Circulating CD14+ monocytes are precursors of phagocytes, such as macrophages and dendritic cells. Here we report primitive cells with a fibroblast-like morphology derived from human peripheral blood CD14+ monocytes that can differentiate into several distinct mesenchymal cell lineages. We named this cell population monocyte-derived mesenchymal progenitor (MOMP). MOMPs were obtained in vitro from human peripheral blood mononuclear cells cultured on fibronectin in the presence of fetal bovine serum alone as a source of growth factors. MOMPs had a unique molecular phenotype-CD14+CD45+CD34+type I collagen+-and showed mixed morphologic and molecular features of monocytes and endothelial and mesenchymal cells. MOMPs were found to be derived from a subset of circulating CD14+ monocytes, and their differentiation required that they bind fibronectin and be exposed to one or more soluble factors derived from peripheral blood CD14- cells. MOMPs could be expanded in culture without losing their original phenotype for up to five passages. The induction of MOMPs to differentiate along multiple limb-bud mesodermal lineages resulted in the expression of genes and proteins specific for osteoblasts, skeletal myoblasts, chondrocytes, and adipocytes. Our findings represent the first evidence that human circulating CD14+ monocytes are a source of progenitors that exhibit mesenchymal cell differentiation.

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Objective To elucidate the pathologic role of follicular helper T (Tfh) cells and their subsets in active, untreated IgG4‐related disease. Methods Fifteen patients with active, untreated, biopsy‐proven IgG4‐related disease, 24 patients with primary Sjögren's syndrome (SS), 12 patients with allergic rhinitis, and 23 healthy controls were evaluated. Tfh cells were defined as CD3+CD4+CXCR5+CD45RA– cells. Circulating Tfh cell subsets among CXCR5+CD45RA–CD4+ T cells were defined as Tfh17 cells (CXCR3–CCR6+), Tfh1 cells (CXCR3+CCR6–), or Tfh2 cells (CXCR3–CCR6–). CD19+CD20–CD27+CD38+ cells were defined as plasmablasts. Serum cytokine levels (interleukin‐4 [IL‐4], IL‐10, IL‐21, and IL‐33) were measured by cytometric bead array or enzyme‐linked immunosorbent assay. Results Patients with IgG4‐related disease had significantly increased levels of Tfh2 cells compared to healthy controls or patients with primary SS or allergic rhinitis. Increased Tfh2 levels were strongly associated with increased serum IgG4 levels and the IgG4:IgG ratio in IgG4‐related disease. A positive correlation was observed between Tfh2 counts, plasmablast counts, and serum IL‐4 levels. Interestingly, levels of plasmablasts and serum IL‐4 and IgG4 decreased after treatment with glucocorticoids, whereas no obvious change was observed in Tfh2 cell counts. Conclusion The Tfh2 cell count was specifically increased in IgG4‐related disease and was correlated with elevated serum levels of IgG4 and IL‐4 and plasmablast counts. Tfh2 cells were the only component that was not affected by glucocorticoid treatment, suggesting that Tfh2 cells are the cell type implicated in IgG4‐related disease.

BackgroundThe aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity.MethodsSeventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman’s disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7lowPD-1high subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score.ResultsThe number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level.ConclusionsTfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1064-4) contains supplementary material, which is available to authorized users.

Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response.

The present study suggests that ASD with chronic articular disease has distinct clinical, cytokine and immunogenetic profiles.

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