RARE DISEASE
Chronic beryllium disease
Chronic beryllium disease
Chronic beryllium disease
Synonyms: Berylliosis, Chronic berylliosis, Chronic beryllium lung disease
Synonyms: Berylliosis, Chronic berylliosis, Chronic beryllium lung disease
Synonyms: Berylliosis, Chronic berylliosis, Chronic beryllium lung disease
Drug discovery
1
drug
With orphan designation
Overview
Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by a T-cell-mediated immune response to beryllium exposure. It manifests with cough, dyspnea, and progressive pulmonary fibrosis, often mimicking sarcoidosis. Diagnosis requires beryllium lymphocyte proliferation test (BeLPT) and granuloma confirmation via biopsy. While incurable, treatment focuses on immunosuppression and symptom management to slow progression [1][2][11].
Therapies
Immunosuppression: First-line corticosteroids (e.g., prednisone 20–40 mg/day) to reduce granulomatous inflammation [1][3][13].
Adjunctive therapies: Methotrexate or azathioprine as steroid-sparing agents; oxygen therapy for hypoxemia [3][8].
Exposure cessation: Critical but does not prevent progression [13][16].
Categories: rare respiratory diseases, rare transplant-related disorders
Research Papers
79 drug discovery papers about Chronic beryllium disease, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
79 drug discovery papers about Chronic beryllium disease, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-14 | Beryllium Sulfate-Induced Cellular Senescence via the IL-6/STAT3 Pathway to Promote Pulmonary Fibrosis.
Beryllium is widely used in nuclear technology, aerospace, and defense. Long-term beryllium exposure causes chronic beryllium disease (CBD) characterized predominantly by pulmonary fibrosis. Cellular senescence is an important mechanism underlying pulmonary fibrosis, and the IL-6/STAT3 pathway has been implicated as a central axis linking inflammation, senescence, and tissue remodeling. However, whether this pathway promotes beryllium sulfate (BeSO4)-induced pulmonary fibrosis through regulation of senescence remains unclear. Herein, Sprague-Dawley rats were exposed to BeSO4, and hematoxylin-eosin (H&E) and Masson's trichrome staining were used to assess lung injury and fibrosis. Immunohistochemistry (IHC) assays were used to assess fibrosis-related factors, pathway molecules, and senescence markers in the lung tissues. In vitro, A549 cells were pretreated with the IL-6/STAT3 inhibitor LMT-28 before BeSO4 exposure, and alterations in cell morphology, proliferation, senescence-related markers, and fibrosis-related markers were evaluated. The results demonstrated that BeSO4 exposure promoted cellular senescence and pulmonary fibrogenesis via activating IL-6/STAT3 signaling, whereas LMT-28 treatment significantly attenuated these processes. These findings elucidate the molecular mechanism by which BeSO4 induces pulmonary fibrosis through cellular aging, providing a basis for the discovery of potential therapeutic targets.
2025-05-02 | Leukemia Inhibitory Factor via JAK-STAT Signaling Drives Beryllium Sulfate-Induced Epithelial-Mesenchymal Transition in 16HBE Cells.
Beryllium and its compounds are classified as carcinogens, and prolonged exposure can trigger chronic beryllium disease. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is known to play a critical role in the development and progression of numerous diseases. Leukemia inhibitory factor (LIF), a key upstream cytokine of the JAK-STAT pathway, has been implicated in regulating inflammatory responses and epithelial-mesenchymal transition (EMT) in various diseases. However, the specific involvement of the JAK-STAT pathway and LIF in beryllium sulfate (BeSO₄)-induced EMT in human bronchial epithelial (16HBE) cells remains unclear. To investigate the regulatory mechanisms, we examined the effects of BeSO₄ on 16HBE cells and targeted the JAK-STAT pathway using both pharmacological inhibition (niclosamide) and genetic silencing of LIF. Subsequently, we assessed cell morphology, proliferative capacity, inflammatory protein levels, and EMT marker expression. Our findings demonstrated that BeSO₄ exposure inhibited 16HBE cell proliferation and activated the JAK-STAT pathway. Pretreatment with niclosamide significantly mitigated cellular inflammation and the EMT process induced by BeSO₄. Additionally, silencing LIF markedly reduced JAK-STAT pathway activation and decreased the expression of EMT markers. This study uncovers a novel mechanism underlying BeSO₄-induced EMT in 16HBE cells, providing valuable insights into the molecular mechanisms of toxicity induced by beryllium and its compounds.
2025-02-12 | Interleukin-1 signaling and CD4+ T cells control B cell recruitment to the lungs in chronic beryllium disease.
Chronic beryllium disease (CBD) is a debilitating pulmonary disorder that occurs due to persistent exposure to beryllium (Be) particles in the workplace. Be-exposure causes activation of the innate immune system, resulting in the secretion of interleukins and chemokines that drive the accumulation of B and T cells in the lungs. However, the mechanisms by which innate molecules influence the recruitment of B cells and B cell-mediated protection in CBD are poorly understood. In this study, we employed multiple approaches to examine the role of innate immune signaling and CD4+ T cells in B cell recruitment and function in the lungs. We show that the absence or blocking of IL-1R1 signaling prevents the recruitment of B cells to the lungs of BeO-exposed mice. Additionally, we show that B cell recruitment to the lungs depends on the chemokine receptor, CXCR5, and CD4+ T cells. In BeO-exposed mice, lung B cells down-regulate IgM but showed an increased IgD and CD44 surface expression. Further, RNA sequencing of pulmonary tissue-specific B cells in CBD revealed distinct gene signatures compared to splenic B cells, with increased expression of pathways involved in antigen presentation, tight junction interactions, and interferon signaling. Overall, our study shows that B cell recruitment and aggregate formation during CBD depend on sequential activation of innate and adaptive immune responses.
2024-09-24 | Pharmacological effect of Berotek and the leading mechanisms of Lung Pathology in miners Central Kazakhstan
In modern production conditions, industrial aerosols are still among the most common harmful occupational factors that determine the increased risk of developing occupational respiratory diseases among workers at industrial enterprises. The dust respiratory diseases are significantly common among workers in the mining and coal industries of Kazakhstan. In recent years, there has been a clear increase in the incidence of chronic dust bronchitis. The particular attention should be paid to such types of metal dust as dust of beryllium, vanadium, molybdenum, tungsten, cobalt and their compounds, under the influence of which not only peculiar damage to the lungs are observed, but also pronounced changes in other organs and systems. Dust of these metals, according to numerous authors, has a general toxic and toxic-allergic effect. An urgent problem of modern occupational medicine is the study of the role of exogenous and endogenous factors in the development of occupational pathology of the bronchopulmonary system. To identify groups at increased risk of developing dust pathology of the bronchopulmonary system, it is necessary to comprehensively study clinical and genetic factors, as well as determine the most significant diagnostic markers for the development of this pathology. An important advantage of inhaled anticholinergic drugs is the minimal frequency and severity of adverse events.The broncholytic effect is expressed in the form of inhibition of phosphodiesterase isoforms with a further increase in intracellular cAMP content and relaxation of smooth muscles of the respiratory tract. Immunomodulatory and anti-inflammatory effects of bronchodilators have also been established.
2023-08-30 | Cytoprotective effect of chloroquine against metal(loid)s and PM 2.5 toxicity in the A549 lung cell line
Abstract The airborne particulate matter (PM) is associated with acute and/or chronic health adverse effects. Metal(loid)s are the main chemical species present in the PM and they can induce oxidative stress (OxS) and cytotoxicity. For this reason, the present study explores a possible alternative to prevent this problem through pharmacological treatments. Chloroquine (CQ) is an antimalarial drug used also as a chemo-, radio-sensitizing, and anti-inflammatory. This work evaluates the effect of individual metal(loid)s founded in PM 2.5 and the complete PM 2.5 , and the CQ cytoprotective effect to these in the A549 lung cell line. Cell viability was evaluated using the MTT assay, the OxS was evaluated by measuring the biochemical assay to glutathione S-transferase (GST), malondialdehyde (MDA), Advanced Oxidation Protein Products (AOPP), and the expression of the surfactant protein SPD by Western blot. Based on the composition of PM 2.5 reported to Toluca Valley, State of Mexico (2017-2018), eight metals were established. The non-cytotoxic concentration of CQ was chosen to evaluate cytoprotective activity to metal(loid)s or PM 2.5 exposures. Simultaneous exposure to CQ-metal(loid)s and CQ-PM 2.5 , in addition to CQ pretreatment before PM 2.5 treatment at 24 h were tested. Data of CQ/metal(loid)s exposure showed that CQ favors cell viability independently of the metal(loid). However, OxS biomarkers suggest damage with differential response metal(loid)-dependent. There are differences between simultaneous and pretreatment with CQ. CQ has a cytoprotective effect towards metal(loid) on cell viability mainly due to GST and surfactant proteins induction; but is not enough to reduce lipoperoxidation, this effect is reproducible to PM 2.5 treatment.
antibodies
2026-05-06 | Immune Regulation by CD55 in Chronic Beryllium Disease.
CD55 is an immune regulator that inhibits T cell activation and also binds to CD97, a molecule involved in immune cell migration and signaling. While CD55 expression is reduced in chronic beryllium disease (CBD), its functional role in disease pathogenesis remains unclear. We hypothesized that CD55 downregulation in peripheral blood mononuclear cells (PBMCs) contributes to heightened beryllium (Be)-specific immune responses in CBD. To test this, we characterized CD55 expression and function in PBMCs from individuals with CBD and beryllium sensitization (BeS), as well as in a human Be-specific T cell model. CD55, sCD55, and CD97 mRNA expression were quantified by qRT-PCR in PBMCs from CBD (n = 25), BeS (n = 36), and control (n = 7) subjects. BeSO4 stimulation was used to assess CD55, STAT1, JAK2, and TNF-α expression over time in CBD PBMCs (n = 8). Serum sCD55 was measured by ELISA in an independent cohort. Functional studies using anti-CD55 neutralizing antibodies and the JAK2 inhibitor TG101348 evaluated effects on TNF-α production and lymphocyte proliferation (BeLPT) in PBMCs, and IL-2 production in a Jurkat-Be cell model. CD55, sCD55, and CD97 were significantly downregulated in CBD PBMCs compared to BeS (P < .001). Serum sCD55 was also reduced in CBD (P < .05). BeSO4 stimulation further downregulated CD55 and upregulated STAT1. CD55 blockade increased TNF-α production and BeLPT responses in CBD (P < .001) and BeS (P < .05); these effects were reversed by JAK2 inhibition. In the Be-cell model, CD55 inhibition enhanced IL-2 production (P < .01), attenuated by JAK2 blockade. These findings suggest that CD55 downregulation amplifies Be-induced immune responses in CBD via JAK2/STAT1 signaling.
2026-05-01 | D94-02 Drivers and Regulators of Granulomatous Inflammation in Cbd: More Than Th1 Mediated Genes
Abstract Rationale Chronic beryllium disease(CBD) is a granulomatous lung disease resulting from beryllium exposure in those sensitized to beryllium(Be). The key drivers of Be-specific immune response in CBD compared to the disease precursor, Be-sensitization(BeS) are not well-defined, and could help define targets for disease therapy or diagnostics. We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on bronchoalveolar (BAL) cells from CBD, BeS and controls stimulated with Be over time to identify molecular changes associated with CBD and BeS at the cellular level. Methods BAL cells from CBD, BeS and control (n = 6 each) were cultured with BeSO4 for 0, 1, 4 and 24 hours. CITE-seq was performed using 22 antibody tags on 5-10,000 cells/sample. Protein epitopes and transcriptome data were used to cluster cells and identify broad cell types. Macrophage and non-macrophage populations were further subclustered to identify more granular sub-populations. We identified cell type-specific gene expression changes by disease/control status at each time point, adjusting for age and sex using linear mixed effects models on normalized pseudobulk counts. Ingenuity Pathway Analysis(IPA) was used to identify pathway enrichment. Results Multiple alveolar macrophages populations were identified, including monocyte-derived recruited and metallophilic macrophages and two specialized populations exhibiting high expression of 1) cytokines and chemokines and 2) NF-ĸB genes (Figure 1A), with changes in abundance of specialized and recruited macrophage populations noted by disease and time. Clusters of T helper cells, cytotoxic T lymphocytes (CTLs), NK/NKT cells, dendritic cells (pDC and mDC), and mast cells were identified, with changes in CTLs noted (Figure 1B). The most significant differential gene expression was observed in macrophages at 24 hours in CBD vs. BeS. Known and novel pathway enrichment was found in CBD in all macrophage populations. Comparing CBD to BeS, NF-ĸB macrophages showed activation of TNFR2-mediated non-canonical NF-ĸB pathway, mTOR and senescence pathways, whereas metallophillic macrophages showed enrichment in multiple development-related pathways (several Hedgehog signaling-related pathways, NOTCH4 signaling, degradation of β-catenin), regulation of apoptosis, noncanonical NF-ĸB signaling, and cellular response to hypoxia. Other groups exhibited activation of known and novel pathways. Conclusions Macrophages exhibited disease- and time-dependent transcriptional differences in CBD, BeS and controls using CITE-seq. Differences in gene expression were also apparent, and associated with different pathways in distinct macrophage subpopulations, including known and novel pathways to CBD. These pathways may serve as therapeutic targets, and we are exploring their functional potential in cell models. This abstract is funded by: R01ES033678
2026-05-01 | D94-03 BAL Proteomics via DIA-MS Reveals Disease-specific Signatures in Chronic Beryllium Disease and Beryllium Sensitization
Abstract Rationale Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by occupational beryllium (Be) exposure. We aimed to define systems-level lung-compartment protein changes in Be sensitization (BeS) and CBD, with the long-term goal to build comprehensive bronchoalveolar lavage fluid (BALF) classifiers for these conditions. Methods We analyzed paired BAL cells and BALF from 125 participants: 50 with CBD, 50 with BeS, and 25 healthy controls (HC). Trypsin-digested peptides from BAL whole-cell lysates and medium- and low-abundance BALF proteins were analyzed using LC-MS/MS on an Orbitrap Eclipse instrument with Data-Independent Acquisition (DIA)-MS. Protein detection and quantification were performed with EncyclopeDIA v4.7.11 against the Human UniProt database and a PROSIT-predicted spectral library. Differential protein abundance was assessed using linear regression models in the limma R package, with significance determined by FDR < 0.05 to correct for multiple comparisons. Gene Ontology (GO) enrichment analysis was conducted using the enrichR R package. Results We detected 4488 proteins in BAL cells and 2063 in BALF, which revealed distinct but related signatures across CBD and BeS. In BAL cells, CBD showed increased abundance of mucins (MUC5A, MUC5B), extracellular matrix proteins (FINC, BP1B1), and others. BeS displayed similar but attenuated changes; direct CBD–BeS comparison identified proteins elevated in CBD (RFTN1, MMP14, GBP1). The differentially abundant proteins are involved in canonical immune and stress response pathways in BeS and CBD versus controls, including neutrophil degranulation, interferon signaling, and MHC class I antigen processing. Upregulation of EIF2 and unfolded protein response pathways indicated enhanced protein synthesis and ER stress, while Rho GTPase and actin cytoskeleton signaling reflected increased immune cell motility and cytoskeletal remodeling. In BALF, several proteins demonstrated differential abundance (Figure 1). CBD exhibited increased extracellular matrix and inflammatory proteins (VCAM1, FBLN1, PLTP, CHIT1) and reduced antioxidant or mitochondrial proteins (MAA2A2, THTM, DAF), whereas BeS showed modest increases in stress response and adhesion proteins (IF4B, APOBR, CO6A1). BALF proteins map to lipid transport and coagulation pathways in CBD, oxidative and cytoskeletal remodeling in BeS, and downregulation of epithelial proliferation and ERK/MAPK signaling in cases versus controls. Conclusions CBD and BeS exhibit distinct but overlapping proteomic signatures in BAL cells and BALF. CBD is characterized by enhanced lipid transport, coagulation, and epithelial-stromal activation, whereas BeS reflects oxidative stress and cytoskeletal remodeling. These findings suggest progressive immune activation and stress adaptation from BeS to CBD and highlight the potential of BAL-derived proteomic profiles for biomarker and classifier development. This abstract is funded by: NIH
2026-01-10 | Interstitial Lung Diseases Presenting as Small Nodules: Imaging Phenotypes.
Interstitial lung disease (ILD) encompasses a diverse range of conditions that lead to inflammation and/or scarring of the lung interstitium, often affecting airspaces and resulting in a progressive decline in lung function. High-Resolution Computed Tomography (HRCT) is a crucial diagnostic tool for ILDs, and their characterization based on imaging. This article specifically focuses on ILD presentations characterized by small lung nodules on HRCT, defined as those measuring less than 10 mm. Small nodules on HRCT are analyzed based on size, distribution, borders, attenuation, associated findings, and temporal evolution to narrow diagnostic considerations. A key factor is the distribution pattern, which is placement within the secondary pulmonary lobule and axial interstitium. Based on their distribution pattern relative to the anatomical core of the lobule, small nodules are classified into 3 specific imaging phenotypes: perilymphatic, centrilobular, and random. Perilymphatic nodular phenotypes typically involve disease processes affecting the pulmonary lymphatics along the interlobular septa, pleura, fissures, and/or bronchovascular bundles. Common conditions include Sarcoidosis, Occupational lung diseases such as coal worker pneumoconiosis (CWP) and silicosis, Chronic beryllium disease, Granulomatous and Lymphocytic interstitial lung disease (GL-ILD), Pulmonary septal amyloidosis, Pulmonary alveolar microlithiasis, Diffuse Pulmonary Ossification. Centrilobular nodular phenotypes are centered on the core structures of the secondary pulmonary lobule, including bronchioles, pulmonary arterioles, and central lymphatic vessels. They can be nonbranching (solid or ground-glass attenuation) or branching, often appearing as a "tree-in-bud" morphology. Nonbranching centrilobular nodules are seen in conditions such as Nonfibrotic hypersensitivity pneumonitis (HP), Respiratory bronchiolitis (RB), Follicular bronchiolitis (FB), Lymphocytic interstitial pneumonitis (LIP), Metastatic pulmonary calcification (MPC), Pulmonary hemosiderosis, and Pulmonary Langerhans cell histiocytosis (LCH). Branching centrilobular nodules ("tree-in-bud") are typically not associated with ILDs and often indicate Infectious bronchiolitis, Aspiration and other disorders. Random pulmonary nodular phenotypes refer to nodules without a consistent relationship to the secondary lobule or other lung structures. While profuse perilymphatic nodules (e.g., in sarcoidosis and occupational lung diseases) can appear randomly distributed, true random patterns are characteristic of hematogenous infections or miliary metastases.
2025-06-25 | An Updated Mortality Study of Beryllium Workers, 1925-2020.
Update and expand a cohort of beryllium workers, to examine risks associated with beryllium solubility and mortality from lung cancer, all cancers, all causes, as well as other neoplasms (kidney, bladder, central nervous system) and other nonmalignant respiratory disease. The study conducted a retrospective cohort study of 17,149 workers employed in 15 US facilities (1925-2020). Data were analyzed using standardized mortality ratios referencing the US population and Cox models. Lung cancer mortality was elevated among mixed beryllium (soluble and insoluble-exposed) workers hired pre-1955, but not among insoluble-only workers during any period. Other nonmalignant respiratory disease mortality was significantly elevated in the total cohort, driven by mortality among mixed-exposure facilities and among workers hired pre-1955. No increase in lung cancer or other mortality for any timeframe for workers at insoluble-only beryllium facilities was observed.
proteins
2022-07-12 | Protective role of tissue-resident Tregs in a murine model of beryllium-induced disease
CD4+ T cells drive the immunopathogenesis of chronic beryllium disease (CBD), and their recruitment to the lung heralds the onset of granulomatous inflammation. We have shown that CD4+ Tregs control granuloma formation in an HLA-DP2 Tg model of CBD. In these mice, beryllium oxide (BeO) exposure resulted in the accumulation of 3 distinct CD4+ T cell subsets in the lung, with the majority of tissue-resident memory cells expressing FoxP3. The amount of Be regulated the number of total and antigen-specific CD4+ T cells and Tregs in the lungs of HLA-DP2 Tg mice. Depletion of Tregs increased the number of IFN-γ-producing CD4+ T cells and enhanced lung injury, while mice treated with IL-2/αIL-2 complexes had increased Tregs and reduced inflammation and Be-responsive T cells in the lung. BeO-experienced resident Tregs suppressed anti-CD3-induced proliferation of CD4+ T cells in a contact-dependent manner. CTLA-4 and ICOS blockade, as well as the addition of LPS to BeO-exposed mice, increased the effector T cell (Teff)/Treg ratio and enhanced lung injury. Collectively, these data show that the protective role of tissue-resident Tregs is dependent on quantity of Be exposure and is overcome by blocking immune regulatory molecules or additional environmental insults.
cell therapies
2026-07-28 | Novel chemokine-peptide-MHC II CAR-T cell treatment alleviates inflammation in chronic beryllium disease 2309489
Abstract Introduction In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium (Be)-modified peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Methods Mice strains: HLA-DP2 Tg WT, FVB-N, CCL3, and TNF-α. Mice were intratracheally administered with BeO (100µg) on days 0,1, and 2 and euthanized at day 12 or boosted at days,14,15,18,19, and euthanized on day 21. BAL fluid (BALF) was obtained from the instillation of 1 ml PBS. BeO-exposed WT HLA-DP2 Tg (CD45.2) mice were injected intravenously with DR-a or CCL4-CAR- T cells on day 8. Flow cytometry, q-PCR, IFN-γ and IL-2 ELISPOT, Histology (H&E), Tetramer staining, RNA-sequencing, and CAR-T cell design and preparation. Results Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirmed that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA sequencing of lung-resident CCL4/Be tetramer-positive CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol metabolism pathways, with elevated IFN-γ, TNF-α, and IL-17a gene expression. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHC II CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses. Conclusion These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHC II CAR-T cells as a novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD. Funding Source NIH R01 HL152756 Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-06-09 | Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHC II CAR-T cell-treated mice.
In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium (Be)-modified peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirmed that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA sequencing of lung-resident CCL4/Be tetramer-positive CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.
2025-11-01 | HLA-DP2-Transgenic (Tg) mice deficient in CCL3 or treated with novel HLA-DP2/CCL-CAR-T cells show reduced accumulation of chemokine specific-CD4+ T cells in BeO-exposed Lungs 4765
Abstract Description Chemokines are important molecules involved in the recruitment and activation of immune cells and the formation of cellular aggregates. However, how these chemokines and chemokines-specific CD4+ T cells contribute to the pathogenesis of chronic beryllium diseases (CBD) is not well defined. RNA sequencing data of sorted CD4+ T cells showed functional heterogeneity in CCL4 tetramer-positive (CD44+Tet+), and naïve (CD44-Tet-) CD4+ T cells. IFNγ and IL-17 expression were significantly increased in CD44+Tet+ cells compared to the CD44-Tet- CD4+ T cells. BeO exposure showed no difference in the innate immune compartment in HLA-DP2 Tg WT and mice deficient in CCL3, but total and antigen-specific CD4+ T cells were significantly reduced in HLA-DP2 Tg CCL3-/- mice. Additionally, ELISpot data showed a significant reduction in IFNγ -producing CD4+ T cells in the lungs of BeO-exposed CCL3-/- mice. Next, using bone marrow chimeric mice, we established the role of hematopoietic and dendritic cells in controlling Be-induced CCL3 and CCL4 responses in the lungs. Further, in HLA-DP mice deficient in TNF-α or mice administered with the novel HLA-DP CAR-T cells targeting CCL-specific CD4+ T cells, we observed a significant reduction in the number of both CCL3 and 4-specific T cells in the lungs of exposed mice. In conclusion, our findings reveal an important role of hematopoietic cell-derived CCL3/4 in the pathogenesis of CBD and provide CAR-T cells as an alternative therapy for controlling CBD. Funding Sources R01HL152756 Topic Categories Translational and Interventional Immunology (TI)
other
2025-10-12 | Genome-wide association study and HLA genotyping for beryllium disease susceptibility in a European descent population.
Workplace exposure to beryllium can result in beryllium sensitization (BeS), a cell-mediated immune response that can progress to chronic beryllium disease (CBD), a granulomatous lung disease. DPB1-E69 is highly associated with CBD and BeS, although DRB1-E71 may also be a risk factor in the absence of DPB1-E69. This study 1) identified novel genetic variants associated with CBD/BeS using a genome-wide association study (GWAS) approach and 2) clarified the role of DRB1-E71 in conjunction with DPB1-E69. We performed GWAS and HLA analysis on 1626 subjects with BeS, CBD and beryllium exposure without disease. We found that rs1042140, the first base of the codon that encodes E69, was associated with CBD and BeS. We also found two single nucleotide polymorphisms (SNPs), rs56011217 and rs72636334, near SRIP1 on chromosome 4 associated with CBD and BeS independent of rs1042140. HLA alleles DRB1*04:04 (non E71) and DQB1*06:04 were significantly associated with CBD and BeS independent of rs1042140. We found both DPB1-E69 and DRB1-E71 carriers have a higher risk of CBD or BeS both independently and jointly, with DPB1-E69 status having higher impact than DRB1-E71 status. DRB1-E71 also increases the risk in subjects without DPB1-E69. Our study also implies that beyond HLA, SRIP1 should be investigated in chronic beryllium disease pathogenesis.
small molecules
2026-04-14 | Beryllium Sulfate-Induced Cellular Senescence via the IL-6/STAT3 Pathway to Promote Pulmonary Fibrosis.
Beryllium is widely used in nuclear technology, aerospace, and defense. Long-term beryllium exposure causes chronic beryllium disease (CBD) characterized predominantly by pulmonary fibrosis. Cellular senescence is an important mechanism underlying pulmonary fibrosis, and the IL-6/STAT3 pathway has been implicated as a central axis linking inflammation, senescence, and tissue remodeling. However, whether this pathway promotes beryllium sulfate (BeSO4)-induced pulmonary fibrosis through regulation of senescence remains unclear. Herein, Sprague-Dawley rats were exposed to BeSO4, and hematoxylin-eosin (H&E) and Masson's trichrome staining were used to assess lung injury and fibrosis. Immunohistochemistry (IHC) assays were used to assess fibrosis-related factors, pathway molecules, and senescence markers in the lung tissues. In vitro, A549 cells were pretreated with the IL-6/STAT3 inhibitor LMT-28 before BeSO4 exposure, and alterations in cell morphology, proliferation, senescence-related markers, and fibrosis-related markers were evaluated. The results demonstrated that BeSO4 exposure promoted cellular senescence and pulmonary fibrogenesis via activating IL-6/STAT3 signaling, whereas LMT-28 treatment significantly attenuated these processes. These findings elucidate the molecular mechanism by which BeSO4 induces pulmonary fibrosis through cellular aging, providing a basis for the discovery of potential therapeutic targets.
2025-05-02 | Leukemia Inhibitory Factor via JAK-STAT Signaling Drives Beryllium Sulfate-Induced Epithelial-Mesenchymal Transition in 16HBE Cells.
Beryllium and its compounds are classified as carcinogens, and prolonged exposure can trigger chronic beryllium disease. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is known to play a critical role in the development and progression of numerous diseases. Leukemia inhibitory factor (LIF), a key upstream cytokine of the JAK-STAT pathway, has been implicated in regulating inflammatory responses and epithelial-mesenchymal transition (EMT) in various diseases. However, the specific involvement of the JAK-STAT pathway and LIF in beryllium sulfate (BeSO₄)-induced EMT in human bronchial epithelial (16HBE) cells remains unclear. To investigate the regulatory mechanisms, we examined the effects of BeSO₄ on 16HBE cells and targeted the JAK-STAT pathway using both pharmacological inhibition (niclosamide) and genetic silencing of LIF. Subsequently, we assessed cell morphology, proliferative capacity, inflammatory protein levels, and EMT marker expression. Our findings demonstrated that BeSO₄ exposure inhibited 16HBE cell proliferation and activated the JAK-STAT pathway. Pretreatment with niclosamide significantly mitigated cellular inflammation and the EMT process induced by BeSO₄. Additionally, silencing LIF markedly reduced JAK-STAT pathway activation and decreased the expression of EMT markers. This study uncovers a novel mechanism underlying BeSO₄-induced EMT in 16HBE cells, providing valuable insights into the molecular mechanisms of toxicity induced by beryllium and its compounds.
2025-02-12 | Interleukin-1 signaling and CD4+ T cells control B cell recruitment to the lungs in chronic beryllium disease.
Chronic beryllium disease (CBD) is a debilitating pulmonary disorder that occurs due to persistent exposure to beryllium (Be) particles in the workplace. Be-exposure causes activation of the innate immune system, resulting in the secretion of interleukins and chemokines that drive the accumulation of B and T cells in the lungs. However, the mechanisms by which innate molecules influence the recruitment of B cells and B cell-mediated protection in CBD are poorly understood. In this study, we employed multiple approaches to examine the role of innate immune signaling and CD4+ T cells in B cell recruitment and function in the lungs. We show that the absence or blocking of IL-1R1 signaling prevents the recruitment of B cells to the lungs of BeO-exposed mice. Additionally, we show that B cell recruitment to the lungs depends on the chemokine receptor, CXCR5, and CD4+ T cells. In BeO-exposed mice, lung B cells down-regulate IgM but showed an increased IgD and CD44 surface expression. Further, RNA sequencing of pulmonary tissue-specific B cells in CBD revealed distinct gene signatures compared to splenic B cells, with increased expression of pathways involved in antigen presentation, tight junction interactions, and interferon signaling. Overall, our study shows that B cell recruitment and aggregate formation during CBD depend on sequential activation of innate and adaptive immune responses.
2024-09-24 | Pharmacological effect of Berotek and the leading mechanisms of Lung Pathology in miners Central Kazakhstan
In modern production conditions, industrial aerosols are still among the most common harmful occupational factors that determine the increased risk of developing occupational respiratory diseases among workers at industrial enterprises. The dust respiratory diseases are significantly common among workers in the mining and coal industries of Kazakhstan. In recent years, there has been a clear increase in the incidence of chronic dust bronchitis. The particular attention should be paid to such types of metal dust as dust of beryllium, vanadium, molybdenum, tungsten, cobalt and their compounds, under the influence of which not only peculiar damage to the lungs are observed, but also pronounced changes in other organs and systems. Dust of these metals, according to numerous authors, has a general toxic and toxic-allergic effect. An urgent problem of modern occupational medicine is the study of the role of exogenous and endogenous factors in the development of occupational pathology of the bronchopulmonary system. To identify groups at increased risk of developing dust pathology of the bronchopulmonary system, it is necessary to comprehensively study clinical and genetic factors, as well as determine the most significant diagnostic markers for the development of this pathology. An important advantage of inhaled anticholinergic drugs is the minimal frequency and severity of adverse events.The broncholytic effect is expressed in the form of inhibition of phosphodiesterase isoforms with a further increase in intracellular cAMP content and relaxation of smooth muscles of the respiratory tract. Immunomodulatory and anti-inflammatory effects of bronchodilators have also been established.
2023-08-30 | Cytoprotective effect of chloroquine against metal(loid)s and PM 2.5 toxicity in the A549 lung cell line
Abstract The airborne particulate matter (PM) is associated with acute and/or chronic health adverse effects. Metal(loid)s are the main chemical species present in the PM and they can induce oxidative stress (OxS) and cytotoxicity. For this reason, the present study explores a possible alternative to prevent this problem through pharmacological treatments. Chloroquine (CQ) is an antimalarial drug used also as a chemo-, radio-sensitizing, and anti-inflammatory. This work evaluates the effect of individual metal(loid)s founded in PM 2.5 and the complete PM 2.5 , and the CQ cytoprotective effect to these in the A549 lung cell line. Cell viability was evaluated using the MTT assay, the OxS was evaluated by measuring the biochemical assay to glutathione S-transferase (GST), malondialdehyde (MDA), Advanced Oxidation Protein Products (AOPP), and the expression of the surfactant protein SPD by Western blot. Based on the composition of PM 2.5 reported to Toluca Valley, State of Mexico (2017-2018), eight metals were established. The non-cytotoxic concentration of CQ was chosen to evaluate cytoprotective activity to metal(loid)s or PM 2.5 exposures. Simultaneous exposure to CQ-metal(loid)s and CQ-PM 2.5 , in addition to CQ pretreatment before PM 2.5 treatment at 24 h were tested. Data of CQ/metal(loid)s exposure showed that CQ favors cell viability independently of the metal(loid). However, OxS biomarkers suggest damage with differential response metal(loid)-dependent. There are differences between simultaneous and pretreatment with CQ. CQ has a cytoprotective effect towards metal(loid) on cell viability mainly due to GST and surfactant proteins induction; but is not enough to reduce lipoperoxidation, this effect is reproducible to PM 2.5 treatment.
antibodies
2026-05-06 | Immune Regulation by CD55 in Chronic Beryllium Disease.
CD55 is an immune regulator that inhibits T cell activation and also binds to CD97, a molecule involved in immune cell migration and signaling. While CD55 expression is reduced in chronic beryllium disease (CBD), its functional role in disease pathogenesis remains unclear. We hypothesized that CD55 downregulation in peripheral blood mononuclear cells (PBMCs) contributes to heightened beryllium (Be)-specific immune responses in CBD. To test this, we characterized CD55 expression and function in PBMCs from individuals with CBD and beryllium sensitization (BeS), as well as in a human Be-specific T cell model. CD55, sCD55, and CD97 mRNA expression were quantified by qRT-PCR in PBMCs from CBD (n = 25), BeS (n = 36), and control (n = 7) subjects. BeSO4 stimulation was used to assess CD55, STAT1, JAK2, and TNF-α expression over time in CBD PBMCs (n = 8). Serum sCD55 was measured by ELISA in an independent cohort. Functional studies using anti-CD55 neutralizing antibodies and the JAK2 inhibitor TG101348 evaluated effects on TNF-α production and lymphocyte proliferation (BeLPT) in PBMCs, and IL-2 production in a Jurkat-Be cell model. CD55, sCD55, and CD97 were significantly downregulated in CBD PBMCs compared to BeS (P < .001). Serum sCD55 was also reduced in CBD (P < .05). BeSO4 stimulation further downregulated CD55 and upregulated STAT1. CD55 blockade increased TNF-α production and BeLPT responses in CBD (P < .001) and BeS (P < .05); these effects were reversed by JAK2 inhibition. In the Be-cell model, CD55 inhibition enhanced IL-2 production (P < .01), attenuated by JAK2 blockade. These findings suggest that CD55 downregulation amplifies Be-induced immune responses in CBD via JAK2/STAT1 signaling.
2026-05-01 | D94-02 Drivers and Regulators of Granulomatous Inflammation in Cbd: More Than Th1 Mediated Genes
Abstract Rationale Chronic beryllium disease(CBD) is a granulomatous lung disease resulting from beryllium exposure in those sensitized to beryllium(Be). The key drivers of Be-specific immune response in CBD compared to the disease precursor, Be-sensitization(BeS) are not well-defined, and could help define targets for disease therapy or diagnostics. We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on bronchoalveolar (BAL) cells from CBD, BeS and controls stimulated with Be over time to identify molecular changes associated with CBD and BeS at the cellular level. Methods BAL cells from CBD, BeS and control (n = 6 each) were cultured with BeSO4 for 0, 1, 4 and 24 hours. CITE-seq was performed using 22 antibody tags on 5-10,000 cells/sample. Protein epitopes and transcriptome data were used to cluster cells and identify broad cell types. Macrophage and non-macrophage populations were further subclustered to identify more granular sub-populations. We identified cell type-specific gene expression changes by disease/control status at each time point, adjusting for age and sex using linear mixed effects models on normalized pseudobulk counts. Ingenuity Pathway Analysis(IPA) was used to identify pathway enrichment. Results Multiple alveolar macrophages populations were identified, including monocyte-derived recruited and metallophilic macrophages and two specialized populations exhibiting high expression of 1) cytokines and chemokines and 2) NF-ĸB genes (Figure 1A), with changes in abundance of specialized and recruited macrophage populations noted by disease and time. Clusters of T helper cells, cytotoxic T lymphocytes (CTLs), NK/NKT cells, dendritic cells (pDC and mDC), and mast cells were identified, with changes in CTLs noted (Figure 1B). The most significant differential gene expression was observed in macrophages at 24 hours in CBD vs. BeS. Known and novel pathway enrichment was found in CBD in all macrophage populations. Comparing CBD to BeS, NF-ĸB macrophages showed activation of TNFR2-mediated non-canonical NF-ĸB pathway, mTOR and senescence pathways, whereas metallophillic macrophages showed enrichment in multiple development-related pathways (several Hedgehog signaling-related pathways, NOTCH4 signaling, degradation of β-catenin), regulation of apoptosis, noncanonical NF-ĸB signaling, and cellular response to hypoxia. Other groups exhibited activation of known and novel pathways. Conclusions Macrophages exhibited disease- and time-dependent transcriptional differences in CBD, BeS and controls using CITE-seq. Differences in gene expression were also apparent, and associated with different pathways in distinct macrophage subpopulations, including known and novel pathways to CBD. These pathways may serve as therapeutic targets, and we are exploring their functional potential in cell models. This abstract is funded by: R01ES033678
2026-05-01 | D94-03 BAL Proteomics via DIA-MS Reveals Disease-specific Signatures in Chronic Beryllium Disease and Beryllium Sensitization
Abstract Rationale Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by occupational beryllium (Be) exposure. We aimed to define systems-level lung-compartment protein changes in Be sensitization (BeS) and CBD, with the long-term goal to build comprehensive bronchoalveolar lavage fluid (BALF) classifiers for these conditions. Methods We analyzed paired BAL cells and BALF from 125 participants: 50 with CBD, 50 with BeS, and 25 healthy controls (HC). Trypsin-digested peptides from BAL whole-cell lysates and medium- and low-abundance BALF proteins were analyzed using LC-MS/MS on an Orbitrap Eclipse instrument with Data-Independent Acquisition (DIA)-MS. Protein detection and quantification were performed with EncyclopeDIA v4.7.11 against the Human UniProt database and a PROSIT-predicted spectral library. Differential protein abundance was assessed using linear regression models in the limma R package, with significance determined by FDR < 0.05 to correct for multiple comparisons. Gene Ontology (GO) enrichment analysis was conducted using the enrichR R package. Results We detected 4488 proteins in BAL cells and 2063 in BALF, which revealed distinct but related signatures across CBD and BeS. In BAL cells, CBD showed increased abundance of mucins (MUC5A, MUC5B), extracellular matrix proteins (FINC, BP1B1), and others. BeS displayed similar but attenuated changes; direct CBD–BeS comparison identified proteins elevated in CBD (RFTN1, MMP14, GBP1). The differentially abundant proteins are involved in canonical immune and stress response pathways in BeS and CBD versus controls, including neutrophil degranulation, interferon signaling, and MHC class I antigen processing. Upregulation of EIF2 and unfolded protein response pathways indicated enhanced protein synthesis and ER stress, while Rho GTPase and actin cytoskeleton signaling reflected increased immune cell motility and cytoskeletal remodeling. In BALF, several proteins demonstrated differential abundance (Figure 1). CBD exhibited increased extracellular matrix and inflammatory proteins (VCAM1, FBLN1, PLTP, CHIT1) and reduced antioxidant or mitochondrial proteins (MAA2A2, THTM, DAF), whereas BeS showed modest increases in stress response and adhesion proteins (IF4B, APOBR, CO6A1). BALF proteins map to lipid transport and coagulation pathways in CBD, oxidative and cytoskeletal remodeling in BeS, and downregulation of epithelial proliferation and ERK/MAPK signaling in cases versus controls. Conclusions CBD and BeS exhibit distinct but overlapping proteomic signatures in BAL cells and BALF. CBD is characterized by enhanced lipid transport, coagulation, and epithelial-stromal activation, whereas BeS reflects oxidative stress and cytoskeletal remodeling. These findings suggest progressive immune activation and stress adaptation from BeS to CBD and highlight the potential of BAL-derived proteomic profiles for biomarker and classifier development. This abstract is funded by: NIH
2026-01-10 | Interstitial Lung Diseases Presenting as Small Nodules: Imaging Phenotypes.
Interstitial lung disease (ILD) encompasses a diverse range of conditions that lead to inflammation and/or scarring of the lung interstitium, often affecting airspaces and resulting in a progressive decline in lung function. High-Resolution Computed Tomography (HRCT) is a crucial diagnostic tool for ILDs, and their characterization based on imaging. This article specifically focuses on ILD presentations characterized by small lung nodules on HRCT, defined as those measuring less than 10 mm. Small nodules on HRCT are analyzed based on size, distribution, borders, attenuation, associated findings, and temporal evolution to narrow diagnostic considerations. A key factor is the distribution pattern, which is placement within the secondary pulmonary lobule and axial interstitium. Based on their distribution pattern relative to the anatomical core of the lobule, small nodules are classified into 3 specific imaging phenotypes: perilymphatic, centrilobular, and random. Perilymphatic nodular phenotypes typically involve disease processes affecting the pulmonary lymphatics along the interlobular septa, pleura, fissures, and/or bronchovascular bundles. Common conditions include Sarcoidosis, Occupational lung diseases such as coal worker pneumoconiosis (CWP) and silicosis, Chronic beryllium disease, Granulomatous and Lymphocytic interstitial lung disease (GL-ILD), Pulmonary septal amyloidosis, Pulmonary alveolar microlithiasis, Diffuse Pulmonary Ossification. Centrilobular nodular phenotypes are centered on the core structures of the secondary pulmonary lobule, including bronchioles, pulmonary arterioles, and central lymphatic vessels. They can be nonbranching (solid or ground-glass attenuation) or branching, often appearing as a "tree-in-bud" morphology. Nonbranching centrilobular nodules are seen in conditions such as Nonfibrotic hypersensitivity pneumonitis (HP), Respiratory bronchiolitis (RB), Follicular bronchiolitis (FB), Lymphocytic interstitial pneumonitis (LIP), Metastatic pulmonary calcification (MPC), Pulmonary hemosiderosis, and Pulmonary Langerhans cell histiocytosis (LCH). Branching centrilobular nodules ("tree-in-bud") are typically not associated with ILDs and often indicate Infectious bronchiolitis, Aspiration and other disorders. Random pulmonary nodular phenotypes refer to nodules without a consistent relationship to the secondary lobule or other lung structures. While profuse perilymphatic nodules (e.g., in sarcoidosis and occupational lung diseases) can appear randomly distributed, true random patterns are characteristic of hematogenous infections or miliary metastases.
2025-06-25 | An Updated Mortality Study of Beryllium Workers, 1925-2020.
Update and expand a cohort of beryllium workers, to examine risks associated with beryllium solubility and mortality from lung cancer, all cancers, all causes, as well as other neoplasms (kidney, bladder, central nervous system) and other nonmalignant respiratory disease. The study conducted a retrospective cohort study of 17,149 workers employed in 15 US facilities (1925-2020). Data were analyzed using standardized mortality ratios referencing the US population and Cox models. Lung cancer mortality was elevated among mixed beryllium (soluble and insoluble-exposed) workers hired pre-1955, but not among insoluble-only workers during any period. Other nonmalignant respiratory disease mortality was significantly elevated in the total cohort, driven by mortality among mixed-exposure facilities and among workers hired pre-1955. No increase in lung cancer or other mortality for any timeframe for workers at insoluble-only beryllium facilities was observed.
proteins
2022-07-12 | Protective role of tissue-resident Tregs in a murine model of beryllium-induced disease
CD4+ T cells drive the immunopathogenesis of chronic beryllium disease (CBD), and their recruitment to the lung heralds the onset of granulomatous inflammation. We have shown that CD4+ Tregs control granuloma formation in an HLA-DP2 Tg model of CBD. In these mice, beryllium oxide (BeO) exposure resulted in the accumulation of 3 distinct CD4+ T cell subsets in the lung, with the majority of tissue-resident memory cells expressing FoxP3. The amount of Be regulated the number of total and antigen-specific CD4+ T cells and Tregs in the lungs of HLA-DP2 Tg mice. Depletion of Tregs increased the number of IFN-γ-producing CD4+ T cells and enhanced lung injury, while mice treated with IL-2/αIL-2 complexes had increased Tregs and reduced inflammation and Be-responsive T cells in the lung. BeO-experienced resident Tregs suppressed anti-CD3-induced proliferation of CD4+ T cells in a contact-dependent manner. CTLA-4 and ICOS blockade, as well as the addition of LPS to BeO-exposed mice, increased the effector T cell (Teff)/Treg ratio and enhanced lung injury. Collectively, these data show that the protective role of tissue-resident Tregs is dependent on quantity of Be exposure and is overcome by blocking immune regulatory molecules or additional environmental insults.
cell therapies
2026-07-28 | Novel chemokine-peptide-MHC II CAR-T cell treatment alleviates inflammation in chronic beryllium disease 2309489
Abstract Introduction In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium (Be)-modified peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Methods Mice strains: HLA-DP2 Tg WT, FVB-N, CCL3, and TNF-α. Mice were intratracheally administered with BeO (100µg) on days 0,1, and 2 and euthanized at day 12 or boosted at days,14,15,18,19, and euthanized on day 21. BAL fluid (BALF) was obtained from the instillation of 1 ml PBS. BeO-exposed WT HLA-DP2 Tg (CD45.2) mice were injected intravenously with DR-a or CCL4-CAR- T cells on day 8. Flow cytometry, q-PCR, IFN-γ and IL-2 ELISPOT, Histology (H&E), Tetramer staining, RNA-sequencing, and CAR-T cell design and preparation. Results Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirmed that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA sequencing of lung-resident CCL4/Be tetramer-positive CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol metabolism pathways, with elevated IFN-γ, TNF-α, and IL-17a gene expression. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHC II CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses. Conclusion These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHC II CAR-T cells as a novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD. Funding Source NIH R01 HL152756 Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-06-09 | Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHC II CAR-T cell-treated mice.
In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium (Be)-modified peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirmed that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA sequencing of lung-resident CCL4/Be tetramer-positive CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.
2025-11-01 | HLA-DP2-Transgenic (Tg) mice deficient in CCL3 or treated with novel HLA-DP2/CCL-CAR-T cells show reduced accumulation of chemokine specific-CD4+ T cells in BeO-exposed Lungs 4765
Abstract Description Chemokines are important molecules involved in the recruitment and activation of immune cells and the formation of cellular aggregates. However, how these chemokines and chemokines-specific CD4+ T cells contribute to the pathogenesis of chronic beryllium diseases (CBD) is not well defined. RNA sequencing data of sorted CD4+ T cells showed functional heterogeneity in CCL4 tetramer-positive (CD44+Tet+), and naïve (CD44-Tet-) CD4+ T cells. IFNγ and IL-17 expression were significantly increased in CD44+Tet+ cells compared to the CD44-Tet- CD4+ T cells. BeO exposure showed no difference in the innate immune compartment in HLA-DP2 Tg WT and mice deficient in CCL3, but total and antigen-specific CD4+ T cells were significantly reduced in HLA-DP2 Tg CCL3-/- mice. Additionally, ELISpot data showed a significant reduction in IFNγ -producing CD4+ T cells in the lungs of BeO-exposed CCL3-/- mice. Next, using bone marrow chimeric mice, we established the role of hematopoietic and dendritic cells in controlling Be-induced CCL3 and CCL4 responses in the lungs. Further, in HLA-DP mice deficient in TNF-α or mice administered with the novel HLA-DP CAR-T cells targeting CCL-specific CD4+ T cells, we observed a significant reduction in the number of both CCL3 and 4-specific T cells in the lungs of exposed mice. In conclusion, our findings reveal an important role of hematopoietic cell-derived CCL3/4 in the pathogenesis of CBD and provide CAR-T cells as an alternative therapy for controlling CBD. Funding Sources R01HL152756 Topic Categories Translational and Interventional Immunology (TI)
other
2025-10-12 | Genome-wide association study and HLA genotyping for beryllium disease susceptibility in a European descent population.
Workplace exposure to beryllium can result in beryllium sensitization (BeS), a cell-mediated immune response that can progress to chronic beryllium disease (CBD), a granulomatous lung disease. DPB1-E69 is highly associated with CBD and BeS, although DRB1-E71 may also be a risk factor in the absence of DPB1-E69. This study 1) identified novel genetic variants associated with CBD/BeS using a genome-wide association study (GWAS) approach and 2) clarified the role of DRB1-E71 in conjunction with DPB1-E69. We performed GWAS and HLA analysis on 1626 subjects with BeS, CBD and beryllium exposure without disease. We found that rs1042140, the first base of the codon that encodes E69, was associated with CBD and BeS. We also found two single nucleotide polymorphisms (SNPs), rs56011217 and rs72636334, near SRIP1 on chromosome 4 associated with CBD and BeS independent of rs1042140. HLA alleles DRB1*04:04 (non E71) and DQB1*06:04 were significantly associated with CBD and BeS independent of rs1042140. We found both DPB1-E69 and DRB1-E71 carriers have a higher risk of CBD or BeS both independently and jointly, with DPB1-E69 status having higher impact than DRB1-E71 status. DRB1-E71 also increases the risk in subjects without DPB1-E69. Our study also implies that beyond HLA, SRIP1 should be investigated in chronic beryllium disease pathogenesis.
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Drug Discovery Landscape
1 orphan drug designation for Chronic beryllium disease.
1 orphan drug designation for Chronic beryllium disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
alpha melanotropin | peptides | FDA | — | mondoBIOTECH Laboratories AG |
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