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OBJECTIVE
The gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic β-cells, a self-tissue located outside the intestine, is still unclear. In the small intestine, lamina propria dendritic cells (LPDCs) induce peripheral differentiation of FoxP3+ regulatory T (Treg) cells. We tested the hypothesis that the intestinal milieu impinges on human T1D by affecting differentiation of FoxP3+ Treg cells.RESEARCH DESIGN AND METHODS
We collected duodenal biopsies of 10 T1D patients, 16 healthy subjects, and 20 celiac individuals and performed a fluorescent-activated cell sorter analysis to measure percentages of various immune cell subsets, including CD4+ and CD8+ T cells, NK cells, γδ T cells, CD103+CD11c+ LPDCs, and CD4+CD25+FoxP3+CD127− Treg cells. In parallel, we assessed the tolerogenic function (i.e., capacity to induce differentiation of FoxP3+ Treg cells) by LPDCs of T1D patients and control subjects.RESULTS
Our analysis revealed a significant reduction in the percentage of intestinal CD4+CD25+FoxP3+CD127− Treg cells in T1D patients compared with healthy subjects (P = 0.03) and celiac individuals (P = 0.003). In addition, we found that LPDCs from T1D patients completely lacked their tolerogenic function; they were unable to convert CD4+CD25− T cells into CD4+CD25+FoxP3+CD127− Treg cells.CONCLUSIONS
Our data indicate that T1D patients have a reduced number of intestinal FoxP3+ Treg cells as a result of their defective differentiation in the gut. These findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic β-cells and preventing T1D.Type 1 diabetes (T1D) is a destructive islet β-cell specific autoimmune disease resulting from a yet undefined interaction between genetic and environmental factors (1). A dramatic increase in T1D incidence was recorded in most developed countries in the past 40 years (e.g., a threefold increase in Western countries) (2,3). The steady and rapid increase in T1D incidence cannot be ascribed to genetic variations and, thus, it must be related to environmental changes. Environmental agents such as viral infections (i.e., enteroviruses and rotaviruses) (4,5), reactions to dietary antigens (i.e., cow’s milk and gluten) (6–8), and microbiota alterations (9) that act at the intestinal level have been observed in association with, or as risk factors for, the development of T1D. The observation that development of clinical diabetes in patients is preceded by intestinal alterations such as increased permeability, immune activation, and ultrastructural abnormalities of the epithelium (10–16) provides additional evidence on the crucial role of the gut environment in human T1D. Although existing evidence is suggestive of a causative link between the gut milieu and the pathogenesis of T1D, it is still unclear whether and by which mechanism(s) a dysfunction in the intestine promotes autoimmunity elsewhere (i.e., in the pancreatic β-cells) and if it does, how this process occurs.Important immune regulatory mechanisms reside in the intestinal mucosa. FoxP3+ regulatory T (Treg) cells, a Treg cell subset that is instrumental to controlling T1D (17), arise centrally in the thymus and peripherally in the gut (18). Specifically, lamina propria CD103+CD11c+ dendritic cells (LPDCs) are responsible for extrathymic FoxP3+ Treg cell development and expansion (18,19). Considering the key immune regulatory role of FoxP3+ Treg cells, it is clear that their defective peripheral differentiation in the gut could lead to failure of self-tolerance and autoimmune disease, particularly in tissues such as pancreatic islets and lymph nodes that are directly connected to the intestinal mucosa and gut-associated lymphoid tissue (20).Here we demonstrate that the extrathymic differentiation of FoxP3+ Treg cells by gut-resident CD103+CD11c+ dendritic cells (DCs) is selectively impaired in humans affected by T1D. Our findings indicate that organ-specific autoimmune diseases such as T1D could be initiated and possibly maintained by virtue of changes in peripheral FoxP3+ Treg cell differentiation and/or expansion in the gut. 相似文献Over the past years laser technology has played a predominant role in prostate surgery, for the treatment of benign prostate hypertrophy (BPH). Various laser devices have been introduced in clinical practice, showing good results in terms of complications and urodynamic outcomes efficacy compared with TURP and Open Prostatectomy.
In this study we describe the efficacy and the safety profile of a novel laser technique, ThuLEP (Thulium Laser Enucleation of Prostate) that permits a complete anatomical endoscopic enucleation of prostatic adenoma independently to prostate size.
Methods148 patients with a mean age of 68.2 years were enrolled between September 2009 and March 2012 (36 months), and treated for BPH with ThuLEP. Every patient was evaluated at base line according to: Digital Rectal Examination (DRE), prostate volume, Post-Voided volume (PVR), International Prostate Symptoms Score (I-PSS), International Index of Erectile Function-5 (IIEF-5), Quality of Life (QoL), PSA values, urine analysis and urine culture, uroflowmetry. The same evaluation was conducted after a 12 month follow-up. ThuLEP was performed by 2 expert surgeons.
ResultsOur data showed a better post-operative outcome in terms of catheter removal, blood loss, TURP syndrome, clot retention and residual tissue compared to large series of TURP and OP. Only 1.3% of patients had bladder wall injury during morcellation. I-PSS, Qmax, Prostate Volume, QoL and PVR showed a highly significant improvement at 12 month follow-up in comparison to preoperative assessment.
ConclusionThuLEP represent an innovative option in patients with BPH. It is a size independent surgical endoscopic technique and it can be considered the real alternative, at this time, to TURP and even more to Open Prostatectomy for large prostate, with a complete removal of adenoma and with a low complication rate.
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