Skin-homing cytotoxic T cells contribute to an imbalanced inflammatory response in the dermis of crusted scabies lesional skin. This, in combination with the lack of B cells, is contributing to the failure of the skin immune system to mount an effective response resulting in uncontrolled growth of the parasite.
The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute posttraumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in "cation-free" solution and blocked by the nonspecific Cl Ϫ channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP--S. Notably, S1P 3 receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P 3 Ϫ/Ϫ mice, whereas in control S1P 1 floxed (S1P 1 fl/fl ) mice and mice with a nociceptor-specific deletion of S1P 1 Ϫ/Ϫ receptor (SNS-S1P 1 Ϫ/Ϫ ), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-proteindependent activation of an excitatory Cl Ϫ conductance that is largely mediated by S1P 3 receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain.
Gamma-aminobutyric acid (GABA) containing neurons were characterized in human association cortex by a combination of Golgi impregnation and immunohistochemistry. Neurons were Golgi impregnated, gold toned, drawn and then classified on the basis of their dendritic and axonal arborization in layers I-VI. An antiserum to GABA was used to determine which of the impregnated neurons were immunopositive. Twenty-four GABA-positive cells were Golgi impregnated: 7 were bitufted with their dendrites predominantly radially oriented, and 17 were multipolar stellate cells. Three of the multipolar cells with large somata in the deep layers showed dendritic patterns similar to previously described basket cells. Nine of the multipolar stellate cells in layers III-VI showed characteristics of 'neurogliaform' neurons (Ramón y Cajal, 1899). The somata and the dendritic field of these cells were spherical, with diameters of about 10-15 microns and 200 microns, respectively. Their dendrites were smooth and slightly beaded. The axon collaterals were densely distributed in and around the dendritic field, in a spherical area with a diameter of at least 300 microns. The thin axon collaterals had only occasional 'en passant' swellings. Contacts between the axons of neurogliaform cells and the distal dendrites of Golgi-impregnated pyramidal cells were observed. Electron microscopic immunocytochemistry revealed that GABA immunopositive nerve terminals formed symmetric synaptic contacts with somata, with GABA immunonegative and immunopositive dendritic shafts and with dendritic spines. The results show that GABAergic neurons are heterogeneous with respect to their dendritic and axonal patterns. In addition to the chandelier and basket cells, which have been shown in animal studies to contain GABA, other cell types, most prominently the neurogliaform cells, terminating on the distal parts of neurons, also contain GABA and may have a inhibitory function. Many of the GABAergic terminals make synapses on dendritic spines and shafts in the human cerebral cortex.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.