Could Celiac Disease and Overweight/Obesity Coexist in School-Aged Children and Adolescents? A Systematic Review.

Background: Celiac disease (CD) is a multifactorial, immune-mediated enteropathic disorder that may occur at any age with heterogeneous clinical presentation. In the last years, unusual manifestations have become very frequent, and currently, it is not so uncommon to diagnose CD in subjects with overweight or obesity, especially in adults; however, little is known in the pediatric population. This systematic review aims to evaluate the literature regarding the association between CD and overweight/obesity in school-age children. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. An electronic database search of articles published in the last 20 years in English was carried out in Web of Sciences, PubMed, and Medline. The quality of the included studies was assessed by using the STrengthening the Reporting of OBservational studies in Epidemiology statement. Results: Of the 1396 articles identified, 9 articles, investigating overweight/obesity in children/adolescents affected by CD or screening CD in children/adolescents with overweight/obesity, met the inclusion criteria. Overall, the results showed that the prevalence of overweight or obesity in school-age children (6-17 years) affected by CD ranged between 3.5% and 20%, highlighting that the coexistence of CD with overweight/obesity in children is not uncommon as previously thought. Conclusion: Although CD has been historically correlated with being underweight due to malabsorption, it should be evaluated also in children with overweight and obesity, especially those who have a familiar predisposition to other autoimmune diseases and/or manifest unusual symptoms of CD.

Pilot study on non-celiac gluten sensitivity: effects of Bifidobacterium longum ES1 co-administered with a gluten-free diet.

BACKGROUND: Bifidobacterium longum ES1 is a strain probiotic, colonizing the human gut and capable of a degradative action on gliadin. In an attempt to find new nutritional solutions aimed at improving the quality of life of patients with non-celiac gluten sensitivity (NCGS) we evaluated the effectiveness of this strain, in association with a gluten-free diet, comparing its efficacy versus diet therapy alone. METHODS: The experimental design included a non-randomized, open-label, 1:1 intervention study in parallel groups. Enrolled patients with symptoms attributable to NCGS, and with negative diagnoses of both wheat allergy and celiac disease, were included in this three-month trial divided into four outpatient visits (baseline, T1, T2 and T3). Fifteen patients for each group completed the experimental protocol. RESULTS: Our results showed that a combination of diet and probiotic determined a more significant reduction in the frequency and intensity of intestinal and extra-intestinal symptoms, and a clear improvement in stool consistency. CONCLUSIONS: Although the study was carried out on a small number of patients, the results of our pilot trial suggest that a combined strategy of naturally gluten-free diet therapy with administration of the probiotic strain ES1 appears to offer a greater advantage than the dietary regime alone in improving the clinical symptomatic picture and in stabilizing the intestinal microbiota.

Functional TRAIL receptors in monocytes and tumor-associated macrophages: A possible targeting pathway in the tumor microenvironment.

Despite the accepted dogma that TRAIL kills only tumor cells and spares normal ones, we show in this study that mononuclear phagocytes are susceptible to recombinant TRAIL via caspase-dependent apoptosis. Human resting monocytes and in vitro-differentiated macrophages expressed substantial levels of the functional TRAIL receptors (TRAIL-R1 and TRAIL-R2), while neutrophils and lymphocytes mostly expressed the non-signaling decoy receptor (TRAIL-R3). Accordingly, exclusively monocytes and macrophages activated caspase-8 and underwent apoptosis upon recombinant TRAIL treatment. TRAIL-Rs were up-regulated by anti-inflammatory agents (IL-10, glucocorticoids) and by natural compounds (Apigenin, Quercetin, Palmitate) and their treatment resulted in increased TRAIL-induced apoptosis. In mice, the only signaling TRAIL-R (DR5) was preferentially expressed by blood monocytes rather than neutrophils or lymphocytes. In both mice and humans, Tumor-Associated Macrophages (TAM) expressed functional TRAIL-R, while resident macrophages in normal tissues did not. As a proof of principle, we treated mice bearing a murine TRAIL-resistant fibrosarcoma with recombinant TRAIL. We observed significant decrease of circulating monocytes and infiltrating TAM, as well as reduced tumor growth and lower metastasis formation. Overall, these findings demonstrate that human and murine monocytes/macrophages are, among leukocytes, uniquely susceptible to TRAIL-mediated killing. This differential susceptibility to TRAIL could be exploited to selectively target macrophages in tumors.

Tertiary lymphoid tissue in the tumor microenvironment: from its occurrence to immunotherapeutic implications.

Recruitment of immune and inflammatory cells in the microenvironment of solid tumors is highly heterogeneous and follows patterns, varying according to the organ of origin and stage of disease, with critical roles in the process of cancer onset and progression. While adaptive cells are endowed with anti-tumor activities, inflammatory components of the immune infiltrate orchestrate an immunosuppressive microenvironment that reveals ambivalent functions of the immune contexture in the tumor milieu. The balance between opposing pro-tumoral and anti-tumoral immune pathways, which occur concomitantly in the tumor microenvironment, and the regulatory networks of these phenomena have been the target of several immunotherapeutic strategies. While the scarcity of adaptive immune effectors in tumors correlates with dismal prognosis, the pathways of activation of tumor-specific lymphocytes are yet to be fully elucidated. Recently, the occurrence of tertiary lymphoid tissue was revealed to be critical in mediating the dynamics of T cell recruitment and local activation of immune cells in the tumor microenvironment. Thus, tertiary lymphoid tissue assessment and targeting emerge as a promising approach for the design of novel prognostic immune signatures and immunotherapeutic strategies. The immunological behavior of tertiary lymphoid tissue, its occurrence in the tumor immune microenvironment and its clinical relevance are discussed here.

Immune-based therapies in pancreatic and colorectal cancers and biomarkers of responsiveness.

Immune-based strategies are the most promising treatments to improve cancer disease control. Early clinical trials are ongoing to test the safety and feasibility of immune-based therapies for gastrointestinal cancers. However, to date, immunotherapy has been only an experimental option for these diseases and a better understanding of their molecular, cellular, structural and clinical dissimilarities is crucial in the generation of tailored immunotherapeutic treatments. In this review, we will summarize the key mechanisms that regulate the action of immune system in cancer and the different immune-based approaches aimed at improving disease control in patients with advanced disease. We will then move on to discussing the current immunotherapeutic approaches in two types of gastrointestinal (colo-rectal and pancreatic) cancers, whose immune microenvironment has been lately object of intense analyses and has emerged as an important determinant of clinical outcome.

Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers.

PURPOSE: Tumor-infiltrating T lymphocytes (TIL) play a key role in the clinical outcome of human colorectal cancer; however, the dynamics of their recruitment along colorectal cancer clinical progression have not been fully elucidated. Tertiary lymphoid tissue (TLT) is an ectopic organized lymph node-like structure that typically forms at sites of chronic inflammation and is involved in adaptive immune responses. Its occurrence in cancer is sporadically documented and its role and clinical relevance is largely unknown. EXPERIMENTAL DESIGN: The occurrence of TLT, the correlation with TILs, and the clinical relevance were evaluated retrospectively, in a cohort study involving a consecutive series of 351 patients with stage II and III colorectal cancer. The role of TLT in lymphocyte recruitment was assessed in a preclinical model of colorectal cancer. RESULTS: In both human colorectal cancer and in a murine model of colorectal cancer, we identified organized TLT, highly vascularized (including high endothelial venules), and correlated with the density of CD3(+) TILs. Intravenous injection in mice of GFP splenocytes resulted in homing of lymphocytes to TLT, suggesting an active role of TLT in the recruitment of lymphocytes to tumor areas. Accordingly, TLT density and TIL infiltration correlated and were coordinated in predicting better patient's outcome among patients with stage II colorectal cancer. CONCLUSIONS: We provide evidence that TLT is associated with lymphocyte infiltration in colorectal cancer, providing a pathway of recruitment for TILs. TLT cooperates with TILs in a coordinated antitumor immune response, when identifying patients with low-risk early-stage colorectal cancer, thus, representing a novel prognostic biomarker for colorectal cancer.

Tertiary intratumor lymphoid tissue in colo-rectal cancer.

Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.