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CMAJ : Canadian Medical Association... Feb 2024
Topics: Humans; Middle Aged; Berylliosis; Metal Workers
PubMed: 38346777
DOI: 10.1503/cmaj.221680-f -
CMAJ : Canadian Medical Association... Dec 2023
Topics: Humans; Middle Aged; Berylliosis; Metal Workers
PubMed: 38049163
DOI: 10.1503/cmaj.221680 -
International Journal of Molecular... Nov 2022Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in... (Review)
Review
Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in bone resorption. Changes in levels of CatK are associated with various pathological conditions, primarily related to bone and cartilage degradation, such as pycnodysostosis (associated with CatK deficiency), osteoporosis, and osteoarthritis (associated with CatK overexpression). Recently, the increased secretion of CatK is being highly correlated to vascular inflammation, hypersensitivity pneumonitis, Wegener granulomatosis, berylliosis, tuberculosis, as well as with tumor progression. Due to the wide spectrum of diseases in which CatK is involved, the design and validation of active site-specific inhibitors has been a subject of keen interest in pharmaceutical companies in recent decades. In this review, we summarized the molecular background of CatK and its involvement in various diseases, as well as its clinical significance for diagnosis and therapy.
Topics: Cathepsin K; Collagen Type I; Bone and Bones; Cysteine Proteases
PubMed: 36430239
DOI: 10.3390/ijms232213762 -
American Journal of Respiratory Cell... Dec 2022Chronic beryllium disease (CBD) is a Th1 granulomatous lung disease preceded by sensitization to beryllium (BeS). We profiled the methylome, transcriptome, and selected...
Chronic beryllium disease (CBD) is a Th1 granulomatous lung disease preceded by sensitization to beryllium (BeS). We profiled the methylome, transcriptome, and selected proteins in the lung to identify molecular signatures and networks associated with BeS and CBD. BAL cell DNA and RNA were profiled using microarrays from CBD ( = 30), BeS ( = 30), and control subjects ( = 12). BAL fluid proteins were measured using Olink Immune Response Panel proteins from CBD ( = 22) and BeS ( = 22) subjects. Linear models identified features associated with CBD, adjusting for covariation and batch effects. Multiomic integration methods identified correlated features between datasets. We identified 1,546 differentially expressed genes in CBD versus control subjects and 204 in CBD versus BeS. Of the 101 shared transcripts, 24 have significant cis relationships between gene expression and DNA methylation, assessed using expression quantitative trait methylation analysis, including genes not previously identified in CBD. A multiomic model of top DNA methylation and gene expression features demonstrated that the first component separated CBD from other samples and the second component separated control subjects from remaining samples. The top features on component one were enriched for T-lymphocyte function, and the top features on component two were enriched for innate immune signaling. We identified six differentially abundant proteins in CBD versus BeS, with two (SIT1 and SH2D1A) selected as important RNA features in the multiomic model. Our integrated analysis of DNA methylation, gene expression, and proteins in the lung identified multiomic signatures of CBD that differentiated it from BeS and control subjects.
Topics: Humans; Berylliosis; T-Lymphocytes; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Immunity, Innate; RNA; Chronic Disease
PubMed: 35972918
DOI: 10.1165/rcmb.2022-0077OC -
JCI Insight Aug 2022CD4+ T cells drive the immunopathogenesis of chronic beryllium disease (CBD), and their recruitment to the lung heralds the onset of granulomatous inflammation. We have...
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.
Topics: Animals; Berylliosis; Beryllium; Disease Models, Animal; Inflammation; Lung Injury; Mice
PubMed: 35819849
DOI: 10.1172/jci.insight.156098 -
Toxicology Letters May 2022Dermal exposure to hazardous substances such as chemicals, toxics, metallic items and other contaminants may present substantial danger for health. Beryllium (Be) is a...
Dermal exposure to hazardous substances such as chemicals, toxics, metallic items and other contaminants may present substantial danger for health. Beryllium (Be) is a hazardous metal, especially when inhaled and/or in direct contact with the skin, associated with chronic beryllium disease (CBD) and Be sensitization (BeS). The objective of this study was to investigate the percutaneous penetration of beryllium and copper contained in metallic items as eyeglass temple tips (specifically BrushCAST® Copper Beryllium Casting Alloys containing Be 0.35 < 2.85%; Cu 95.3-98.7%), using Franz diffusion cells. This work demonstrated that the total skin absorption of Cu was higher (8.86%) compared to Be (4.89%), which was expected based on the high percentage of Cu contained in the eyeglass temple tips. However, Be accumulated significantly in the epidermis and dermis (up to 0.461 µg/cm) and, to a lesser extent, in the stratum corneum (up to 0.130 µg/cm) with a flux of permeation of 3.52 ± 4.5 µg/cm/hour and lag time of 2.3 ± 1.3 h, after cutaneous exposure of temple tip into 1.0 mL artificial sweat for 24 h. Our study highlights the importance of avoiding the use of Be alloys in items following long-term skin contact.
Topics: Alloys; Berylliosis; Beryllium; Copper; Eyeglasses; Humans
PubMed: 35427767
DOI: 10.1016/j.toxlet.2022.04.001 -
Journal of Immunology (Baltimore, Md. :... Apr 2022Sarcoidosis and chronic beryllium disease are noninfectious lung diseases that are characterized by the presence of noncaseating granulomatous inflammation. Chronic... (Review)
Review
Sarcoidosis and chronic beryllium disease are noninfectious lung diseases that are characterized by the presence of noncaseating granulomatous inflammation. Chronic beryllium disease is caused by occupational exposure to beryllium containing particles, whereas the etiology of sarcoidosis is not known. Genetic susceptibility for both diseases is associated with particular MHC class II alleles, and CD4 T cells are implicated in their pathogenesis. The innate immune system plays a critical role in the initiation of pathogenic CD4 T cell responses as well as the transition to active lung disease and disease progression. In this review, we highlight recent insights into Ag recognition in chronic beryllium disease and sarcoidosis. In addition, we discuss the current understanding of the dynamic interactions between the innate and adaptive immune systems and their impact on disease pathogenesis.
Topics: Adaptive Immunity; Berylliosis; Beryllium; Chronic Disease; Granuloma; Humans; Lung Diseases; Sarcoidosis
PubMed: 35418504
DOI: 10.4049/jimmunol.2101159