Detailed mapping of CGRP mRNA expression in the rat central nervous system: Comparison with previous immunocytochemical findings

The localization of CGRP mRNA in neurons of the rat brain and spinal cord was assessed by in situ hybridization histochemistry (ISH) using a radiolabeled synthetic 57-mer oiigodeoxynucleotide probe complementary to the rat prepro CGRP mRNA. Results were compared with previously published findings of CGRP-immunoreactive (CGRP-IR) cell bodies revealed by an indirect immunofluorescence technique. The highest numbers of CGRP mRNA expressing neurons as well as the greatest intensity of staining were found in the lateral hypothalamic area, the parabrachial nuclei, and among the cranial motor nuclei, especially in the nuclei of the 7th and 12th nerve and the ambiguus nucleus, which is generally in good agreement with findings assessed by immunocytochemistry (ICH). However, some mismatches between the localizaton of the peptide by ICH and the localization of the CGRP mRNA were also observed. Thus, ISH was not able to confirm CGRP-IR in cells of the amygdaloid complex and parts of the medial hypothalamus, the central gray, and the inferior colliculus, but ISH revealed considerably more CGRP mRNA expressing cells in the lateral hypothalamic area, arcuate nucleus, posterior and peripeduncular thalamic nuclei, and all cranial motor nuclei than CGRP-IR containing cells found by ICH. Moreover, ISH also revealed CGRP mRNA synthesis in the nucleus of the lateral olfactory tract and in the perihypoglossal nuclei that were devoid of CGRP-IR. The reasons for the observed mismatches still remain to be elucidated; however, intracerebroventricular colchicine pretreatment used to increase immunocytochemical signals also might have induced or suppressed gene expression in certain brain regions in an unpredictable matter. On the other hand, detection of only the mRNA in a certain region does not necessarily mean that also the active peptide is synthesized there.     

Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia.

BACKGROUND: Metabotropic glutamate receptors (mGlus) may be involved in the pathophysiology of schizophrenia. Group II mGlus (mGlu2 and mGlu3) have attracted considerable interest since the development of potent specific agonists that exhibit atypical antipsychotic-like activity and reports of a genetic association between the mGlu3 gene and schizophrenia. METHODS: In this postmortem study, mGlu3 protein levels in Brodmann area 10 of prefrontal cortex from schizophrenic (n = 20) and control (n = 35) subjects were analyzed by western immunoblotting using a novel specific mGlu3 antibody and an antibody for the vesicular glutamate transporter 1 (VGluT1). RESULTS: We report a significant decrease in the dimeric/oligomeric forms of mGlu3 in schizophrenic patients compared with control subjects, whereas total mGlu3 and VGluT1 levels were not altered significantly. CONCLUSIONS: This is the first experimental evidence that mGlu3 receptor levels are altered in schizophrenia and supports the hypothesis that neurotransmission involving this particular excitatory amino acid receptor is impaired in schizophrenia.     

T-Cell receptor αβ and γδ T cells in rat and human skin — are they equivalent?

In the not-so-distant past the skin was generally viewed as a passive target for immune-mediated injury. Over the last decade, however, concepts of a previously unrecognized role for the skin have unfolded, whereby resident bone marrow-derived leukocytes (e.g. Langerhans cells and T cells) initiate and regulate the immune responses that protect it. Their combination with other immunomodulatory resident cells (e.g. keratinocytes, melanocytes, endothelial cells, fibroblasts) led to the idea that the skin may function as a self-sustaining lymphoid tissue. Although T lymphocytes or, at least, certain subpopulations thereof have the general propensity to populate epithelial tissues, there exist major species differences regarding the phenotype of intraepidermal T cells. The purpose of this review is to fill gaps in our understanding of the relationship of rodent skin T cells to T cells identified in human skin and the normal physiologic and pathologic role(s) of these cells.     

Epidermal T lymphocytes--ontogeny, features and function.

Conclusions The murine epidermis contains a network of Thy-1⁺ dendritic T cells. These T cells arise from early fetal stem cells and differentiate in the fetal or neonatal thymic or epidermal microenvironment. Their lack of expression of CD5, CD4, and CD8 antigens, as well as their virtually exclusive expression of a CD3/TCR V3/V1 complex, distinguishes DETC from the bulk of peripheral T cells.The early appearance of TCR / cells in ontogeny, the lack of expression of CD4 and CD8 antigens, and the relative paucity of and genes compared to and genes, indicates that / T cells provide a phylogenetically primitive, broadly acting, and poorly discriminating immunologic defense system. In this system, recognition of antigen is not restricted by classical MHC class I and class II antigens, but may occur in the context of relatively nonpolymorphic restricting elements, such as Qa [82], Tla [10] or CD1 [62]. This rather primitive immune system provided by DETC may serve to protect the epidermal integrity. Upon recognition of self proteins released following epidermal injury, DETC may become activated and assist in the removal of altered cells. In this limited fashion, the epidermis may be an independently competent immunologic system. However, the fact that the TCR repertoire of DETC does not allow for the recognition of antigenic peptides in conjunction with MHC moieties excludes the possibility that the diverse immune response elicited by topical contact with foreign antigens is mediated by DETC.Whether this statement also applies to the human epidermis cannot be answered at the present time. Let us consider a few plausible concepts concerning derivation and function of human epidermal T cells. First, one could postulate that in early ontogeny, the human epidermis harbors a small, indigenous population of naive T lymphocytes with monomorphic TCR representing an analogue to murine DETC. These cells could function in a manner similar to that proposed for murine DETC. They may even persist into adult life, so far undetected because they would be outnumbered by immigrating polymorphic T cells from peripheral lymphoid organs. Second, it is conceivable that the human epidermis contains an indigenous population of naive T lymphocytes with a polymorphic TCR repertoire representing a phylogenetically advanced analogue to murine DETC. Although equipped with TCR allowing antigen recognition in the context of MHC, their density is probably too low to make them an effective host defense system against the multitude of environmental antigens presented by Langerhans cells. One could rather assume that they proliferate upon recognition of self antigens occurring in a perturbed epidermis. The autoreactivity of these cells may not necessarily be beneficial. Finally, the fact that the entry of circulating HECA-452⁺ memory cells into the skin is dependent upon the injury-induced ELAM-1 expression by endothelial cells of the dermal microvasculature could indicate that all T cells present in adult human epidermis are recruited upon alteration of the skin. Following this reasoning, the human epidermis should not be regarded as a complete, self-sustaining immunologic organ but rather as a homing site for and a target of lymphocytes antigenically sensitized in peripheral lymphoid organs.     

The MPO Study: just a European HEMO Study or something very different?

Although results from observational and epidemiological studies suggested a survival benefit associated with high-flux hemodialysis, conclusive evidence from prospective randomized clinical trials has been lacking. Both the HEMO Study in the USA and the Membrane Permeability Outcome Study (MPO Study) in Europe are randomized studies investigating the effect of high- and low-flux hemodialysis on patient outcomes, even though there were some significant differences in the design of the two studies. An earlier randomized clinical trial could not show differences on patient survival between patient groups being treated with membranes of different material and permeability, but this trial was not designed specifically to examine this particular endpoint. Based on these previous experiences, the MPO Study addressed a hemodialysis patient population which was considered to be more susceptible to the intervention with high-flux dialysis. To identify these patients with an elevated risk, low serum albumin levels were chosen as an indicator; low serum albumin is associated with malnutrition, inflammation, atherosclerosis, and with increased risk of morbidity and mortality. Together with low serum albumin, patients had to be new to dialysis to be selected for the MPO Study. These particular considerations on patient selection, together with additional methodological refinements in the study design allow the conclusion that the MPO Study is valid on its own rather than being a European version of the HEMO Study.     

NK cells – Versatile tools for viral defense and cancer treatment

About 150 NK cell researchers met at the German Cancer Research Center (DKFZ) in Heidelberg, Germany from 26–28 September 2012 for the Natural Killer Cell Symposium which was organized by the NK cell study group of the German Society for Immunology (DGfI) and sponsored by the European Journal of Immunology (EJI), the European Federation of Immunological Societies (EFIS) and the DGfI. The meeting was a forum for the discussion of the function and regulation of these fascinating innate immune cells and the opportunities for the transfer of this knowledge to cancer immunotherapy.