PubMed Health⌕ Search

Biomedical subjects

Lisa A Maier

Publications and source records attributed to Lisa A Maier.

At least 19 recordsLinked to original sources
PubMed2026

Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHCII 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-modified (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 confirm that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA-seq of lung-resident CCL4/Be tetramer+ 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 potentially novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.

Animals↗
PubMed2007

TNF polymorphism and bronchoalveolar lavage cell TNF-alpha levels in chronic beryllium disease and beryllium sensitization.

BACKGROUND: Beryllium stimulates TNF-alpha from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells. OBJECTIVE: We sought to relate TNF polymorphisms to beryllium-stimulated TNF-alpha production, to the development of CBD, and to the risk of more severe CBD over time. METHODS: We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-alpha production from a subset of subjects. RESULTS: Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-alpha production was significantly increased in patients with CBD compared with that seen in those only sensitized (P = .0002). Those subjects with the TNF -857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-alpha production compared with that seen in noncarriers (P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-alpha levels (P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pao(2) at maximum exercise was noted in patients with CBD with the -1031C allele (P = .03) and with haplotypes other than the TNF haplotype 1 (P = .01), 3 (from 5) of which contain the -1031C allele. CONCLUSIONS: The -857T allele and haplotype 1 are associated with BAL cell TNF-alpha production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD. CLINICAL IMPLICATIONS: TNF promoter variants are not risk factors for CBD or sensitization.

Adult↗
PubMed2006

Beryllium-induced TNF-alpha production is transcription-dependent in chronic beryllium disease.

Beryllium (Be)-antigen presentation to Be-specific CD4(+) T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF-alpha secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-alpha secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF-alpha (range, 608-1,275 pg/ml) versus 198 pg/ml (range, 116-245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99-9,424 pg/ml) TNF-alpha versus 55 pg/ml (range, 0-454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF-alpha production at 6 h was preceded by a 5-fold increase in TNF-alpha pre-mRNA copy number:beta-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-alpha mRNA:beta-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF-alpha pre-mRNA levels > 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF-alpha mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-kappaB. The data suggest that Be exposure induces transcription-dependent TNF-alpha production, potentially due to upregulation of specific transcription factors.

Adult↗
PubMed2006

Chronic beryllium disease and glutathione biosynthesis genes.

OBJECTIVE: Because glutathione (GSH) has been reported to be increased in chronic beryllium disease (CBD) and is associated with immune modulation, associations between CBD and gene polymorphisms of the rate-limiting enzyme in GSH synthesis, glutamate cysteine ligase (GCL), were investigated. Glutamate cysteine ligase consists of a catalytic subunit (GCLC) and modifier subunit (GCLM). METHODS: Patients with CBD, beryllium-sensitized subjects (BeS), and beryllium-exposed subjects without CBD were genotyped for the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR), the GCLC-129 single nucleotide polymorphism (SNP), and the GCLM-588 SNP. RESULTS: Results indicate that GCLC TNR genotype 7/7 is negatively associated with CBD (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.08-0.95) and the GCLM-588 C/C SNP genotype is associated with CBD susceptibility (OR = 3.07, 95% CI = 1.00-9.37). No differences were noted in the BeS group. CONCLUSIONS: This study suggests that GSH modulation may play a role in CBD pathogenesis, but not in sensitization to beryllium.

Aged↗
PubMed2006

A new tool to assess sarcoidosis severity.

STUDY OBJECTIVES: Sarcoidosis is a granulomatous disorder primarily affecting the lung, but with frequent extrapulmonary organ involvement. There are no comprehensive scoring systems for sarcoidosis disease severity. Our goal was to develop and validate an objective and comprehensive sarcoidosis disease severity scoring system. DESIGN: Three sarcoidosis experts reviewed clinical data on 104 patients with biopsy-confirmed sarcoidosis. Each expert independently scored disease severity using a visual analog scale. Interrater agreement was assessed. Univariate analysis was performed, and those variables with p values < or = 0.25 were used in backward regression multivariable analysis. A model was obtained including variables with a p value of < or = 0.15 to predict severity scores. This model was subsequently validated using an independent panel of three additional international experts. SETTING: Granuloma clinic at National Jewish Medical and Research Center. PATIENTS: A total of 104 patients with biopsy-confirmed sarcoidosis. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Pairwise assessment of interrater agreement yielded high degrees of correlation with Spearman correlation coefficients of 0.86 to 0.89 and an intraclass correlation coefficient of 0.87. Univariate analysis showed that smoking status, immunosuppressive therapy, percent predicted for diffusing capacity of the lung for carbon monoxide (Dlco), FEV1, FVC, and total lung capacity, FEV1/FVC ratio, disease duration, sites of organ involvement, and African-American race were associated with mean severity score. The multivariable model included cardiac and neurologic involvement, current therapy with noncorticosteroid immunosuppressive agents, Dlco percent predicted, FEV1/FVC ratio, African-American race, FVC percent predicted, and skin involvement. This model was validated using additional reviewer scores yielding Spearman correlation coefficients of 0.66 to 0.76 and an intraclass correlation coefficient of 0.74. CONCLUSIONS: We derived an objective disease severity scoring system that incorporates data on demographics, pulmonary function, and organ involvement to produce a whole-body sarcoidosis assessment. This preliminary tool has potential applicability in the assessment of disease severity in sarcoidosis research.

Adolescent↗
PubMed2005

Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II beta-chain.

Chronic beryllium disease (CBD) is characterized by a CD4+ T cell alveolitis and granulomatous inflammation in the lung. Genetic susceptibility to this disease has been linked with HLA-DP alleles, particularly those possessing a glutamic acid at position 69 (Glu69) of the beta-chain. However, 15% of CBD patients do not possess a Glu69-containing HLA-DP allele, suggesting that other MHC class II alleles may be involved in disease susceptibility. In CBD patients without a Glu69-containing HLA-DP allele, an increased frequency of HLA-DR13 alleles has been described, and these alleles possess a glutamic acid at position 71 of the beta-chain (which corresponds to position 69 of HLA-DP). Thus, we hypothesized that beryllium presentation to CD4+ T cells was dependent on a glutamic acid residue at the identical position of both HLA-DP and -DR. The results show that HLA-DP Glu69- and HLA-DR Glu71-expressing molecules are capable of inducing beryllium-specific proliferation and IFN-gamma expression by lung CD4+ T cells. Using fibroblasts expressing mutated HLA-DP2 and -DR13 molecules, beryllium recognition was dependent on the glutamic acid at position 69 of HLA-DP and 71 of HLA-DR, suggesting a critical role for this amino acid in beryllium presentation to Ag-specific CD4+ T cells. Thus, these results demonstrate that a single amino acid residue of the MHC class II beta-chain dictates beryllium presentation and potentially, disease susceptibility.

Alleles↗
PubMed2005

Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response.

Beryllium exposure can lead to the development of beryllium-specific CD4+ T cells and chronic beryllium disease (CBD), which is characterized by the presence of lung granulomas and a CD4+ T cell alveolitis. Studies have documented the presence of proliferating and cytokine-secreting CD4+ T cells in blood of CBD patients after beryllium stimulation. However, some patients were noted to have cytokine-secreting CD4 T cells in blood in the absence of beryllium-induced proliferation, and overall, the correlation between the 2 types of responses was poor. We hypothesized that the relative proportion of memory T cell subsets determined antigen-specific proliferation. In most CBD patients, the majority of beryllium-specific CD4+ T cells in blood expressed an effector memory T cell maturation phenotype. However, the ability of blood cells to proliferate in the presence of beryllium strongly correlated with the fraction expressing a central memory T cell phenotype. In addition, we found a direct correlation between the percentage of beryllium-specific CD4+ T(EM) cells in blood and T cell lymphocytosis in the lung. Together, these findings indicate that the functional capability of antigen-specific CD4+ T cells is determined by the relative proportion of memory T cell subsets, which may reflect internal organ involvement.

Aged↗
PubMed2005

Beryllium-stimulated reactive oxygen species and macrophage apoptosis.

Beryllium (Be), the etiologic agent of chronic beryllium disease, is a toxic metal that induces apoptosis in human alveolar macrophages. We tested the hypothesis that Be stimulates the formation of reactive oxygen species (ROS) which plays a role in Be-induced macrophage apoptosis. Mouse macrophages were exposed to 100 microM BeSO4 in the absence and presence of the catalytic antioxidant MnTBAP (100 microM). Apoptosis was measured as the percentage of TUNEL+ and caspase-8+ cells. ROS production was measured by flow cytometry using the fluorescence probes, dihydroethidine (DHE) and dichlorofluorescein diacetate (DCFH-DA). Be-exposed macrophages had increased TUNEL+ cells (15+/-1% versus controls 1+/-0.2%, P<0.05) and increased caspase-8+ cells (18.7+/-2% versus controls 1.8+/-0.4%, P<0.05). Be-induced caspase-8 activation, and a 4-fold increase in ROS formation, was ameliorated by exposure to MnTBAP. Hydrogen peroxide (30 microM) exposure potentiated Be-induced caspase-8 activation, and was also attenuated by MnTBAP. Our data are the first to demonstrate that Be stimulates macrophage ROS formation which plays an important role in Be-induced macrophage apoptosis.

Animals↗
PubMed2005

Genetic susceptibility and immune-mediated destruction in beryllium-induced disease.

Chronic beryllium disease (CBD) is a hypersensitivity disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of beryllium-specific CD4(+) T cells in the lung and granulomatous inflammation. This disorder occurs in 2-16% of exposed workers, depending on genetic susceptibility and the nature of the exposure. Susceptibility has been associated with HLA-DP alleles possessing a glutamic acid at the 69th position (Glu(69)) of the beta-chain. The mechanism for this association lies in the ability of these HLA-DP molecules to present beryllium to pathogenic CD4(+) T cells. These findings in CBD have important implications for studies in autoimmune diseases, including those in which the inciting antigen is unknown and the target organ is inaccessible.

Berylliosis↗
PubMed2005

Frequency of beryllium-specific, TH1-type cytokine-expressing CD4+ T cells in patients with beryllium-induced disease.

BACKGROUND: Beryllium sensitization is caused by exposure to beryllium in the workplace. A subset of beryllium-sensitized (BeS) subjects progress to chronic beryllium disease (CBD), a disorder characterized by a CD4+ T-cell alveolitis and granulomatous inflammation. Whether biomarkers are present in blood that would allow separation of CBD from beryllium sensitization without invasive pulmonary procedures is unknown. OBJECTIVE: The aim of this study was to determine whether the quantity of beryllium-specific T cells in blood of patients with CBD differs from that found in BeS subjects. METHODS: Beryllium-induced T-cell proliferation and T H 1-type cytokine secretion were determined in blood cells from 33 patients with CBD and 18 BeS subjects. RESULTS: We demonstrate here that patients with CBD have a significantly elevated number of IFN-gamma-producing and IL-2-producing beryllium-specific CD4+ T cells in blood compared with both BeS and normal control subjects. In contrast, no difference in beryllium-induced proliferation of blood T cells was seen between BeS patients and patients with CBD. Compared with the blood beryllium lymphocyte proliferation test, which detected beryllium-induced proliferation in 65% of BeS patients and patients with CBD, ELISPOT analysis detected IFN-gamma secretion in 80% of these subjects. Higher numbers of beryllium-specific cells in blood were also associated with the extent of alveolar inflammation, as measured by both bronchoalveolar lavage white blood cell and lymphocyte counts. CONCLUSION: The frequency of beryllium-specific T cells in the blood of beryllium-exposed subjects may be a useful biomarker that helps discriminate between beryllium sensitization and progression to CBD.

Adult↗
PubMed2004

Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk.

The blood beryllium lymphocyte proliferation test is used in medical surveillance to identify both beryllium sensitization and chronic beryllium disease. Approximately 50% of individuals with beryllium sensitization have chronic beryllium disease at the time of their initial clinical evaluation; however, the rate of progression from beryllium sensitization to chronic beryllium disease is unknown. We monitored a cohort of beryllium-sensitized patients at 2-year intervals, using bronchoalveolar lavage and repeated transbronchial lung biopsies to determine progression to chronic beryllium disease as evidenced by granulomatous inflammation in lung tissue. Fifty-five individuals with beryllium sensitization were monitored with a range of 2 to 5 clinical evaluations. Disease developed in 17 sensitized individuals (31%) within an average follow-up period of 3.8 years (range, 1.0-9.5 years). Thirty-eight of the 55 (69%) remained beryllium sensitized without disease after an average follow-up time of 4.8 years (range, 1.7-11.6 years). Progressors were more likely to have worked as machinists. We found no difference in average age, sex, race or ethnicity, smoking status, or beryllium exposure time between those who progressed to chronic beryllium disease and those who remained sensitized without disease. We conclude that beryllium sensitization is an adverse health effect in beryllium-exposed workers and merits medical follow-up.

Adult↗
PubMed2004

Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease.

A beryllium (Be)-ferritin adduct containing 270 pm of Be stimulated proliferation of bronchoalveolar lavage (BAL) lymphocytes from subjects with chronic beryllium disease (CBD) at concentrations 5-6 logs lower than the amounts of beryllium sulfate (BeSO4) needed to induce proliferation. We observed increased apoptotic CBD BAL macrophages after exposure to both BeSO4 (50 +/- 6%, mean +/- SEM, P <0.05 versus unstimulated controls) and Be-ferritin (40 +/- 2%), whereas only 2.0 +/- 0.2% of BAL lymphocytes underwent activation-induced cell death. Be-ferritin also induced apoptosis in BAL macrophages from subjects with Be sensitization (25 +/- 3%) and in the H36.12j hybrid macrophage cell line (15 +/- 2%). Be-ferritin induced lung macrophage CD95 (Fas) expression and the activation of intracellular caspase-3, -8 and -9. Thus, lung macrophages take up Be-ferritin, delivering physiologically relevant levels of Be that promote Be antigen presentation and macrophage apoptosis. Be-ferritin thereby serves as a "Trojan Horse," triggering proliferation of Be-ferritin-specific CBD BAL T cells. We hypothesize that Be-ferritin exposure may result in persistent antigen exposure inducing Be-specific T cell clonal expansion and T cell helper type 1-type cytokine production and potentially explains the chronicity of CBD and its development years after environmental Be exposure has ceased.

Adult↗
PubMed2004

Beryllium-induced tumor necrosis factor-alpha production by CD4+ T cells is mediated by HLA-DP.

Beryllium (Be) presentation to CD4+ T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4+ T cells undergo clonal proliferation and T-helper 1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti-HLA-DP, but not anti-HLA-DR, monoclonal antibody inhibited Be-stimulated TNF-alpha expression in lung CD3+ CD4+ T cells. This monoclonal antibody also blocked Be-specific T cell proliferation, increased production of TNF-alpha mature-mRNA transcripts, and increased TNF-alpha protein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated upregulation of TNF-alpha mature-mRNA levels with TNF-alpha protein production was a unique property of CBD BAL cells, and did not occur in BAL cells from Be-sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4+ T cells from CBD patients resulting in proliferation and proinflammatory cytokine production.

Antibodies, Monoclonal↗
PubMed2004

Beryllium medical surveillance at a former nuclear weapons facility during cleanup operations.

Despite increasing need to remediate beryllium-contaminated buildings in industry, little is known about the magnitude of risk associated with beryllium abatement or the merits of beryllium medical surveillance for cleanup workers. We examined beryllium lymphocyte proliferation tests and reviewed medical evaluations on workers at a nuclear weapons facility during the process of decontamination and decommissioning. Of 2,221 workers, 19 (0.8%) were beryllium sensitized based on two or more abnormal beryllium lymphocyte proliferation tests. Eight of 19 sensitized individuals underwent full clinical evaluation, of whom two were diagnosed with chronic beryllium disease (CBD). Notably, seven beryllium sensitized and CBD cases were hired after the start of cleanup operations. Beryllium medical surveillance detects sensitization and CBD in cleanup workers. Exposure controls and medical surveillance need to be 'broad-based' to include all cleanup workers involved in beryllium-contaminated building remediation.

Adolescent↗
PubMed2003

Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease.

A glutamic acid at residue 69(Glu(69)) in the HLA-DPB1 gene (Glu(69)) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu(69) variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n = 50), CBD (n = 104), and beryllium-exposed nondiseased (Be-nondiseased) (n = 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu(69) gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu(69) alleles. Glu(69) homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu(69). Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO(2) at rest, maximum workload on exercise testing, and a higher arterial-alveolar gradient at rest, were associated with Glu(69) homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu(69) homozygosity acts as a functional marker associated with markers of CBD severity.

Adult↗
PubMed2003

Beryllium-stimulated neopterin as a diagnostic adjunct in chronic beryllium disease.

BACKGROUND: The diagnosis of chronic beryllium disease (CBD) relies on the beryllium lymphocyte proliferation test (BeLPT) to demonstrate a Be specific immune response. This test has improved early diagnosis, but cannot discriminate beryllium sensitization (BeS) from CBD. We previously found high neopterin levels in CBD patients' serum and questioned whether Be-stimulated neopterin production by peripheral blood cells in vitro might be useful in the diagnosis of CBD. METHODS: CBD, BeS, Be exposed workers without disease (Be-exp) normal controls and sarcoidosis subjects were enrolled. Peripheral blood mononuclear cells (PBMN) were cultured in the presence and absence of beryllium sulfate. Neopterin levels were determined from cell supernatants by enzyme linked immunosorbent assay (ELISA). Clinical evaluation of CBD subjects included chest radiography, pulmonary function testing, exercise testing, and the BeLPT. RESULTS: CBD patients produced higher levels of neopterin in both unstimulated and Be-stimulated conditions compared to all other subjects (P < 0.0001). Unstimulated neopterin mononuclear cell levels overlapped among groups, however, Be-stimulated neopterin levels in CBD showed little overlap. Using a neopterin concentration of 2.5 ng/ml as a cutoff, Be-stimulated neopterin had a sensitivity of 80% and specificity of 100% for CBD and was able to differentiate CBD from BeS. Be-stimulated neopterin was inversely related to measures of pulmonary function, exercise capacity, and gas exchange. CONCLUSIONS: Neopterin may be a useful diagnostic adjunct in the non-invasive assessment of CBD, differentiating CBD from BeS. Further studies will be required to determine how it performs in workplace screening.

Adult↗