E-cadherin interactions are required for Langerhans cell differentiation

Human skin contains the following two distinct DC subsets: (i) Langerhans cells (LCs), expressing Langerin but not DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), are predominantly localized in the epidermis; and (ii) dermal DCs, expressing DC-SIGN but not Langerin, are observed mainly in the dermis. It is not known whether localization in the epidermis provides cues for LC differentiation. Here, we show that E-cadherin expressed by epidermal keratinocytes (KCs) is crucial for differentiation of LCs. Monocytes differentiated into LC-like cells in presence of IL-4, GM-CSF, and TGF-β1. However, these LC-like cells expressed not only Langerin but also DC-SIGN. Notably, co-culturing of these LC-like cells with KCs expressing E-cadherin or recombinant E-cadherin strongly decreased expression of DC-SIGN and further induced a phenotype similar to purified epidermal LCs. Moreover, pretreatment of LC-like cells with anti-E-cadherin-specific antibody completely abolished their Langerin expression, indicating the requirement of E-cadherin-E-cadherin interactions for the differentiation into Langerin(+) cells. These findings suggest that E-cadherin expressed by KCs provide environmental cues that induce differentiation of LCs in the epidermi

Adjuvant Activities in Production of Reaginic Antibody by Bacterial Cell Wall Peptidoglycan or Synthetic N-Acetylmuramyl Dipeptides in Mice

This paper is concerned with the adjuvant activity in stimulatory immunoglobulin E production against ovalbumin (OA) by bacterial cell walls, cell wall peptidoglycan (PG), and their PG fragments and synthetic N-acetylmuramyl (MurNAc) dipeptides in A/J mice. A PG isolated from Streptococcus pyogenes, PG subunit polymer and dimer obtained from Staphylococcus epidermidis, and water-soluble fragments of cell walls or PG prepared from Nocardia corynebacteriodes and Streptomyces gardneri were found to enhance both the primary and secondary responses of anti-OA immunoglobulin E antibody production. It was suggested that the PG portion, either intact or highly degraded, was capable of enhancing the immunoglobulin E antibody production, and there was no need for the non-PG moiety or intactness of PG structure for the adjuvant activity. This finding was confirmed and extended by the use of synthetic MurNAc dipeptides. Among eight MurNAc dipeptides tested, MurNAc-l-Ala-d-isoGln, MurNAc-l-Ala-d-Gln, MurNAc-l-Ala-d-Glu, and MurNAc-l-Ser-d-isoGln were found active as an adjuvant in the stimulation of the primary and secondary reaginic anti-OA antibody production in a similar way to the cell wall PG and their fragments. None of the synthetic MurNAc-l-Ala-l-isoGln, MurNAc-l-Ala-l-Gln, MurNAc-l-Ala-l-Glu, and MurNAc-l-Ala-d-isoAsn, on the other hand, stimulated the anti-OA immunoglobulin E antibody production in either primary or secondary response, indicating the importance for the adjuvancy in immunoglobulin E production of the configuration of the glutamic acid residues adjacent to the l-Ala (or l-Ser) in muramyl dipeptides

Solid Pseudopapillary Neoplasm of the Pancreas with High-Grade Malignant Transformation Involving p16-RB Pathway Alterations

Solid pseudopapillary neoplasm (SPN) of the pancreas has generally been regarded as a low-grade malignant tumour that preferentially develops in young women and can have a good prognosis with surgery. Among the few patients who have died from metastatic SPN are mostly those whose tumours harbour an undifferentiated component characterized by diffuse sheets of cells with increased nuclear atypia and proliferative index. We herein report a case of an aggressive, fatal, solid pseudopapillary neoplasm (SPN) of the pancreas in a 63-year-old woman complaining of epigastric pain. Despite having undergone surgical resection for a 10 cm pancreatic mass and multiple liver metastases, the patient later died due to uncontrollable metastases 36 months after the initial surgery. Histological examination showed that the tumour displayed unusual high-grade malignant features, showing diffuse sheets of cells with increased nuclear atypia and proliferative activity, along with conventional low-grade malignant features. The tumour was subsequently recognized as an SPN with foci of high-grade malignant transformation according to the 2010 World Health Organization classification. Immunohistochemical studies revealed that p16-RB pathway alterations contributed to the high-grade malignant transformation. The present case report suggests the necessity for developing diagnostic and treatment methods targeting p16 and RB for high-grade variants of SPN