Biomedical subjects

Lisa A Maier

Publications and source records attributed to Lisa A Maier.

23 records · Page 2Linked to original sources

PubMed2002

Beryllium skin patch testing to analyze T cell stimulation and granulomatous inflammation in the lung.

Chronic beryllium disease (CBD) is characterized by granulomatous inflammation and the accumulation of CD4(+) T cells in the lung. Patch testing of CBD patients with beryllium sulfate results in granulomatous inflammation in the skin. We investigated whether the T cell clonal populations present in the lung of CBD patients would also be present in the involved skin of a positive beryllium patch test and thus mirror the granulomatous process in the lung. CBD patients with clonal TCR expansions in bronchoalveolar lavage (BAL) were selected for study. All three CBD patients studied had a positive response to beryllium sulfate application and a negative patch test to normal saline. Immunohistochemistry showed extensive infiltration with CD4(+) T cells and few, if any, CD8(+) T cells both at 3 days and at later times when granulomas were apparent. T cell infiltration early after skin testing appeared to be nonspecific with the TCR repertoire of infiltrating T cells being distinct from that present in BAL. At later times when granulomas were present, T cell clones in skin overlapped with those in BAL in all patients tested. Total TCR matches in skin and BAL were as high as 40% in selected Vbeta T cell subsets. Studies of peripheral blood T cells before and after patch testing provided evidence for mobilization of large numbers of pathogenic beryllium-reactive T cells into the circulating pool. These studies using skin patch testing provide new insight into the dynamics of T cell influx and mobilization during granulomatous inflammation.

Amino Acid Sequence↗

PubMed2002

Genetic and exposure risks for chronic beryllium disease.

Exposure to beryllium results in beryllium sensitization, or development of a beryllium-specific, cell-mediated immune response, in 2% to 19% of exposed individuals. Sensitization usually precedes the development of the scarring lung disease, chronic beryllium disease. The development of granulomatous inflammation in patients with CBD is associated with the production of numerous inflammatory cytokines, including IFN-gamma, IL-2, and TNF-alpha (see Fig. 1). In some individuals this can result in increased granulomatous inflammation and a more severe form of the disease. Although the exposure response relationship in sensitization and disease is nonlinear, in some studies, higher exposures were associated with higher rates of sensitization and CBD. Machinists usually have higher levels of beryllium exposure and increased risk of developing sensitization and disease. The impact of the physicochemical properties of beryllium, such as form, solubility, and particle size, on the risk of sensitization and disease are less well understood. It is clear from numerous studies that genetic susceptibility affects risk of beryllium-related health effects. The role of HLA-DPB1 Glu69 in the proliferative response to beryllium and risk of sensitization has been the most well-studied. Some genes, such as Glu69, are important in the development of an antigen-specific, cell-mediated immune response to beryllium or sensitization, whereas others may be important in the development of beryllium-specific granulomatous inflammation or CBD (see Fig. 1). Two copies of the Glu69 gene may be a disease-specific genetic risk factor. The TNF-alpha -308 A variant is associated with beryllium-stimulated TNF-alpha production, which, in turn, is associated with more severe CBD. Whether the TNF-alpha -308 A is a genetic risk factor in CBD, sensitization, or more severe disease still needs to be determined. It is likely that sensitization and CBD are multigenetic processes, and that these genes interact with exposure to determine risk of disease. Current genetic markers are not ready for clinical use as a screening test for beryllium-related health effects because of the low specificity of the markers and the low prevalence of BeS and CBD.

Berylliosis↗

PubMed2002

Chronic beryllium disease: a model interaction between innate and acquired immunity.

Beryllium (Be) is a lightweight and durable metal useful to a variety of manufacturing processes. With the use of Be in industrial settings, a number of health effects were noted including acute pneumonitis, sensitization to Be, interstitial lung disease and dermatological disease. Interstitial mononuclear cell inflammation and granuloma formation are the primary processes that occur in the lungs of Be-exposed workers, resulting in chronic beryllium disease (CBD). Recent studies have begun to describe the role of Be in the pathogenesis of CBD. These studies reveal that the host's response to Be involves components of the innate immune system or inflammatory responses. Inflammatory responses to Be can establish a state of acquired, Be antigen-specific, cell-mediated immunity. Despite triggering both the innate and acquired immune responses, Be is not eliminated from the host. Rather, it establishes pathways leading to chronic granulomatous inflammation. We will examine recent studies describing the host's cellular and molecular responses to Be, responses that promote granuloma formation.

Acute Disease↗

PubMed2002

Clinical approach to chronic beryllium disease and other nonpneumoconiotic interstitial lung diseases.

Exposures in the workplace result in a diverse set of diseases ranging from the pneumoconiosis to other interstitial lung diseases to acute lung injury. Physician awareness of the potential disease manifestations associated with specific exposures is important in defining these diseases and in preventing additional disease. Most occupational diseases mimic other forms of lung disease, including pulmonary fibrosis, sarcoidosis, adult respiratory distress syndrome (ARDS), and bronchiolitis. A "sarcoidosis"-like syndrome, usually limited to the lungs, may result from exposure to bioaerosols and a number of metals. Exposure to beryllium in the workplace produces a granulomatous lung disease clinically indistinguishable from sarcoidosis, chronic beryllium disease (CBD). Beryllium's ability to produce a beryllium-specific immune response is used in the beryllium lymphocyte proliferation tests to confirm a diagnosis of CBD and exclude sarcoidosis. Exposure to other metals must also be considered in the differential diagnosis of sarcoidosis. When an individual presents acutely with ARDS or acute lung injury, an acute inhalational exposure must be considered. Exposure to a number of irritant substances at high levels may cause a "chemical pneumonitis" or acute lung injury, depending on the solubility and physicochemical properties of the substance. Some of the most notable agents include nitrogen and sulfur oxides, phosgene, and smoke breakdown products. Ingestion of paraquat may also result in an ARDS syndrome, with pulmonary fibrosis eventually resulting. Bronchiolitis is a rare manifestation of inhalational exposures but must also be considered in the clinical evaluation of inhalational exposure.

Adult↗

PubMed2002

Beryllium induces apoptosis in human lung macrophages.

The link between metal-induced apoptosis and granulomatous inflammation in human disease pathogenesis is not established. The presence of TUNEL positive nuclei in chronic beryllium disease (CBD) pulmonary granulomas suggested the possibility that beryllium (Be) could induce apoptosis in adherent macrophages from CBD bronchoalveolar (BAL) cells. Apoptosis was measured in un-stimulated and Be-stimulated BAL adherent macrophages from CBD (n = 21) and Be-sensitized (BeS, n = 16) subjects. Be-stimulated CBD and BeS macrophages underwent caspase-dependent nuclear fragmentation, cytoplasmic membrane blebbing and CD14 loss. Be-stimulated adherent macrophage apoptosis was not due to TNF-alpha production. Apoptosis, CD14 loss and TNF-alpha production were not observed in unstimulated BAL macrophages. Thus, Be-stimulated BAL adherent macrophage apoptosis occurred whether cells were derived from patients with granulomatous inflammation or not, was caspase-mediated and occurred independent of TNF-alpha levels. We conclude that Be-induced human lung adherent macrophage apoptosis could contribute to the host's continued re-exposure to Be resulting in chronic granulomatous inflammation.

Apoptosis↗