Keiko Konoha

Oral Clarithromycin Enhances Airway Immunoglobulin A (IgA) Immunity through Induction of IgA Class Switching Recombination and B-Cell-Activating Factor of the Tumor Necrosis Factor Family Molecule on Mucosal Dendritic Cells in Mice Infected with Influenza A Virus

ABSTRACT We previously reported that the macrolide antibiotic clarithromycin (CAM) enhanced the mucosal immune response in pediatric influenza, particularly in children treated with the antiviral neuraminidase inhibitor oseltamivir (OSV) with low production of mucosal antiviral secretory IgA (S-IgA). The aims of the present study were to confirm the effects of CAM on S-IgA immune responses, by using influenza A virus (IAV) H1N1-infected mice treated with or without OSV, and to determine the molecular mechanisms responsible for the induction of mucosal IgA class switching recombination in IAV-infected CAM-treated mice. The anti-IAV S-IgA responses and expression levels of IgA class switching recombination-associated molecules were examined in bronchus-lymphoid tissues and spleens of infected mice. We also assessed neutralization activities of S-IgA against IAV. Data show that CAM enhanced anti-IAV S-IgA induction in the airway of infected mice and restored the attenuated antiviral S-IgA levels in OSV-treated mice to the levels in the vehicle-treated mice. The expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iμ-Cα transcripts on B cells were enhanced by CAM, compared with the levels without CAM treatment, but CAM had no effect on the expression of the BAFF receptor on B cells. Enhancement by CAM of neutralization activities of airway S-IgA against IAV in vitro and reinfected mice was observed. This study identifies that CAM enhances S-IgA production and neutralizing activities through the induction of IgA class switching recombination and upregulation of BAFF molecules in mucosal dendritic cells in IAV-infected mice.

Carnosine inhibits ß-sheet formation of PrP106-126 and protects against its neurotoxicity

Background: The frequent co-occurrence of Alzheimer’s disease (AD) pathology in patients with clinically diagnosed normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of potentially faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of A-beta in CSF in preclinical and early AD. Methods: CSF biomarker data (A-beta, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volume data were obtained from the Alzheimer’s Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 819 subjects classified as being either normal (n1⁄4229), having the syndrome of mild cognitive impairment (n1⁄4397), or mild AD (n1⁄4193). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. Subjects in each diagnostic group were further stratified by ApoE genotype. Results: For controls, ventricular volume was negatively associated with A-beta in E4 positive subjects, independent of age. Ventricular volume as well as age was negatively associated with tau in E4 negative control subjects. A significant reversed pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not A-beta, in E4 positive subjects, independent of age. Abeta and tau were not significantly related to whole brain volume in either controls or AD; however, tau was negatively related to whole brain volume in MCI subjects. Conclusions: Increased ventricular volume may be associated with decreased levels of CSF A-beta in preclinical AD. The basis for the apparent effect of ApoE4 genotype on the relationship of ventricular volume to A-beta and tau levels is unknown, but could involve altered CSF-bloodbrain barrier function early in the course of the disease. Further experimental evidence with animal models of hydrocephalus and ApoE may shed light on the exact nature of these relationships.