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Chronic beryllium disease (CBD) is a CD4(+) T cell-mediated disorder characterized by persistent lung inflammation. Naturally occurring regulatory T (T(reg)) cells modulate adaptive immune responses. The role of this T-cell subset in beryllium-induced lung disease is unknown.The aim of this study was to determine whether dysfunctional T(reg) cells in the lung contribute to the "unchecked" inflammatory response that characterizes CBD.Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and individuals with beryllium-induced disease, we determined the frequency and function of naturally occurring T(reg) cells.A significantly decreased percentage and expression of FoxP3 in BAL CD4(+) T cells from CBD patients compared with beryllium-sensitized subjects was seen, and the percentage of FoxP3-expressing CD4(+) T(reg) cells in BAL inversely correlated with disease severity. In contrast to blood T(reg) cells derived from beryllium-sensitized subjects and patients with CBD that completely suppressed blood responder T-cell proliferation, BAL FoxP3-expressing T(reg) cells from patients with CBD are unable to suppress anti-CD3-mediated BAL T-cell proliferation. Mixing studies showed that blood T(reg) cells are capable of suppressing autologous BAL responder T cells. Conversely, BAL CD4(+) T(reg) cells are incapable of suppressing blood T cells, confirming that the failure of BAL T(reg) cells to suppress T-cell proliferation is caused by a dysfunctional T(reg) cell subset and not by resistance of BAL effector T cells to suppression.These findings suggest that the deficient and dysfunctional T(reg) cells in the lung of patients with CBD contribute to the persistent inflammatory response in this disease.

Rationale: There are unexplained geographical and seasonal differences in the short-term effects of fine particulate matter (PM2.5) on human health. The hypothesis has been advanced to include the possibility that such differences might be due to variations in the PM2.5 chemical composition, but evidence supporting this hypothesis is lacking. Objectives: To examine whether variation in the relative risks (RR) of hospitalization associated with ambient exposure to PM2.5 total mass reflects differences in PM2.5 chemical composition. Methods: We linked two national datasets by county and by season: (1) long-term average concentrations of PM2.5 chemical components for 2000–2005 and (2) RRs of cardiovascular and respiratory hospitalizations for persons 65 years or older associated with a 10-μg/m3 increase in PM2.5 total mass on the same day for 106 U.S. counties for 1999 through 2005. Measurements and Main Results: We found a positive and statistically significant association between county-specific estimates of the short-term effects of PM2.5 on cardiovascular and respiratory hospitalizations and county-specific levels of vanadium, elemental carbon, or nickel PM2.5 content. Conclusions: Communities with higher PM2.5 content of nickel, vanadium, and elemental carbon and/or their related sources were found to have higher risk of hospitalizations associated with short-term exposure to PM2.5.

Background: Human cases of hypersensitivity pneumonitis (HP) have been reported among machinists for over 10 yr. Although mycobacteria have been implicated as causal agents, this has not been established in experimental studies and the mechanisms remain unclear. Other constituents of in-use metalworking fluids (MWFs) may also contribute to the development of lung disease. We investigated the potential for Mycobacterium immunogenum (MI) in MWFs to induce HP. Methods: Mice were exposed intranasally for 3 wk to MI (isolated from MWFs), Saccharopolyspora rectivirgula (positive control), saline, endotoxin, MWFs spiked with endotoxin and/or MI, used MWFs, and particulate-fortified used MWFs. Responses were assessed 96 h after the last exposure. Results: Mice exposed to MI in MWFs developed lung pathology consistent with HP along with significantly more monocytes and neutrophils in lung lavage, increased CD4+/CD8+ T-lymphocyte ratio, and marked pulmonary lymphocytosis on histologic examination when compared with saline-treated control mice. Mice with Grade 2 or higher pathology (0–4 point scale) exhibited significantly elevated macrophage inflammatory protein–1α and IL-10 and a trend toward higher RANTES 96 h after the final dose. Endotoxin coexposure augmented lung pathology. Conclusion: MWFs containing mycobacteria induced granulomatous lung lesions, peribronchiolar lymphocytosis, increased cell concentrations in lavage, and up-regulation of several cytokines. These findings are consistent with HP.