Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4 + T cell response to liver Ags. However, the pathogenic function of CD4 + effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4 + T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4 + T cells producing IFN-g or IL-17. In AIH, TNF-producing CD4 + T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4 + T cells were not. However, the majority of the TNF-producing CD4 + T cells in AIH also produced IFN-g, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4 + T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4 + T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH.
Background Leprosy continues to be a health problem in endemic areas. More than 200,000 new cases of leprosy per year suggest that transmission of the disease is still ongoing, presumably as airborne infection through nasal droplets. Late diagnosis supports continued transmission and increases the individual risk for functional disabilities. Laboratory tools are considered beneficial to facilitate early detection and clinical assessment of cases. The aim of this study was to validate molecular tools allowing detection, quantification and assessment of viability of M. leprae from nasal swab samples which are easy to obtain without the need of any invasive procedures. Methods Validation of two real-time PCRs detecting M. leprae DNA (RLEP qPCR) and RNA (16S rRNA RT qPCR) was conducted on “must not detect”/“must detect” samples and 160 pre-treatment nasal swab samples from 20 clinically diagnosed multibacillary (MB) leprosy patients from Togo. Results Both assays were 100% M. leprae specific and showed analytical sensitivities of three templates each. Out of 20 clinically diagnosed MB leprosy patients, 15 (75.0%) had a positive RLEP qPCR result from nasal swab samples. The 16S rRNA RT qPCR detected viable bacilli in nasal swab samples of ten out of these 15 RLEP positive patients (66.7%). Conclusion The combined RLEP/16S rRNA (RT) qPCR assay provides a sensitive and specific tool to determine the bacterial load and viability of M. leprae from nasal swab samples and is applicable for early diagnosis, monitoring treatment response and investigating the role of nasal carriage of M. leprae in human-to-human transmission through aerosol infection. Electronic supplementary material The online version of this article (10.1186/s12879-019-4349-9) contains supplementary material, which is available to authorized users.
Life-long brain function and mental health are critically determined by developmental processes occurring before birth. During mammalian pregnancy, maternal cells are transferred to the fetus. They are referred to as maternal microchimeric cells (MMc). Among other organs, MMc seed into the fetal brain, where their function is unknown. Here, we show that, in the offspring’s developing brain in mice, MMc express a unique signature of sensome markers, control microglia homeostasis and prevent excessive presynaptic elimination. Further, MMc facilitate the oscillatory entrainment of developing prefrontal-hippocampal circuits and support the maturation of behavioral abilities. Our findings highlight that MMc are not a mere placental leak out, but rather a functional mechanism that shapes optimal conditions for healthy brain function later in life.
Objective Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood. Methods mRNA expression levels of pro-and anti-inflammatory markers in 39 EAC patients without neoadjuvant radiochemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry. Results Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4 + T cells with a reduction in CD4 + T cells producing IL-22 or IL-17A. We also observed an increase in CD4 + CD127 low FOXP3 + cells producing IL-10. Accumulation of FOXP3 + T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis. Conclusion EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.
Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of Axl and Mertk in Mφs or IL-10 receptor in DCs or Timp1 substantially reduced MPE progression. Our results delineate an inflammatory cascade—from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs—that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE.
Introduction. Current modalities to predict tumor recurrence and survival in esophageal cancer are insufficient. Even in lymph node-negative patients, a locoregional and distant relapse is common. Hence, more precise staging methods are needed. So far, only the CellSearch system was used to detect circulating tumor cells (CTC) with clinical relevance in esophageal cancer patients. Studies analyzing different CTC detection assays using advanced enrichment techniques to potentially increase the sensitivity are missing. Methods. In this single-center, prospective study, peripheral blood samples from 90 esophageal cancer patients were obtained preoperatively and analyzed for the presence of CTCs by Magnetic Cell Separation (MACS) enrichment (combined anti-cytokeratin and anti-epithelial cell adhesion molecules (EpCAM)), with subsequent immunocytochemical staining. Data were correlated with clinicopathological parameters and patient outcomes. Results. CTCs were detected in 25.6% (23/90) of the patients by combined cytokeratin/EpCAM enrichment (0-150 CTCs/7.5 mL). No significant correlation between histopathological parameters and CTC detection was found. Survival analysis revealed that the presence of more than two CTCs correlated with significantly shorter overall survival (OS) and progression-free survival (PFS). Conclusion. With the use of cytokeratin as an additional enrichment target, the CTC detection rate in esophageal cancer patients can be elevated and displays the heterogeneity of cytokeratin (CK) and EpCAM expression. The presence of >2CTCs correlated with a shorter relapse-free and overall survival in a univariate analysis, but not in a multivariate setting. Moreover, our results suggest that the CK7/8 + /EpCAM + or CK7/8 + /EpCAM − CTC subtype does not lead to an advanced tumor staging tool in non-metastatic esophageal cancer (EC) patients.
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