A common environmental pollutant, 4-nonylphenol, promotes allergic lung inflammation in a murine model of asthma.

BACKGROUND: Exposure to environmental hormones, such as alkylphenols, has been suggested to be associated with the development of asthma, but the mechanism of action remains unclear. OBJECTIVE: This study examined the effect of 4-nonylphenol (NP), one of the most important alkylphenols, on conventional dendritic cells (cDCs) and adaptive T-cell responses. It also explored the role of aryl hydrocarbon receptor (AhR) in NP's effect. METHODS: NP-conditioned bone marrow-derived DCs (BM-DCs) and splenic CD11c(+) cDCs were assessed regarding function in a murine model under conditions relevant to route and level of exposure in humans. RESULTS: Our results showed that splenic cDCs from NP-exposed mice have potent Th2-skewing ability and secrete increased levels of IL-6 and TNF-α, but not IL-10 and IL-12, at baseline and after stimulation with LPS. Further, bone marrow-derived DCs were cultured in the presence of NP and showed similar cytokine pattern and influenced the antigen-specific T cells secreting significantly less IFN-γ. Importantly, NP-exposed mice developed more severe OVA-induced allergic lung inflammation compared with control group. Interestingly, in a congenic strain of mice carrying low-affinity, ligand-binding mutant AhR (AhR(d) ), NP's effect on DC functions and lung inflammation was not observed in vitro and in vivo. CONCLUSION: These results suggested that NP may disturb physiologic function of DCs through, in part, AhR-dependent mechanisms, supporting the importance of NP exposure on the regulation of DC functions and allergic inflammation.

Differential expression and modulation of costimulatory molecules CD80 and CD86 on monocytes from patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) were recently shown to be defective in costimulatory molecule CD80 (B7-1) expression on antigen-presenting cells. This study was undertaken to further investigate the expression and cytokine regulation of both CD80 and CD86 (B7-2) on monocytes from patients with SLE. Freshly isolated and in vitro cytokine-stimulated peripheral blood mononuclear cells from 13 patients with SLE and 10 healthy subjects were analysed, cytometrically with dual-fluorescence staining, to detect expression of CD80 and CD86 in the CD14+ monocyte population. The results showed that, as in normal individuals, an overwhelming majority (95.62+/-3.54%) of monocytes from patients with SLE expressed the CD86 molecule, but only a few monocytes (5.54+/-4.36%) had detectable CD80 expression. The effects of interleukin-10 (IL-10) on the expression of CD80 and CD86 on monocytes from patients with SLE and normal controls were similar. IL-10 down-regulated the expression of CD86 while it slightly enhanced that of CD80. Interferon-gamma (IFN-gamma) increased both CD80 and CD86 expression on monocytes from both SLE patients and normal groups, albeit less significantly in the former than in the latter, i.e. CD80: 142.84+/-65.99% versus 226.08+/-78.90%, P<0.05; and CD86: 72.55+/-74.23% versus 153.99+/-94.14%, P<0.05, when expressed as percentage modulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) showed a capacity for up-regulation of CD80 and CD86 expression on monocytes, of a magnitude that was similar both in patients with SLE and in normal subjects. We concluded that CD80 and CD86 were differentially expressed and modulated on monocytes and the defective IFN-gamma-induced up-regulation of CD80 and CD86 expression on SLE monocytes might be a factor in the pathogenesis of SLE.

Distribution of double-negative (CD4- CD8-, DN) T subsets in blood and synovial fluid from patients with rheumatoid arthritis.

Double-negative (CD4- CD8-) T (DNT) cells have been postulated to be potentially autoreactive. However, the role of DNT cells in rheumatoid arthritis (RA) has received limited attention. We investigated the distribution of DNT subsets in peripheral blood (PB) and synovial fluid (SF) from patients with active RA to determine whether these cells have relevance to RA. Two-colour flow cytometric analysis was performed to detect DNT cells in PB from 35 RA patients, 26 healthy controls and in SF aspirated from 19 inflamed rheumatoid joints. The subsets of DNT cells, i.e those expressing T cell receptor alphabeta (alphabeta DNT) or gammadelta (gammadelta DNT) were simultaneously examined. Our results showed that DNT cells constituted a very minor subset of PB lymphocytes. When expressed as a percentage of total lymphocytes, alphabeta DNT levels in normal individuals ranged from 0.27 to 2.08% (average 0.76%), while those of gammadelta DNT ranged from 1.02 to 11.42% (average 3.23%). Compared with normal individuals, RA patients had a similar distribution of alphabeta DNT cells in both PB and SF. However, RA patients had significantly lower levels of gammadelta DNT cells in PB than control subjects (1.38 +/- 1.08% vs 3.23 +/- 2.12%, p<0.05), while the levels of gammadelta DNT cells in SF of RA patients were higher than those in PB from RA patients and normal controls. The difference between PB and SF in RA was statistically significant (3.90 +/- 1.88% vs 1.38 +/- 1.08%, p<0.05). A higher level of gammadelta DNT in SF than their paired PB was consistently noted from nine available paired samples. Our findings suggest that gammadelta NT cells, but not alphabeta DNT cells, are probably relevant to RA. The lower percentage of circulating gammadelta DNT cells might have resulted from migration from the circulation into the synovium, suggesting a role for gammadelta DNT cells in the pathogenesis of rheumatoid synovitis.

Clinical experience of 13 cases with severe pulmonary hemorrhage in systemic lupus erythematosus with active nephritis.

Pulmonary hemorrhage is a rare, but serious manifestation of systemic lupus erythematosus (SLE). Herein, we report 13 cases of severe pulmonary hemorrhage in SLE. Hemoptysis was present in 11 patients. All thirteen patients had active nephritis and were in the stage of nephrotic syndrome. A majority of the patients had neuropsychiatric manifestations and coagulopathy including thrombocytopenia or lupus anticoagulant. All episodes of pulmonary hemorrhage occurred after large dose of corticosteroid had been administered in treating nephritis. Recurrent pulmonary hemorrhage was noted in four patients. Ten (77%) of the 13 patients finally died. Respiratory failure was the main cause of death. Our observation suggests that active nephritis with hypoalbuminemia is a major risk factor for severe pulmonary hemorrhage in SLE patients and that high dose corticosteroid use can not prevent the occurrence of severe pulmonary hemorrhage in SLE.

Double-negative (CD4-CD8-) TCRalphabeta+ cells in patients with systemic lupus erythematosus.

Massive accumulation of CD4-CD8-TCRalphabeta+ cells in secondary lymphoid organs is characteristic of lupus-prone MRL/lpr mice. However, the role of these double negative T cells (DNT) in human lupus patients receive only limited attention. Herein, we investigate the frequency of DNT in the peripheral blood mononuclear cells of forty seven Chinese patients with systemic lupus erythematosus (SLE) and forty four normal individuals. DNT were measured with dual-fluorescence flow cytometry. The results showed that DNT only constituted a very minor subset of lymphocytes both in patients and normals, it normally did not exceed 2% of the lymphocyte population. Compared with normal subjects, patients with SLE had slightly increased levels of DNT within the total lymphocyte population (0.66+/-0.45% vs 0.51+/-0.33%) or within TCRalphabeta+ population (1.14+/-0.88% vs 0.88+/-0.54%). The difference, however, did not reach statistical significance. The levels of DNT correlated neither with the titers of anti-DNA antibodies in sera nor with the presence of active and severe lupus nephritis in SLE patients. Longitudinal follow-up of six patients at the stages of active and inactive nephritis revealed similar levels of DNT in the same individual. The preliminary results suggest that circulating DNT do not appear to play a critical role in Chinese patients with SLE.