T cells in primary Sjögren's syndrome:targets for early intervention

A histologic hallmark of primary SS (pSS) is lymphocytic infiltration of the salivary and lacrimal glands, in particular by CD4+ T and B cells. In the early stages of the disease, infiltrates are dominated by CD4+ T cells, while B cell accumulation occurs at later stages. Activated T cells contribute to pathogenesis by producing pro-inflammatory cytokines and by inducing B cell activation, which results in the establishment of a positive feedback loop. In the inflamed glandular tissues, many different CD4+ effector subsets are present, including IFN-γ-producing Th1 cells, IL-17-producing Th17 cells and IL-21-producing T follicular helper cells. In blood from pSS patients, frequently observed abnormalities of the T cell compartment are CD4+ T cell lymphopenia and enrichment of circulating follicular helper T (Tfh) cells. Tfh cells are critical mediators of T cell-dependent B cell hyperactivity and these cells can be targeted by immunotherapy. Inhibition of T cell activation, preferably early in the disease process, can mitigate B cell activity and may be a promising treatment approach in this disease

Scanning Electron Microscopy of Immuno-Gold Labeled Antigens Associated with Bladder Cancer

Scanning electron microscopy (SEM), in the backscattered electron imaging (BEI) mode, has been used to study the topographical distribution of colloidal gold labeled antigens expressed on the luminal surface of the bladder urothelium in biopsies from three categories of patients: 1) normal controls; 2) patients with a history of bladder cancer but no pathological diagnosi s at time of cystoscopy; and 3) patients with overt transitional cell carcinoma (TCC) of various histopathological stages and grades. Cold cup biopsies were processed for immuno-SEM according to a previously described method. Antigens under investigation were: 1) ABH blood group antigens; and 2) those identified by the following murine monoclonal antibodies (mAbs): LEU-Ml, T16, 19A211, G4 and E7. In most cases labeling patterns were correlated with the surface features of the superficial urothelial cells as revealed in the secondary electron imaging (SEI) mode of the SEM. Results, to date, indicate that the immuno-gold labeling method is more sensitive than immuno-peroxidase, and that phenotypic heterogeneity of antigenic expression (or deletion) is a frequent observation of potential diagnostic or prognostic value

Ruthenium Complexes with PNN Pincer Ligands Based on (Chiral) Pyrrolidines:Synthesis, Structure, and Dynamic Stereochemistry

We report the synthesis of lutidine-based PNN type metal pincer complexes, using achiral (pyrrolidine) as well as chiral ((R,R)-2,5-dimethylpyrrolidine and (R)-2-methylpyrrolidine) substituents at the N side arm of the pincer ligand. With the six-coordinate saturated Ru pincers (PNN)Ru(H)(CO)(Cl), which have an aromatic pyridine ligand backbone, as the starting materials, treatment with strong base (KOtBu) generated the corresponding dearomatized pincer complexes (PNN′)Ru(H)(CO). Spectroscopic, crystallographic, and computational studies demonstrate that the C-centered chirality from the chiral pyrrolidine group exerts a small but non-negligible influence on the preferred stereochemistry at Ru (and N in the case of (R)-2-methylpyrrolidine) that is reflected in the equilibrium distribution of diastereomers of these Ru complexes in solution. Our data show that the N- and Ru-based stereogenic centers in this class of compounds are stereochemically labile and the mechanisms for epimerization are discussed. Inversion at the Ru center in the dearomatized complexes is proposed to occur via a rearomatized Ru(0) intermediate in which the Ru-bound hydride is transferred to the ligand. Support for this comes from the spectroscopic characterization of a closely related Ru(0) species that is obtained by reaction with CO. Testing these catalysts in enantioselective oxa-Michael addition or transfer hydrogenation led to racemic products, while a low ee (8%) was observed in the hydrogenation of 4-fluoroacetophenone. The lack of appreciable enantioinduction with these catalysts is ascribed to the kinetic lability of the Ru stereocenter, which results in the formation of equilibrium mixtures in which several diastereomers of the catalyst are present.</p