Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis.

BACKGROUND: Depending on the cytokine microenvironment, macrophages (Mϕ) can adopt a proinflammatory (M1) or a profibrotic (M2) phenotype characterized by the expression of cell surface proteins such as CD206 and CD163 and soluble factors such as CC chemokine ligand 18 (CCL18). A key role for Mϕ in fibrosis has been observed in diverse organ settings. We studied the Mϕ population in a human model of peritoneal dialysis in which continuous stress due to dialysis fluids and recurrent peritonitis represent a risk for peritoneal membrane dysfunction reflected as ultrafiltration failure (UFF) and peritoneal fibrosis. METHODS: We used flow cytometry and quantitative reverse transcription-polymerase chain reaction to analyse the phenotype of peritoneal effluent Mϕ and tested their ability to stimulate the proliferation of human fibroblasts. Mϕ from non-infected patients were compared with those from patients with active peritonitis. Cytokine production was evaluated by enzyme-linked immunosorbent assay (ELISA) in spent dialysates and cell culture supernatants. RESULTS: CD206(+) and CD163(+) M2 were found within peritoneal effluents by flow cytometry analysis, with increased frequencies of CD163(+) cells during peritonitis (P = 0.003). TGFB1, MMP9 and CCL18 messenger RNA (mRNA) levels in peritoneal macrophages (pMϕ) were similar to those found in M2 cells differentiated in vitro. The ability of pMϕ to stimulate fibroblast proliferation correlated with CCL18 mRNA levels (r = 0.924, P = 0.016). CCL18 production by pMϕ was confirmed by immunostaining of cytospin samples and ELISA. Moreover, CCL18 effluent concentrations correlated with decreased peritoneal function, which was evaluated as dialysate to plasma ratio of creatinine (r = 0.724, P < 0.0001), and were significantly higher in patients with UFF (P = 0.0025) and in those who later developed sclerosing peritonitis (P = 0.024). CONCLUSIONS: M2 may participate in human peritoneal fibrosis through the stimulation of fibroblast cell growth and CCL18 production as high concentrations of CCL18 are associated with functional deficiency and fibrosis of the peritoneal membrane.

An update on the immunopathogenesis of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic clinicopathological entity characterized by large numbers of intraepithelial eosinophils infiltrating the esophageal mucosa, which is not caused by gastroesophageal reflux. This disease has become widely recognized over the past few years and new methods have been developed to reveal its underlying pathophysiological mechanisms. Owing to the high prevalence of food and/or airborne allergen sensitization in EoE patients, the allergic nature of the disease had to be defined, which has certain factors in common with other IgE-dependent entities, such as bronchial asthma or allergic rhinitis. Of these, some cytokines and chemokines previously studied in asthma have also been implicated in molecular mechanisms causing eosinophil-rich esophageal inflammation. However, the role played by IgE in relation to the esophageal eosinophilic infiltrate must be clarified, together with the possible function of mast cells in the inflammatory infiltrate and its activation stimuli. A putative role has also been recently suggested for gastroesophageal reflux in the origin of EoE that should be profoundly analyzed, together with the role of specific genes implicated in other digestive inflammatory disorders. This article reviews recent advances in the immunopathogenesis of EoE, which should also consider other pathways to activate the esophageal mucosal immune system.

The role of mast cells in eosinophilic esophagitis.

Eosinophilic esophagitis (EE) is a chronic inflammatory disease of the esophagus which is characterized by the presence of dense infiltrate of eosinophilic leukocytes restricted to this organ mucosa. Accumulating published evidence suggests a strong role of mast cells in the inflammatory infiltrate in the physiopathology of EE. We have reviewed published articles with relevant information about the presence and possible role of mast cells in EE. Although mast cells have been studied indirectly in EE, reported data allow us to confirm that the number of mast cells infiltrating the esophageal epithelium in adult and child patients with EE is higher with respect to the normal state and in gastroesophageal reflux disease. Mast cells linked to IgE, which are not found in other conditions, have been identified in EE. Despite that fact, an anaphylactic reaction history after exposure to allergens is not common in these patients. Therefore, the mast cells' function in EE could be dependent on T lymphocytes, as suggested by a mast cell gene expression analysis. Bi-directional crosstalk is established between mast cells and eosinophils, hence establishing interesting hypotheses regarding their relationship to EE physiopathology. Mast cells' function as an immune response leader seems to substitute for their effector functions in EE, while at the same time opening new research pathways for consideration of these cells as a therapeutic target in EE. However, the inefficiency of therapies that inhibit mast cell functions while they are effective in other respiratory tract diseases results in the need for specific studies to identify the real function of such complex cells in the physiopathology of EE. There is indirect proof of the role of mast cells in EE, while many doubts exist about their activation mechanism, which does not seem to be IgE-mediated. Specific approach studies are needed to clarify the function of these cells in the physiopathology of EE, which could be a possible therapeutic target.