-1 mice were immunized with vaccines prepared from freeze-thawed or ultra-sonicated epimastigotes, blood trypomastigotes, or "plasma antigen", of Trypanosoma cruzi strains Y, M1 and Tulahuen. The mice were challenged by the injection of blood stream trypomastigotes obtained from mice, or of metacyclic trypomastigotes harvested from the rectum of Rhodnius prolixus. Both challenges induced virulent infections in control mice. Blood-stream trypomastigotes killed mice more rapidly than the same number of bug-derived trypomastigotes. Vaccinated mice resisted infection with bug-derived trypomastigotes as well as with blood trypomastigotes, and in some instances better. It is concluded that results obtained with the more convenient, but artificial blood trypomastigote challenge are comparable with the more natural, bug-derived, challenge.
Animals↗
Histocompatibility antigens and other genetic markers in ankylosing spondylitis and inflammatory bowel diseases.
Of 118 Dutch patients suffering from ankylosing spondylitis (AS) 81-4% were found to be positive for the HLA antigen B27. The B27 frequency proved to be significantly higher in patients in whom the disease had an early onset. In addition to B27, another HLA antigen may be associated with AS; the antigen Bw 16 was found to be significantly increased in B27 negative AS patients. HLA phenotype frequencies were also determined in 109 patients with idiopathic inflammatory bwel disease (IBD). In fifty-eight ulcerative colitis (UC) patients a raised incidence of A 11 was noticed. In fifty-one patients with Crohn's disease (CD) the antigen B18 showed an increased frequency. Both deviations were statistically significant. In thirty-nine patients suffering from both AS and IBD 50% proved to be B27 positive, which is significantly diffrent from B27 frequency in patients with AS alone. In the B27 negative patients with AS and IBD and increased frequency of Bw16 was also shown.
Colitis, Ulcerative↗
Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.
B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.
Amino Acid Motifs↗
Elevated expression of transferrin receptor-1 in pancreatic cancer: clinical implications and prognostic significance.
PURPOSE: Many advanced-stage pancreatic cancers are fatal, highlighting the need for solid prognostic indicators. This study evaluates transferrin receptor-1 (TfR1) expression in pancreatic cancer tissues and cell lines for clinical and therapeutic potential. METHOD: The GuangRe database, which integrates mRNA data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, was used to assess TFRC gene expression in pancreatic cancer and normal tissues. ROC curves and Kaplan-Meier and Log-rank tests were used to evaluate TFRC gene expression's diagnostic and survival efficacy. In vitro Western blotting and immunofluorescence experiments on pancreatic cancer cell lines assessed TfR1 expression. IHC staining was done on tissue samples from 90 patients to determine TfR1's clinical importance. RESULTS: The study found that TFRC mRNA levels were significantly higher in pancreatic cancer tissues compared to nearby normal tissues (P < 0.05), with an AUC of 0.936. We found higher TfR1 protein levels in pancreatic cancer cell lines (P < 0.01) using western blot and immunofluorescence studies. Immunohistochemistry showed that pancreatic cancer tissues expressed 30.1% TfR1 compared to paracancer (11.1%) (P = 0.003). In COX regression analysis, increased TfR1 expression was related with lower overall survival (OS) and progression-free survival (PFS), making it an independent prognostic factor. CONCLUSION: Higher TfR1 expression is associated with poor pancreatic cancer outcomes, suggesting its potential as a prognostic biomarker and therapeutic target.
Humans↗
Intratumoral PD-1+LAG-3+CD8+ T cells are associated with improved prognosis in gastric cancer.
PURPOSE: PD-1 and LAG-3 are frequently used as markers of T cell exhaustion, yet the prognostic relevance and phenotypic characteristics of PD-1+LAG-3+CD8+ T cells in gastric cancer (GC) remain poorly defined. This study aimed to investigate their association with clinical outcomes and characterize their immune characteristics across independent GC cohorts. METHODS: Four independent GC cohorts were analyzed: the Zhongshan Hospital cohort (ZSGC, n = 298), The Cancer Genome Atlas cohort (TCGA, n = 371), an Immune Checkpoint Blockade cohort (ICB, n = 45), and the Yonsei cohort (n = 433). Intratumoral PD-1+LAG-3+CD8+ T cell infiltration was quantified by immunofluorescence staining and transcriptomic gene signature scoring. Survival analysis was performed using Kaplan-Meier estimation and multivariate Cox regression. Functional characterization was performed by flow cytometry on resected GC tissue. The immune microenvironment composition was evaluated using computational analyses. RESULTS: PD-1+LAG-3+CD8+ T cells were enriched within tumors compared to adjacent normal mucosa, and their infiltration correlated with advanced tumor stage, poor differentiation, microsatellite instability, and Epstein-Barr virus (EBV)-positive molecular subtypes. High intratumoral infiltration was significantly associated with improved overall survival in both the ZSGC and TCGA cohorts, whereas single-positive PD-1+CD8+ or LAG-3+CD8+ T cells showed no such association. In the ICB cohort, higher infiltration was associated with a higher response rate to pembrolizumab. Intratumoral PD-1+LAG-3+CD8+ T cells exhibit an activated phenotype characterized by increased expression of CD137, IFN-γ, perforin, and CXCL13, along with elevated TCF7 and lower PD-1 levels, suggesting a tumor-reactive, pre-exhausted state. High infiltration was further associated with an immune-active tumor microenvironment. CONCLUSIONS: High intratumoral infiltration of PD-1+LAG-3+CD8+ T cells is associated with favorable prognosis and an immune-active microenvironment in GC. These cells display phenotypic features consistent with a pre-exhausted state and may serve as independent prognostic biomarkers and candidate predictive biomarkers for immunotherapy stratification.
Humans↗
Clinical and Genomic Characteristics of Mexican Patients with Early Onset Gastric Adenocarcinoma.
BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths in Mexico, with a rising incidence of early onset gastric cancer (EOGC) in young adults. This single-center study aimed to describe the clinical and mutational characteristics associated with EOGC in Mexican patients, based on an age cutoff of 50 years. METHODS: Clinical information was retrieved from electronic records and compared between EOGC and late-onset gastric cancer (LOGC). Whole exome sequencing data from 50 patients were analyzed and compared between both groups to elucidate the genomic overview of EOGC. RESULTS: Clinical data from 2,034 patients were analyzed. Of those, 35.69% had EOGC, with higher proportions of women (52.50%), diffuse histology (74.38%), signet ring cells (79.90%), and advanced stages (IVB: 79.58%; all p <0.001). Multivariate analysis in young patients identified ECOG (hazard ratio [HR]: 1.49) and clinical stage (HR: 1.78) as independent prognostic factors that increased mortality risk. However, the presence of Helicobacter pylori (HR: 0.76) and participation in genetic counseling (HR: 0.61) were independent prognostic factors that decreased the mortality risk. The molecular profile of Mexican patients demonstrated a high prevalence of CDH1 mutations and SBS44 mutational signatures. CONCLUSION: Mexican patients demonstrated higher rates of EOGC compared to other ethnicities. Genetic counseling enhances the overall survival of patients with EOGC; efforts should be made to incorporate it into routine practice. Molecular profiling revealed high CDH1 and SBS44 prevalence; however, sample size limitations warrant caution.
Humans↗