Yoshio Wakatsuki

Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria

The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. Selective expression of FcRn in the epithelium is shown here to be associated with secretion of IgG into the lumen that allows for defense against an epithelium-associated pathogen (Citrobacter rodentium). This pathway of host resistance to a bacterial pathogen as mediated by FcRn involves retrieval of bacterial antigens from the lumen and initiation of adaptive immune responses in regional lymphoid structures. Epithelial-associated FcRn, through its ability to secrete and absorb IgG, may thus integrate luminal antigen encounters with systemic immune compartments and as such provide essential host defense and immunoregulatory functions at the mucosal surfaces.

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

Ags administered orally at a high dose are absorbed in immunogenic forms and perfuse the liver, which raises a question regarding the relevance of hepatic lymphocyte activation to the systemic hyporesponsiveness against the ingested Ag. Oral administration of 100 mg of OVA to the mice led to massive cell death of OVA-specific (KJ1-26+) CD4+ T cells by Fas-Fas ligand (FasL)-mediated apoptosis in the liver, which was associated with the emergence of hepatic KJ1-26+CD4+ T cells expressing FasL. Hepatic CD4+ T cells in OVA-fed mice secreted large amounts of IL-4, IL-10, and TGF-β1 upon restimulation in vitro and inhibited T cell proliferation. Adoptive transfer of these hepatic CD4+ T cells to naive mice and subsequent antigenic challenge led to suppression of T cell proliferation as well as IgG Ab responses to OVA; this effect was mostly abrogated by a blocking Ab to FasL. i.p. administration of an Ag at a high dose also generated hepatic CD4+FasL+ T cells with similar cytokine profile as T cells activated by oral administration of Ags at a high dose. Finally, we did not see an increase in FasL+ cells in the hepatic CD4+Vβ8+ T cell subset of MRL/lpr/lpr mice given staphylococcal enterotoxin B, indicating the requirement for Fas-mediated signals. These hepatic CD4+FasL+ regulatory cells may explain the tolerogenic property of the liver and play roles in systemic hyporesponsiveness induced by an Ag administered at a high dose.

Stroke-Independent Association Between Metabolic Syndrome and Functional Dependence, Depression, and Low Quality of Life in Elderly Community-Dwelling Brazilian People

OBJECTIVES: Metabolic syndrome (Met.S) is a risk factor for stroke, dementia, and ischemic heart disease (IHD). It is unclear whether Met.S is an independent risk factor for functional dependence, depression, cognitive impairment, and low health‐related quality of life (HRQoL) in a population free of clinical stroke.

Identification and characterization of IgG4‐associated autoimmune hepatitis

Background: Autoimmune hepatitis (AIH) and autoimmune pancreatitis (AIP) share clinical and pathological features such as high serum levels of immunoglobulin (Ig) G and autoantibodies, and lymphoplasmacytic infiltration, suggesting the presence of common immunological abnormalities. However, little is known about the possible involvement of IgG4, a hallmark of AIP, in AIH.

The vast majority of gastric T cells are polarized to produce T helper 1 type cytokines upon antigenic stimulation despite the absence of Helicobacter pylori infection

Abstract:Helicobacter pylori infection is associated with chronic infiltration by various cell types, including T cells, whose cytokine production may regulate the inflammatory reaction as well as local immune response to the bacterium. We prospectively analyzed the constituents of the cellular infiltrates and the cytokines produced by T cells in antral biopsies obtained from 73 subjects with and without H. pylori infection, before and after eradication therapy, and compared them with a histological grade of gastritis. We found that T cells predominated in cell number, followed by granulocytes/monocytes and plasma cells in both H. pylori-infected and H. pylori-uninfected subjects. Despite the absence of H. pylori infection, more than 70% of gastric CD4-positive T cells obtained from uninfected tissue produced interferon-γ (IFN-γ) in the cytosol. Upon receptor cross-linking of a CD3 and a CD28 molecule, T cells in both infected and uninfected tissue continuously secreted a far greater amount of IFN-γ than those in peripheral blood mononuclear cell controls for a period of cell culture, whereas the increase in interleukin-4 (IL-4) was very small, and no increase in IL-2 secretion was seen. In H. pylori-infected patients, IFN-γ secretion was correlated with the grade of mononuclear cell infiltration and decreased to an uninfected control level after eradication therapy. We did not see the effect of eradication on IL-4 secretion. Anti-H. pylori antibody of the IgG2 subclass was remarkably increased in H. pylori-infected subjects. These results together suggest that gastric T cells are already differentiated to produce a large amount of IFN-γ by a mechanism unrelated to H. pylori infection. H. pylori infection appeared to activate T cells to secrete even more IFN-γ, which may contribute to maintaining a perpetual inflammation in H. pylori-infected stomach.

Host factors are important in determining clinical outcomes of Helicobacter pylori infection

whereas in Western countries gastritis is usually restricted to the antrum (type B gastritis). Moreover, there are more patients with gastric ulcer (GU) than duodenal ulcer (DU) in Japan,5,6 but the number of patients with DU far exceeds that with GU in Western countries as well as in India and southern China 3,7,8 (Fig. 1). Several studies have postulated that differences in H. pylori strains are the cause of the divergent clinical outcomes. Indeed, almost all H. pylori-infected Japanese are infected with CagA/CagPAI-positive H. pylori, the so-called virulent strain,9 whereas a considerable number of patients in Western countries are infected with CagAand/or CagPAI-negative strains.10 The prevalence of H. pylori-related upper gastrointestinal diseases in Japan is much higher than that in Western countries, even when taking the higher infection rate into account, which suggests that those infected with the virulent strains are more likely to develop pangastritis, peptic ulcer disease, and gastric cancer. However, almost all patients with gastritis, peptic ulcer diseases, GU and DU, and gastric cancer, both in East Asian and in Western countries, are infected with CagA/CagPAIpositive H. pylori.9,11 Therefore, although the virulent strains appear to induce upper gastrointestinal diseases more frequently than the negative strains, the presence or absence of CagA/CagPAI does not explain the diversity of disease outcomes induced by H. pylori infection. More recently, Higashi et al.12 reported a distinct amino acid sequence motif in the proximity of the tyrosine phosphorylation site of CagA in a Japanese H. pylori isolate that has a higher affinity for src homology 2containing protein tyrosine phosphatase (SHP-2) than that of Western isolates. Thus, the Japanese isolates with a distinct CagA phosphorylation site might be linked specifically to corpus gastritis, mucosal atrophy, and gastric cancer. No differences at this site, however, have been reported among H. pylori strains from normal subjects and patients with atrophic gastritis, GU, DU, or gastric cancer in Japan.13

Oxidized-LDL and Atherosclerosis: Role of LOX-1

Abstract: The accumulation of substantial numbers of monocyte/macrophages and activated T lymphocytes in focal areas of the arterial intima appears to be a hallmark of atherosclerosis. Our report demonstrated that lysophosphatidylcholine (lyso‐PC), a polar phospholipid component that is increased in atherosclerotic lipoproteins, such as oxidized LDL and remnant lipoproteins in diabetic and Type 3 hyperlipidemia, can upregulate adhesion molecules for monocytes and T lymphocytes, and growth factors, such as heparin‐binding epidermal growth factor‐like growth factor and PDGF A and B chains. Recently, we identified the novel receptor for oxidized LDL, named LOX‐1. We summarize the importance of the interaction between oxidized LDL and its receptor, LOX‐1, in terms of early stage atherogenesis.

Oral immunization with size-purified microsphere beads as a vehicle selectively induces systemic tolerance and sensitization

Oral administration of antigens has long been recognized as a method to prevent or delay the onset of diseases associated with untoward immune responses to self and non-self antigens. Although oral administration of antigens offers a convenient way to induce systemic tolerance, its therapeutic potential has been seriously limited by the fact that it requires repeated feeding of a large amount of antigens and that it may deteriorate ongoing autoimmune diseases when autoantigens are employed. We have previously shown that orally administered poly-D,L-lactic acid (PDLLA) microspheres containing an antigen were selectively distributed to Peyers patches (PP) and systemic lymphoid tissues according to their diameter and then released the antigen over a long period of time. We now report that a single dose of intragastric immunization with a PDLLA microsphere 7-10 micrometer in diameter and containing 2 mg of OVA was as effective as 100 mg of water soluble OVA to suppress OVA-specific IgG and DTH response. This was associated with a large increase of Interferon-gamma production by PPT cells stimulated with an antigen and a small increase in secretory IgA specific to OVA. In contrast, administration of an antigen encapsulated in microspheres 3-4 microm in diameter led to an enhanced OVA-specific IgG response and no significant increase in OVA-specific secretory IgA. Thus, by utilizing microspheres of an appropriate diameter as a vaccination vehicle, we were able to selectively induce both systemic tolerance and sensitization by oral ingestion of single low dose of an antigen.

Lysophosphatidylcholine Increases Expression of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Human T Lymphocytes

Atherosclerotic lesions contain substantial numbers of activated T lymphocytes in addition to monocytes/macrophages. T cell-derived cytokines and growth factors may play a role in atherogenesis; however, stimuli responsible for T-cell activation in atherogenesis have not been fully elucidated. In this study, we provide evidence that lysophosphatidylcholine (lyso-PC), a polar phospholipid component increased in atherogenic lipoproteins and atherosclerotic lesions, can upregulate gene expression and secretion of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in cultured T lymphocytes isolated from human peripheral blood. Effects of lyso-PC on T lymphocytes appear to be selective and specific, since lyso-PC also increases interleukin (IL)-2 receptor expression but does not affect mRNA levels for IL-2 or IL-4. Lyso-PC-induced upregulation of HB-EGF and IL-2 receptor mRNA in peripheral T cells is mostly dependent on exogenous IL-2 in conditioned medium. The effect of lyso-PC on HB-EGF induction was more potent in CD4+ cells than in CD8+ cells, although lyso-PC increases IL-2 receptor expression dramatically in both CD4+ cells and CD8+ cells. Lyso-PC similarly increased HB-EGF expression in Jurkat cells, a cell line for human CD4+ T lymphocytes. These results in vitro suggest that lyso-PC may be an important stimulus for T cells in atherogenesis in vivo to upregulate HB-EGF and that T cell-derived smooth muscle growth factors may modulate atherosclerotic progression.

Isoflavones regulate innate immunity and inhibit experimental colitis.

Background and Aim:  Dysregulated immune responses in the gut to luminal antigens can cause inflammatory bowel diseases (IBD). The roles played by dietary antigens in the pathogenesis or prevention of IBD are poorly understood. Soybean isoflavones are digested in large amounts and have many biological activities. The aim of this study was to determine whether isoflavones in aglycon and bioavailable forms have any effect on gut immunity and protect the host from tissue damage in a mouse model of colitis.