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
78 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:
78 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:
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.
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
2026-06-09 | 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.
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
Access all drug discovery articles and probability of success in trials forecasts:
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
alpha melanotropin | peptides | FDA | 2010-09-02 | — | mondoBIOTECH Laboratories AG |
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