Dietary Factors Modulate Helicobacter-associated Gastric Cancer in Rodent Models

Since its discovery in 1982, the global importance of Helicobacter pylori–induced disease, particularly in developing countries, remains high. The use of rodent models, particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen, and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori–induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive.National Institutes of Health (U.S.) (P01CA028842)National Institutes of Health (U.S.) (P01CA026731)National Institutes of Health (U.S.) (P30ES002109

Stromal Fibroblasts in Digestive Cancer

The normal gastrointestinal stroma consists of extra-cellular matrix and a community of stromal cells including fibroblasts, myofibroblasts, smooth muscle cells, pericytes, endothelium and inflammatory cells. α-smooth muscle actin (α-SMA) positive stromal fibroblasts, often referred to as myofibroblasts or activated fibroblasts, are critical in the development of digestive cancer and help to create an environment that is permissive of tumor growth, angiogenesis and invasion. This review focusses on the contribution of activated fibroblasts in carcinogenesis and where possible directly applies this to, and draws on examples from, gastrointestinal cancer. In particular, the review expands on the definition, types and origins of activated fibroblasts. It examines the molecular biology of stromal fibroblasts and their contribution to the peritumoral microenvironment and concludes by exploring some of the potential clinical applications of this exciting branch of cancer research. Understanding the origin and biology of activated fibroblasts will help in the development of an integrated epithelial-stromal sequence to cancer that will ultimately inform cancer pathogenesis, natural history and future therapeutics

Thrombosis in vasculitis: from pathogenesis to treatment

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behçet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behçet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients

Altered balance of helper T cells in Rai-/- mice

A number of immune related pathologies, such as autoimmune and allergic disorders, develop as the result of an imbalance among Th subsets. A Th1 bias has been consistently observed in autoimmunity both in man and in mouse, which has led to the notion that autoimmunity is a disease initiated by an abnormal polarization of CD4+ T cells towards the proinflammatory Th1 lineage. In addition to Th1 and Th2 cells, a third subset of effector Th cells producing IL-17 has recently been described and termed Th17. Th17 cells have been causally associated to the pathogenesis of human autoimmune diseases, of which multiple sclerosis is a striking example. Recent data have identified molecular adaptors as master regulators not only of T-cell activation, but also of Th cell development, highlighting these molecules as attractive targets for pharmacological manipulation. We have recently demonstrated that loss of Rai, a member of the Shc family expressed both in neuronal and in T cells, results in the development of systemic autoimmunity (Savino et al 2009). Since peripheral T cells from Rai -/- mice show an up-regulation of the Th17 cytokines we addressed the potential role of Rai in the signaling pathways controlling Th17 development and in the pathogenesis of multiple sclerosis. Our results indicate that Rai interferes with Th17 development by altering key steps of the signaling pathways triggered by TCR in combination with TGFβ and IL-6 and alter the severity of EAE disease

The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 cell development.

Objective Rai acts as a negative regulator of antigen receptor signaling in T and B cells. Rai-/- mice develop lupus-like autoimmunity associated to the spontaneous activation of self-reactive lymphocytes. Here we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets. Materials and methods Lymph node T cells or naïve T cells were isolated from wild-type and Rai-/- mice and their cytokine profile was determined by ELISPOT and qRT-PCR both as such and after stimulation in vitro with immobilized anti-CD3 mAb in the presence or absence of polarizing cytokines. The expression of rai was measured in PBL from SLE patients and healthy donors by qRT-PCR. Results We show that Rai-/- mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments demonstrate that rai deficiency favours the development and expansion of Th17, but not Th1, cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4+ T cell differentiation to the Th17 lineage. Th1 and Th17 cell infiltrates were found in the kidneys of Rai-/- mice, providing evidence that Rai deficiency contributes to the development of lupus nephritis not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis. Conclusions We have identified Rai as a negative regulator of Th17 cell differentiation and expansion in the mouse and found evidence of an impairment of Rai expression in PBL from SLE patients