„Black esophagus“ – zwei Obduktionsfälle mit infektiöser Beteiligung

„Black esophagus“ oder „akute Ösophagusnekrose“ (AÖN) ist eine seltene Erkrankung, die sich makroskopisch durch eine zirkumferente Schwarzverfärbung der Ösophagusmukosa mit abruptem Ende am gastroösophagealen Übergang auszeichnet. Die genaue Pathogenese ist unbekannt; es werden multifaktorielle Einflüsse wie z. B. Säurereflux, Ischämie und verringerte Schutzmechanismen der Mukosa als mögliche Ursachen diskutiert. Vorgestellt werden 2 Obduktionsfälle, die typische Befunde einer AÖN aufwiesen. Zusätzlich hatten Fall 1 eine Candida-Infektion und Fall 2 eine Appendizitis, sodass eine infektiöse Genese in beiden Fällen eine Rolle gespielt haben könnte.Black esophagus, also known as acute esophageal necrosis, is a rare disease characterized by a circumferential black discoloration of the esophageal mucosa with an abrupt stop at the gastroesophageal junction. The exact pathogenesis is unknown, but multifactorial influences, such as acid reflux, ischemia and reduced protective mechanisms of the mucosa are discussed as possible causes. Two autopsy cases are presented with typical signs of a black esophagus. The first case showed an infection with Candida albicans, the second one died of appendicitis, so in both cases an infectious genesis might have played a role

Targeting tumor-resident mast cells for effective anti-melanoma immune responses

Immune checkpoint blockade has revolutionized cancer treatment. Patients developing immune mediated adverse events, such as colitis, appear to particularly benefit from immune checkpoint inhibition. Yet, the contributing mechanisms are largely unknown. We identified a systemic LPS signature in melanoma patients with colitis following anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) checkpoint inhibitor treatment and hypothesized that intestinal microbiota-derived LPS contributes to therapeutic efficacy. Because activation of immune cells within the tumor microenvironment is considered most promising to effectively control cancer, we analyzed human and murine melanoma for known sentinels of LPS. We identified mast cells (MCs) accumulating in and around melanomas and showed that effective melanoma immune control was dependent on LPS-activated MCs recruiting tumor-infiltrating effector T cells by secretion of CXCL10. Importantly, CXCL10 was also upregulated in human melanomas with immune regression and in patients with colitis induced by anti-CTLA-4 antibody. Furthermore, we demonstrate that CXCL10 upregulation and an MC signature at the site of melanomas are biomarkers for better patient survival. These findings provide conclusive evidence for a "Trojan horse treatment strategy" in which the plasticity of cancer-resident immune cells, such as MCs, is used as a target to boost tumor immune defense

NFAT5 controls the integrity of epidermis

The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most abundant epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. Here, we studied the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress in KCs. Cultured KCs from adult mice were found to secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous members of the 'Epidermal Differentiation Complex' (EDC), such as small proline-rich (Sprr) and S100 proteins. NFAT5 and Mmp3 as well as NFAT5 and Klk7 are co-expressed in the basal KCs of fetal and adult epidermis but not in basal KCs of newborn (NB) mice. The poor NFAT5 expression in NB KCs is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of NB mice. These data suggests that, along with the fragile epidermis of adult Nfat5-/- mice, NFAT5 keeps in check the expression of matrix proteases in epidermis. The NFAT5-mediated control of matrix proteases in epidermis contributes to the manifold changes in skin development in embryos before and during birth, and to the integrity of epidermis in adults