Peggy M. Mroz

Efficacy of mycophenolate mofetil in sarcoidosis

BACKGROUND Immunosuppressive (IS) therapy is indicated to treat progressive sarcoidosis, but randomized controlled trials to guide physicians in the use of steroid sparing agents are lacking. The aim of this retrospective study was to examine the role of mycophenolate mofetil (MMF) as an alternative therapy in the treatment of sarcoidosis. METHODS A retrospective chart review of all patients who had been prescribed MMF between January 2008 and October 2011 was conducted. Patients with insufficient data or who had another IS therapy initiated concomitantly with MMF, including prednisone, were excluded. Physiological data obtained at the time MMF therapy was initiated as well as six and twelve months before and after therapy was extracted. Longitudinal analyses of the effect of MMF on changes in pulmonary function at MMF start, 6 months, 12 months pre and post MMF therapy were conducted. RESULTS 37/76 patients met our inclusion/exclusion criteria. There were no statistically significant changes in PFT measurements pre and post MMF therapy. We did find a trend (p = 0.07) towards improvement in DLCO 12 months pre and post MMF in patients who were started on MMF due to intolerance to previous IS therapy compared to those who were unresponsive to their previous IS therapy. We also noted a reduction in prednisone dose in those treated with MMF. CONCLUSION MMF appears to offer no extra benefit to sarcoidosis patients unresponsive to previous steroid-sparing agents, but may be beneficial in patients intolerant to their previous steroid-sparing agent. Additional studies investigating the efficacy of MMF as the initial steroid-sparing agent are needed to further clarify the role of MMF in sarcoidosis.

p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation

Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (p<0.05) on HLA-DP Glu69+ moDCs after 100 μM BeSO₄-stimulation. BeSO₄ induced p38MAPK phosphorylation, while IκB-α was degraded in Be-stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-κB activation in moDCs, suggesting that p38MAPK and NF-κB are dependently activated by BeSO₄. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be-stimulated TNF-α and IFNγ cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases.

Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis.

A subset of beryllium-exposed workers develop beryllium sensitisation (BeS) which precedes chronic beryllium disease (CBD). We conducted an in-depth analysis of differentially expressed candidate genes in CBD. We performed Affymetrix GeneChip 1.0 ST array analysis on peripheral blood mononuclear cells (PBMCs) from 10 CBD, 10 BeS and 10 beryllium-exposed, nondiseased controls stimulated with BeSO4 or medium. The differentially expressed genes were validated by high-throughput real-time PCR in this group and in an additional group of cases and nonexposed controls. The functional roles of the top candidate genes in CBD were assessed using a pharmacological inhibitor. CBD gene expression data were compared with whole blood and lung tissue in sarcoidosis from the Gene Expression Omnibus. We confirmed almost 450 genes that were significantly differentially expressed between CBD and controls. The top enrichment of genes was for JAK (Janus kinase)–STAT (signal transducer and activator of transcription) signalling. A JAK2 inhibitor significantly decreased tumour necrosis factor-α and interferon-γ production. Furthermore, we found 287 differentially expressed genes overlapped in CBD/sarcoidosis. The top shared pathways included cytokine–cytokine receptor interactions, and Toll-like receptor, chemokine and JAK–STAT signalling pathways. We show that PBMCs demonstrate differentially expressed gene profiles relevant to the immunnopathogenesis of CBD. CBD and sarcoidosis share similar differential expression of pathogenic genes and pathways. Chronic beryllium disease and sarcoidosis share similar differential expression of pathogenic genes and pathways http://ow.ly/YgjIA

Beryllium Increases the CD14dimCD16+ Subset in the Lung of Chronic Beryllium Disease

CD14dimCD16+ and CD14brightCD16+ cells, which compose a minor population of monocytes in human peripheral blood mononuclear cells (PBMC), have been implicated in several inflammatory diseases. The aim of this study was to investigate whether this phenotype was present as a subset of lung infiltrative alveolar macrophages (AMs) in the granulomatous lung disease, chronic beryllium disease (CBD). The monocytes subsets was determined from PBMC cells and bronchoalveolar lavage (BAL) cells from CBD, beryllium sensitized Non-smoker (BeS-NS) and healthy subjects (HS) using flow cytometry. The impact of smoking on the AMs cell phenotype was determined by using BAL cells from BeS smokers (BeS-S). In comparison with the other monocyte subpopulations, CD14dimCD16+ cells were at decreased frequency in PBMCs of both BeS-NS and CBD and showed higher HLA-DR expression, compared to HS. The AMs from CBD and BeS-NS demonstrated a CD14dimCD16+phenotype, while CD14brightCD16+ cells were found at increased frequency in AMs of BeS, compared to HS. Fresh AMs from BeS-NS and CBD demonstrated significantly greater CD16, CD40, CD86 and HLA-DR than HS and BeS-S. The expression of CD16 on AMs from both CBD and BeS-NS was downregulated significantly after 10μM BeSO4 stimulation. The phagocytic activity of AMs decreased after 10μM BeSO4 treatment in both BeS-NS and CBD, although was altered or reduced in HS and BeS-S. These results suggest that Be increases the CD14dimCD16+ subsets in the lung of CBD subjects. We speculate that Be-stimulates the compartmentalization of a more mature CD16+ macrophage phenotype and that in turn these macrophages are a source of Th1 cytokines and chemokines that perpetuate the Be immune response in CBD. The protective effect of cigarette smoking in BeS-S may be due to the low expression of co-stimulatory markers on AMs from smokers as well as the decreased phagocytic function.