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At least 19 recordsLinked to original sources
PubMed1992

Identification of a source of biologically active CD40 ligand.

We have identified the murine thymoma line EL4 as a source of biologically active CD40 ligand. Using a biotin-labeled soluble CD40.Fc fusion protein, consisting of the extracellular domain of human CD40 and the Fc region of human IgG1, EL4 cells were subjected to repeated flow cytometric cell sorting to select for cells with enhanced biotinylated CD40.Fc binding. After nine rounds of sorting, the number of CD40.Fc binding sites/cell had risen from 450 on the unsorted parental EL4 cells to 15,000 on EL40.9 cells (EL4 cells sorted with biotinylated CD40.Fc for nine rounds). Scatchard analysis of radiolabeled CD40.Fc binding revealed that the surface-expressed CD40 ligand on parental EL4 and EL40.9 cells bound its receptor with a single class of high-affinity sites (Kd = 0.5 nM). Supernatant (SN) from the sorted EL40.9 cells was found to contain human and murine B cell stimulatory activity which could be removed by preclearing with immobilized CD40.Fc, confirming the presence of soluble CD40 ligand in the preparations. EL40.9 supernatant enhanced soluble CD23 (sCD23) release and induced IgE secretion from interleukin 4-stimulated human B cells. In addition, EL40.9 SN contained proliferative activity for anti-IgM-activated murine B cells which could be removed by treatment with immobilized CD40.Fc. However, the same SN had no demonstrable activity on the proliferation of human B cells. The results presented here describe, for the first time, a source of membrane-bound and soluble CD40 ligand. The soluble form of this murine ligand has activity on murine and human B cells and induces some of the functional responses predicted for the ligand based on the action of stimulatory antibodies directed against the human CD40 surface molecule.

Animals↗
PubMed1992

Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion.

Signaling through the cell surface molecule, CD40, is known to play an important role in the proliferation and differentiation of B lymphocytes. Using the thymoma cell line EL4, we recently identified and cloned a cDNA encoding a murine ligand for the CD40 molecule (mCD40-L) and showed that it has biological activity in vitro. A cDNA encoding a human homologue of the mCD40-L was isolated using crosshybridization techniques from an activated peripheral blood T cell library. The predicted amino acid sequence indicates that this human ligand for CD40 (hCD40-L) is a 261 amino acid type II membrane protein that exhibits 78% amino acid identity with its murine counterpart. Northern blot and FACS analyses suggest that the hCD40-L is restricted in its expression to T lymphocytes, and that it is most abundant on the CD4+ T cell subpopulation. Cells transfected with hCD40-L caused the proliferation of human tonsil B cells in the absence of costimuli and, in the presence of interleukin 4, induced immunoglobulin E secretion from purified human B cells. A comparison of the efficacy of the hCD40-L and mCD40-L in these assays is presented.

Amino Acid Sequence↗
PubMed1992

Cloning of TRAP, a ligand for CD40 on human T cells.

A cDNA clone, designated TRAP (TNF-related activation protein) was isolated from a collection of T cell activation genes. The polypeptide encoded by a mRNA of approx. 2.3 kb is 261 amino acids long with a calculated M(r) of 29.3 kDa. The structural features predict a type II transmembrane protein, but are also compatible with a secreted form. TRAP is highly similar to an identified murine CD40 ligand both at the cDNA (82.8% identity) and the protein (77.4% identity) levels, and related to tumor necrosis factor/lymphotoxin. Expressed in a murine myeloma, TRAP was identified as a ligand for CD40 by binding to a soluble CD40 construct. TRAP mRNA is expressed in a T cell-specific fashion with a maximum at 8 h after stimulation. The TRAP gene is located in the q26.3-q27.1 region of the X chromosome.

Amino Acid Sequence↗
PubMed1992

Molecular and biological characterization of a murine ligand for CD40.

The CD40 surface molecule is a 277-amino-acid glycoprotein expressed on B lymphocytes, epithelial cells and some carcinoma cell lines. Monoclonal antibodies against CD40 mediate a variety of effects on B lymphocytes, including induction of intercellular adhesion, short- and long-term proliferation, differentiation and enhanced tyrosine phosphorylation of proteins. In addition, germinal centre centrocytes are prevented from undergoing apoptosis by activation through CD40 and receptor for antigen. These data indicate that CD40 could be a receptor for an unknown ligand with important functions in B-cell development and activation. This hypothesis is strengthened by the homology of the extracellular region of the CD40 molecule with a family of cell-surface glycoproteins that includes the receptors for nerve growth factor and tumour necrosis factor. Here we report the cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interleukin-4.

Amino Acid Sequence↗
PubMed2026

X-linked hyper-IgM syndrome presenting as severe Pneumocystis pneumonia in a 6-month-old infant: a case report.

BACKGROUND: X-linked hyper-immunoglobulin M (XHIGM) syndrome is a rare primary immunodeficiency caused by mutations in the CD40 ligand gene (CD40LG), characterized by defective T-cell-dependent B-cell class-switch recombination. Patients typically present with recurrent infections in early childhood, but diagnosis is often delayed due to heterogeneous clinical manifestations and the fact that serum IgM levels may remain within the normal range in a significant proportion of patients. Here we report a case of XHIGM in an infant whose diagnostic journey began with recurrent lymphadenitis and culminated in life-threatening Pneumocystis jirovecii pneumonia (PJP). CASE PRESENTATION: A 6-month-old male infant was admitted with severe respiratory distress and hypoxemia. He had recurrent axillary lymphadenitis at 1 and 2 months of age and significant failure to thrive. Chest CT showed bilateral consolidative and interstitial opacities. Immunological evaluation revealed markedly decreased IgA, normal IgM and IgG, and profound T-cell lymphopenia. Sputum metagenomic sequencing identified Pneumocystis jirovecii. Whole-genome sequencing identified a hemizygous likely pathogenic CD40LG mutation (NM_000074.3:c.520C>T, p.Q174*); his mother was a carrier. He was treated with mechanical ventilation, trimethoprim-sulfamethoxazole (TMP-SMX), micafungin, corticosteroids, and intravenous immunoglobulin (IVIG), and was discharged after 36 days. CONCLUSIONS: In infants with recurrent or opportunistic infections, persistently low IgA and declining T-cell counts-even when initial screening appears normal-should raise suspicion for underlying immunodeficiency and prompt genetic evaluation. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.Serial immunological evaluation is essential in infants with recurrent or opportunistic infections, as persistently low IgA and declining T-cell counts-even when initial screening appears normal-should prompt genetic evaluation for underlying immunodeficiency. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.

Humans↗
PubMed2025

Circulating miRNAs and inflammatory markers - Associations between miRNAs and cytokine levels point to miRNA-mediated sCD40L release from platelets.

MicroRNAs (miRNAs) are gaining increasing attention, particularly because of their involvement in immune-related signaling pathways. We investigated the association between 179 plasma-circulating miRNAs (Plasma Focus microRNA PCR Panel) and 47 cytokines ("MILLIPLEX® panel) in 692 participants of the population-based SHIP-TREND cohort (age range 21-79) and two additional cohorts to present a comprehensive map of miRNA-cytokine relations. Multivariate linear regression models identified Bonferroni-corrected significant associations between miRNAs and cytokines for EGF (pro-epidermal growth factor), PDGF-AA, PDGF-AB/BB (platelet-derived growth factor subunit A and B), VEGF-A (vascular endothelia growth factor A), and sCD40L (soluble CD40 ligand) with sCD40L showing the most robust pattern. These models were adjusted for age, sex, platelet count, BMI, smoking, and technical parameters. In the follow-up sample (N = 191, 7 years after initial sampling), we confirmed that the observed associations were stable over time and replicated our findings in an independent clinical cohort (N = 74). Furthermore, the causal mediation results provide evidence for the involvement of platelet activity in the regulation of sCD40L mediated by five miRNAs in the range of 25 %-69 % of the effect being mediated (strongest mediation for hsa-miR-223-3p). Our study highlights a strong and stable miRNA-mediated modulation of sCD40L, at the stage of platelet activation with potential subsequent effects on the interaction of immune cells and haemostasis pointing to a complex regulatory mechanism. Future research is needed to determine the clinical relevance of our observations in the context of vascular thrombosis, immunological disorders, and neurodegeneration.

Humans↗
PubMed1992

The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.

Signals delivered to B cells via CD40 can synergize with those provided by other B cell surface receptors to induce B cell proliferation and antibody class switching as well as modulate cytokine production and cell adhesion. Recently, it has been shown that the ligand for CD40 is a cell surface protein of approximately 39 kDa expressed by activated T cells, gp39. Here we report on the isolation and characterization of a cDNA clone encoding human gp39, a type II membrane protein with homology to TNF, and the construction and characterization of a soluble recombinant form of gp39. COS cell transfectants expressing gp39 synergized with either anti-CD20 mAb or PMA to drive strong B cell proliferation and alone were able to drive B cells to proliferate weakly. In all cases the B cell proliferation induced by gp39-expressing COS cells was reduced to background levels by the addition of soluble CD40. Unlike gp39-expressing COS cells, recombinant soluble gp39 was not mitogenic alone and required co-stimulation to drive B cell proliferation. These results suggest that B cells require a second signal besides gp39-CD40 to drive proliferation and that soluble gp39 alone in a non-membrane bound form is able to provide co-stimulatory signals to B cells.

Amino Acid Sequence↗
PubMed2026

Systemic Platelet Activation and Respiratory Exacerbations, Pulmonary Symptoms, and Mortality among Current and Former Smokers in SPIROMICS.

RATIONALE: Platelet activation is elevated in chronic obstructive pulmonary disease (COPD) and associated with self-reported respiratory symptoms. Observational studies link the antiplatelet drug aspirin to lower exacerbation rates and fewer symptoms. However, it is unknown if platelet activation predicts incident respiratory exacerbations or mortality. OBJECTIVE: Is systemic platelet activation prospectively associated with respiratory exacerbations and mortality among ever-smokers with or at risk for COPD? METHODS: We measured two systemic platelet activation biomarkers, urinary 11-dehydro-thromboxane B2 (11dTxB2) and plasma soluble CD40 ligand (sCD40L), at baseline in self-reported aspirin non-users in the longitudinal SPIROMICS cohort. Adjusted generalized negative binomial and linear mixed-effects models assessed associations between these biomarkers and prospective rates of total and severe exacerbations, plus cross-sectional and longitudinal respiratory health (St. George's Respiratory Questionnaire, COPD Assessment Test, modified Medical Research Council questionnaire, and six minute walk distance). Cox proportional hazard and competing risk models evaluated associations between platelet activation biomarkers and all-cause and cause-specific mortality. RESULTS: Among 2,711 participants, 1,572 (58.0%) reported aspirin non-use; of these, 1,433 and 1,437 had 11dTxB2 and sCD40L measured, respectively. Over a median 6.6 years, a two-fold higher baseline 11dTxB2 was associated with increased rates of total (8.8%; 95%CI: 0.4-17.8%) and severe (18.1%; 95%CI: 5.1-32.6%) exacerbations. Although there were no significant interactions, there was a trend toward higher severe exacerbation rates among current cigarettes smokers and those with COPD. There were no significant results for sCD40L. Among aspirin non-users, higher 11dTxB2, but not sCD40L, was associated with worse cross-sectional respiratory health and modestly increased all-cause mortality over a median 8.2 years (adjusted hazard ratio 1.11; 95%CI: 1.00-1.24). After covariate adjustment, there were no associations with longitudinal respiratory health or cause-specific mortality. CONCLUSIONS: Systemic platelet activation, measured by urinary 11dTxB2, is a statistically significant but modest predictor of respiratory exacerbations and all-cause mortality in individuals with or at risk for COPD, suggesting its potential utility as a prognostic and predictive biomarker for antiplatelet therapy trials. CLINICAL TRIAL REGISTRATION: NCT01969344.

aspirin↗
PubMed2026

Mapping the plasma proteomic architecture of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, yet the molecular basis underlying this variability remains incompletely understood. We profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n = 207 SLE, n = 45 HVs) and validation sets (n = 53 SLE, n = 41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering delineated correlated protein modules, including an interferon-associated (IFN-associated) module and a kidney-associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes; positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti-RNP68, anti-RNP-A) was associated with increased IFN-stimulated protein levels (e.g., MX1, ISG15, and CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A, and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the neutrophil protease, proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA-positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular phenotypes, and provide a basis for precision medicine.

Humans↗
PubMed2025

CD40 transcriptomic expression patterns across malignancies: implications for clinical trials of CD40 agonists.

BACKGROUND: CD40 is a T-cell co-stimulatory receptor targeted by next-generation immunotherapies. We conducted a pan-cancer transcriptome analysis of CD40, its ligand, and related immune markers to evaluate co-expression patterns and clinical outcomes. METHODS: We analyzed transcriptome data for CD40, its ligand, and other common checkpoints and co-stimulators (PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, ICOS, CD27, CD28, OX40, and GITR). RNA expression was classified as high (75-100th percentile), moderate (25-74th), or low (0-24th) against a reference population of 735 previously tested solid tumors. RESULTS: Of 514 patients, 114 (22%) showed high, 247 (48%) moderate, and 153 (30%) low CD40 RNA expression. High CD40 expression was most frequent in liver and bile duct (42%), pancreatic (42%), and ovarian (40%) cancers. Both high CD40 and low-moderate CD40 ligand expression-potentially conducive to CD40 agonist therapy-was most frequent in ovarian (33%) and pancreatic (24%) cancer. In both UCSD (N = 514) and TCGA (N = 10,953) cohorts, high CD40 expression significantly correlated with high CD28 and GITR. High CD40 RNA levels were not prognostic for overall survival (OS) from metastatic disease (P = 0.2) (n = 272 immune checkpoint inhibitor (ICI)-naïve patients). High CD40 expression correlated with longer OS from immunotherapy initiation (n = 217 ICI-treated patients; P = 0.04, univariable analysis), but not multivariable analysis, suggesting it may not be an independent predictive biomarker. CONCLUSION: High CD40 expression correlated with liver and bile duct, pancreatic, and ovarian cancers, as well as with CD28 and GITR transcripts. Immune marker co-expression in individual patients merits further exploration for the development of CD40-based and other immunotherapy interventions.

Humans↗
PubMed1992

Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes.

To identify the ligand for the B cell-associated antigen CD40, we constructed a chimeric immunoglobulin molecule where the extracellular portion of the CD40 protein replaced the normal immunoglobulin variable region. No binding was detected on resting peripheral blood T cells. However, following T cell activation with phorbol esters and ionomycin, the chimeric protein bound specifically to activated human T cells and precipitated a 35-kDa protein from such cells. The induction of the CD40 ligand was detectable on the cell surface after 1 h, with maximal expression after 8 h of stimulation. The T cells expressing CD40 ligand were predominantly CD4 positive, although a proportion of CD8-positive cells also expressed the protein. There was no particular correlation with CD45 phenotype. Finally, we found that soluble CD40 inhibited T-dependent B cell proliferation. The results are discussed in the context of cognate interactions between B and T cells.

Adult↗
PubMed1992

Soluble forms of CD40 inhibit biologic responses of human B cells.

We have expressed the CD40 surface Ag as both a soluble 28-kDa molecule and a 57-kDa Fc fusion protein containing the human IgG1 Fc region. Soluble CD40 and the Fc fusion protein inhibited the proliferative response of anti-IgM-activated human B cells to the CD40 mAb G28-5. Similarly, G28-5- and IL-4-induced IgE secretion from PBMC depleted of T cells was effectively blocked by both forms of soluble CD40. Although the soluble constructs of CD40 had only a minimal inhibitory effect on IL-4-mediated proliferation of anti-IgM-activated B cells, IL-4-induced soluble CD23 shedding from both PBMC and T cells depleted of PBMC, and IgE secretion from PBMC, were significantly reduced in a concentration-dependent manner when soluble CD40 was present in the culture. The data presented demonstrate that both soluble forms of the CD40 molecule are biologically active, and suggest that the ligand for CD40 is inducible in IL-4-stimulated cultures and that it mediates both shedding of sCD23 and IgE secretion.

Antibodies, Monoclonal↗
PubMed1992

A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells.

CD40 is a B-cell surface molecule that has been shown to induce B-cell growth upon ligation with monoclonal antibodies. This report shows that triggering via CD40 is essential for the activation of resting B cells by helper T cells (Th). A soluble fusion protein of CD40 and human immunoglobulin, CD40-Ig, inhibited the induction of B-cell cycle entry, proliferation, and differentiation by activated Th1 and Th2. The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated Th. A monoclonal antibody specific for the 39-kDa protein inhibited CD40-Ig binding and also inhibited the activation of B cells by Th. These data indicate that the 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation.

Animals↗
PubMed2023

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

Mice↗
PubMed2026

A stromal platform for robust expansion of functional IL-10-producing B cells for immune regulation.

IL-10-producing B cells exert immunosuppressive effects, yet their low abundance and poor in vitro viability have limited their therapeutic application. Here, we developed a stromal coculture system using MS5 cells engineered to express human CD40L, BAFF, and IFN-β1 (MS5-3F, for "3 factors"), which enables robust induction and greater than 1000-fold expansion of human IL-10-producing B cells. The expanded cells showed phenotypic and transcriptional profiles characteristic of unswitched (IgM+) plasmablasts and potently suppressed CD4+ T cell proliferation in an IL-10-dependent manner. MS5-3F-expanded B cells also increased the frequency of regulatory T cells in vitro, an effect that was not abrogated by IL-10/IL-10R blockade, suggesting contributions from additional mechanisms. IL-10 production originated predominantly from naive B cells, rather than memory B cells. Furthermore, B cells from patients with systemic lupus erythematosus, despite impaired IL-10 production under conventional conditions, were efficiently differentiated into IL-10-producing B cells using this system. The expanded cells showed minimal IgG-secreting output. Our platform offers a scalable strategy for generating human regulatory B cells, laying the foundation for B cell-based immunotherapies.

Humans↗
PubMed1992

Genomic organization and chromosomal localization of the human CD27 gene.

CD27 is a lymphocyte-specific member of a recently identified receptor family with at least 10 members that includes the receptors for nerve growth factor and TNF, CD40, and Fas. Several members of this family play a role in cell differentiation, proliferation, and survival. Within the amino terminal ligand binding domain of these receptors, repeat motifs have been identified. These repeats contain many cysteine residues in a conserved pattern, characteristic of this family. We have isolated and characterized the human CD27 gene to gain insight into the evolution of this type of receptor domain. The gene was localized on chromosome 12, band 12p13. Sequence analysis showed no correlation between the intron/exon organization and the subdivision of the protein into distinct domains. Structural information for the cysteine-rich domain is contained within three exons. In addition, the splice sites in the CD27 gene are located in a different position from those in the related nerve growth factor receptor gene. However, a comparison of the splice sites within the regions encoding the respective ligand-binding domains of the CD27 and nerve growth factor receptor genes identifies the archetypal cysteine-rich building blocks, from which the members of this family may have arisen during the course of evolution. From this observation, we propose a new organization of the repeat motifs.

Amino Acid Sequence↗