A New Proposal for the Pathogenic Mechanism of Non-Coeliac/Non-Allergic Gluten/Wheat Sensitivity: Piecing Together the Puzzle of Recent Scientific Evidence.

Non-coeliac/non-allergic gluten/wheat sensitivity (NCG/WS) is a gluten-related disorder, the pathogenesis of which remains unclear. Recently, the involvement of an increased intestinal permeability has been recognized in the onset of this clinical condition. However, mechanisms through which it takes place are still unclear. In this review, we attempt to uncover these mechanisms by providing, for the first time, an integrated vision of recent scientific literature, resulting in a new hypothesis about the pathogenic mechanisms involved in NCG/WS. According to this, the root cause of NCG/WS is a particular dysbiotic profile characterized by decreased butyrate-producing-Firmicutes and/or Bifidobacteria, leading to low levels of intestinal butyrate. Beyond a critical threshold of the latter, a chain reaction of events and vicious circles occurs, involving other protagonists such as microbial lipopolysaccharide (LPS), intestinal alkaline phosphatase (IAP) and wheat α-amylase trypsin inhibitors (ATIs). NCG/WS is likely to be a multi-factor-onset disorder, probably transient and preventable, related to quality and balance of the diet, and not to the presence of gluten in itself. If future studies confirm our proposal, this would have important implications both for the definition of the disease, as well as for the prevention and therapeutic-nutritional management of individuals with NCG/WS.

B lymphocyte reconstitution after hematopoietic stem cell transplantation: functional immaturity and slow recovery of memory CD27+ B cells.

OBJECTIVE: Functional recovery of B lymphocytes after hematopoietic stem cell transplantation (HSCT) can take up to 2 years. HSCT recipients may obtain protective titers of pathogen-specific antibody through vaccination, but optimal timing of reimmunization remains to be defined. PATIENTS AND METHODS: In this study, we evaluated the reconstitution of B-cell number and activity in 139 children given HSCT, by B-cell subset phenotyping and in vitro immunoglobulin (Ig) production. RESULTS: Patients were longitudinally studied at 3, 6, 12, and 18 to 24 months after transplantation. At all time points, recipients displayed a significantly higher percentage of naive (IgD+CD27-) B cells and showed significantly lower production of stimulated in vitro Ig as compared to healthy controls. Moreover, during follow-up, we observed an increase in the proportion of patients who had CD27+ B subsets and who were able to mount in vitro Ig production greater than the 5th percentile. CONCLUSION: Similar to what has been described in adults, most children lack memory B cells and produce low amounts of Ig. However, the number of B cells, as well as their function, gradually recovered over time and the spread of data we observed suggests that the reimmunization schedule should be individualized for each patient. It remains to be defined in a prospective clinical study the time point at which a patient should start reimmunization. A reasonable hypothesis to be explored is the time point at which a percentage of memory B cells greater than the 5th percentile of normal controls is reached.

DNase I behaves as a transcription factor which modulates Fas expression in human cells.

DNase I is the major nuclease present in biological fluids and is ubiquitously expressed in mammalian tissues. It is responsible for the removal of DNA from nuclear antigens, and consistently with this function, DNase I-deficient mice show features of autoimmunity. The enzyme seems also to be involved in apoptosis (programmed cell death). We demonstrate that DNase I is internalized by human cells upon binding mannose 6-phosphate receptor and gains access into the cells. Following internalization of the enzyme, the cells show an increased surface expression of Fas molecule, a key regulator of apoptosis. Here we show that DNase I up-regulates fas transcription upon interaction with the fas gene promoter. Moreover, overexpression of the DNase I gene in human cells results in a similar modulation of the fas gene expression. Our data provide the first evidence that the endonuclease DNase I behaves as a transcription factor which selectively regulates cell surface Fas expression in human cells and point towards a fundamental role of DNase I in the regulation of the apoptotic machinery.