In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

Systemic inflammation enhances stimulant-induced striatal dopamine elevation.

Changes in the mesolimbic dopamine (DA) system are implicated in a range of neuropsychiatric conditions including addiction, depression and schizophrenia. Dysfunction of the neuroimmune system is often comorbid with such conditions and affects similar areas of the brain. The goal of this study was to use positron emission tomography with the dopamine D2 antagonist tracer, 11C-raclopride, to explore the effect of acute immune activation on striatal DA levels. DA transmission was modulated by an oral methylphenidate (MP) challenge in order to reliably elicit DA elevation. Elevation in DA concentration due to MP was estimated via change in 11C-raclopride binding potential from the baseline scan. Prior to the post-MP scan, subjects were pre-treated with either the immune activator lipopolysaccharide (LPS) or placebo (PBO) in a cross-over design. Immune activation was confirmed by measuring tumor necrosis factor alpha (TNFα), interleukin (IL)-6 and IL-8 concentration in plasma. Eight healthy subjects were scanned four times each to determine the MP-induced DA elevation under both LPS and PBO pre-treatment conditions. MP-induced DA elevation in the striatum was significantly greater (P<0.01) after LPS pre-treatment compared to PBO pre-treatment. Seven of eight subjects responded similarly. This effect was observed in the caudate and putamen (P<0.02), but was not present in ventral striatum. DA elevation induced by MP was significantly greater when subjects were pre-treated with LPS compared to PBO. The amplification of stimulant-induced DA signaling in the presence of systemic inflammation may have important implications for our understanding of addiction and other diseases of DA dysfunction.

Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis.

We conducted a meta-analysis of randomized, placebo-controlled trials of omega-3 fatty acid (FA) treatment of major depressive disorder (MDD) in order to determine efficacy and to examine sources of heterogeneity between trials. PubMed (1965-May 2010) was searched for randomized, placebo-controlled trials of omega-3 FAs for MDD. Our primary outcome measure was standardized mean difference in a clinical measure of depression severity. In stratified meta-analysis, we examined the effects of trial duration, trial methodological quality, baseline depression severity, diagnostic indication, dose of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in omega-3 preparations, and whether omega-3 FA was given as monotherapy or augmentation. In 13 randomized, placebo-controlled trials examining the efficacy of omega-3 FAs involving 731 participants, meta-analysis demonstrated no significant benefit of omega-3 FA treatment compared with placebo (standard mean difference (SMD)=0.11, 95% confidence interval (CI): -0.04, 0.26). Meta-analysis demonstrated significant heterogeneity and publication bias. Nearly all evidence of omega-3 benefit was removed after adjusting for publication bias using the trim-and-fill method (SMD=0.01, 95% CI: -0.13, 0.15). Secondary analyses suggested a trend toward increased efficacy of omega-3 FAs in trials of lower methodological quality, trials of shorter duration, trials which utilized completers rather than intention-to-treat analysis, and trials in which study participants had greater baseline depression severity. Current published trials suggest a small, non-significant benefit of omega-3 FAs for major depression. Nearly all of the treatment efficacy observed in the published literature may be attributable to publication bias.

Neurotrophin and Trk neurotrophin receptors in the inner ear of Salmo salar and Salmo trutta.

Neurotrophins (NTs) and their signal transducing Trk receptors play a critical role in the development and maintenance of specific neuronal populations in the nervous system of higher vertebrates. They are responsible for the innervation of the inner ear cochlear and vestibular sensory epithelia. Neurotrophins and Trks are also present in teleosts but their distribution in the inner ear is unknown. Thus, in the present study, we used Western-blot analysis and immunohistochemistry to investigate the expression and cell localization of both NTs and Trk receptors in the inner ear of alevins of Salmo salar and Salmo trutta. Western-blot analysis revealed the occurrence of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor (NGF), as well as all three Trk receptors, i.e. TrkA, TrkB and TrkC, the estimated molecular weights of which were similar to those expected for mammals. Specific immunoreactivity for neurotrophins was detected mainly in the sensory epithelia. In particular, BDNF immunoreactivity was found in the maculae of the utricle and saccule, whereas NT-3 immunoreactivity was present in the sensory epithelium of the cristae ampullaris. As a rule the sensory epithelia of the inner ear lacked immunoreactivity for Trks, thus excluding possible mechanisms of autocrinia and/or paracrinia. By contrast, overlapping subpopulations of neurons in the statoacoustic ganglion expressed TrkA (about 15%), TrkB (about 65%) and TrkC (about 45%). The present results demonstrate that, as in mammals and birds, the inner ear of teleosts expresses the components of the neurotrophin-Trk system, but their roles remain to be elucidated.

St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response.

Both the prototypic tricyclic antidepressant imipramine (IMI) and the herbal product St John's wort (SJW) can be effective in the treatment of major depressive disorder. We studied hypothalamic gene expression in rats treated with SJW or IMI to test the hypothesis that chronic antidepressant treatment by various classes of drugs results in shared patterns of gene expression that may underlie their therapeutic effects. Individual hypothalami were hybridized to individual Affymetrix chips; we studied three arrays per group treatment. We constructed 95% confidence intervals for expression fold change for genes present in at least one treatment condition and we considered genes to be differentially expressed if they had a confidence interval excluding 1 (or -1) and had absolute difference in expression value of 10 or greater. SJW treatment differentially regulated 66 genes and expression sequence tags (ESTs) and IMI treatment differentially regulated 74 genes and ESTs. We found six common transcripts in response to both treatments. The likelihood of this occurring by chance is 1.14 x 10(-23). These transcripts are relevant to two molecular machines, namely the ribosomes and microtubules, and one cellular organelle, the mitochondria. Both treatments also affected different genes that are part of the same cell function processes, such as glycolytic pathways and synaptic function. We identified single-nucleotide polymorphisms in the human orthologs of genes regulated both treatments, as those genes may be novel candidates for pharmacogenetic studies. Our data support the hypothesis that chronic antidepressant treatment by drugs of various classes may result in a common, final pathway of changes in gene expression in a discrete brain region.

Immunohistochemical localization of BDNF-, TrkB- and TrkA-like proteins in the teleost lateral line system.

The lateral line system, formed of both superficial (pit organs) and canal neuromasts, is one of the major mechanosensory systems in fish. It has always been assumed that this system depends on neurotrophins and their cognate Trk receptors for development and maintenance, as has been shown in other mechanosensitive systems of vertebrates. However, until nowthis issue has not been specifically addressed. In this study we used immunohistochemistry to investigate the occurrence and localization both of neurotrophins (NGF-, BDNF- and NT-3-like) and of Trk-like proteins (TrkA-, TrkB-, TrkC-like) in alevins of Salmo salar and S. trutta. All cells in the pit organs of S. salar displayed strong immunoreactivity for TrkB-like and BDNF-like, whereas they were restricted to the hair cells in S. trutta. The hair, supporting and mantle cells of S. salar, and the mantle cells of S. trutta, also expressed TrkA-like immunoreactivity. In the canal neuromasts BDNF-, TrkA- and TrkB-like proteins were present in all cells, without differences between species. NGF-, NT-3- and TrkC-like immunoreactivity were never detected. The present results suggest that mechanoreceptive hair cells, as well as supporting cells, in the lateral line system are under the control of the BDNF-TrkB-like complex, and probably of ligands of TrkA-like receptors.

Involvement of the NGF receptors (Trka and p75lngfr) in the development and maintenance of the thymus.

Nerve growth factor (NGF) and its main low- (p75LNGFR) and high-affinity (TrkA) receptors have been found in the vertebrate thymus, thus suggesting they are involved in the control of thymic function. However, its role in this organ is poorly known. In the present study we used combined morphological and immunohistochemical techniques to analyze the distribution of TrkA and p75LNGFR in the rat thymus, as well as the structural changes in the thymus of p75 LNGFR or TrkA deficient mice. In adult rats both TrkA and p75LNGFR were localized in a subset of thymic epithelial cells found primarily in the subcapsular and medullary thymic regions, regarded to be endodermal-derived cells. Consistently, animals with a non-functional TrkA, but not those lacking p75LNGFR, showed structural changes consisting of a decrease in the density of thymocytes, absence of cortico-medullary border, and large cysts lined of endodermal epithelium. These results strongly suggest a function of the TrkA-NGF system in thymic functions mediated by epithelial cells, as well as a role of TrkA in the development of the murine thymus. The function of p75LNGFR remains to be established.

The thymus of the hairless rhino-j (hr/rh-j) mice.

The hairless (hr) gene is expressed in a large number of tissues, primarily the skin, and a mutation in the hr gene is responsible for the typical cutaneous phenotype of hairless mice. Mutant hr mouse strains show immune defects involving especially T cells and macrophages, as well as an age-related immunodeficiency and an accelerated atrophy of the thymus. These data suggest that the hr mutation causes a defect of this organ, although hr transcripts have not been detected in fetal or adult mice thymus. The present study analyses the thymus of young (3 mo) and adult (9 mo) homozygous hr-rh-j mice (a strain of hairless mice) by means of structural techniques and immunohistochemistry to selectively identify thymic epithelial cells, dendritic cells, and macrophages. There were structural alterations in the thymus of both young and adult rh-rh-j mice, which were more severe in older animals. These alterations consisted of relative cortical atrophy, enlargement of blood vessels, proliferation of perivascular connective tissue, and the appearance of cysts. hr-rh-j mice also showed a decrease in the number of epithelial and dendritic cells, and macrophages. Taken together, present results strongly suggest degeneration and accelerated age-dependent regression of the thymus in hr-rh-j mice, which could explain at least in part the immune defects reported in hairless mouse strains.

Changes in the expression of the nerve growth factor receptors TrkA and p75LNGR in the rat thymus with ageing and increased nerve growth factor plasma levels.

The nerve growth factor (NGF) receptors p75LNGR and TrkA are expressed by thymic epithelial cells. Presumably, the NGF-TrkA system is involved in the paracrine communication between thymic epithelial cells and thymocytes, whereas the functional role of p75LNGR is still unknown. The thymus of vertebrates undergoes age-related changes that in part depend on hormonal factors. In order to find out whether thymic epithelial cells are responsive to NGF during the whole lifespan of the rat, we studied NGF receptor expression in the thymus from birth to 2 years of age, using immunohistochemistry. Furthermore, to evaluate whether increased plasma levels of NGF affected the ageing process, either NGF or 4-methylcatechol (4MC), an inductor of NGF synthesis, was administered. Both TrkA and p75LNGR were expressed by a subpopulation of thymic epithelial cells during the whole age range studied and their expression peaked at around 3 months. TrkA was primarily found in subcortical and medullary epithelial cells, whereas p75LNGR was seen in a subpopulation of medullary cells. Cortical epithelial cells, neural crest-derived cells, other stromal cells and thymocytes were not immunoreactive for NGF receptors. Neither the administration of NGF nor the increased NGF plasma levels obtained after 4MC treatment seemed to affect the ageing of the thymus as assessed by morphological and immunohistochemical criteria, but this increase in NGF levels did produce a shift in the expression of p75LNGR from epithelial cells to ED1-positive macrophages in animals of 6 months and older. Present results indicate that the expression of p75LNGR and TrkA in the rat thymus undergoes age-dependent changes that parallel those of epithelial cells. NGF could therefore be important for thymus homeostasis, possibly acting on epithelial cells. Nevertheless, NGF did not seem to be able to prevent the involution of this organ, although it produced a switch in the expression of p75LNGR, the significance of which remains to be established.

TrkA is necessary for the normal development of the murine thymus.

Nerve growth factor (NGF) and its signal-transducing receptor TrkA are expressed in the thymus. However, their possible role during thymic organogenesis is unknown. Here we analyze the thymus of trkA-kinase deficient 2-week-old mice. trkA-kinase +/+ and +/- mice had a normal thymus, whereas the thymus of trkA-kinase -/- mice showed lack of delimitation between the cortex and medulla, lower thymocyte density, and the presence of epithelial cell islands and numerous cysts lined with endodermal epithelium. The present results indicate that TrkA is necessary for the normal development of the thymus, and that its absence causes an arrest in the differentiation of endodermal epithelial cells. Whether this lack of differentiation has functional implication has yet to be determined.

Trk neurotrophin receptor-like proteins in the teleost Dicentrarchus labrax.

In recent years, data have accumulated suggesting that the role of neurotrophins and Trk receptors may not be limited to the nervous system, and the presence of these substances has been detected in a variety of vertebrate and invertebrate non-nervous tissues. This study was designed to map the expression of immunoreactivity (IR) for Trk-like proteins in alevins of the teleost Dicentrarchus labrax, with particular emphasis on non-nervous structures. We used antibodies against specific epitopes of the intracellular domain of these proteins, a region that is highly conserved in phylogeny. Trk-like IR was seen in segregate cell populations of the nervous system, and non-nervous tissues. In the central nervous system TrkA-like and TrkC-like IR was abundant, whereas TrkB-like IR was restricted to a low number of brain areas. Expression of Trk-like protein IR was observed in the peripheral nervous system and sensory organs, with the exception of the lateral line organ. Outside the nervous system, TrkA-like IR was mainly found in different epithelia, TrkB-like IR in the endocrine and digestive system, and TrkC-like IR in the cardiovascular and immune systems. The gills showed IR for all three Trk-like proteins, whereas they were absent from the gonads. Furthermore, scattered cells positive for Trk-like proteins were found in most of the investigated tissues. The distribution of Trk-like IR in this teleost is compared with that of mammals and birds, which it often paralleled, and the possible role of neurotrophins and Trk-like receptor proteins in different non-neuronal tissues is discussed.

Expression of the neurotrophin receptor TrkB in rat spleen macrophages.

Increasing evidence suggests that some members of the family of the neurotrophins could be involved in immune system functioning. Both neurotrophins and their tyrosine-kinase signal-transducing receptors, the so-called Trk receptors, have been detected in various lymphoid tissues in a number of species. Nevertheless, their cellular localisation remains unclear in most cases. In this study, we used immunohistochemical techniques to localise TrkB in the rat spleen (from 0 days to 2 years). Cells expressing TrkB-like immunoreactivity were found exclusively within the white pulp of the spleen, along the marginal zone-follicle border and inside the follicles and periarteriolar lymphoid sheaths. These cells probably represented macrophage subpopulations, since they expressed the ED3 rat macrophage antigen. No evidence of TrkB-like protein expression in lymphocytes or follicular dendritic cells could be found. Furthermore, the density of TrkB-immunoreactive cells was observed to increase with age. Although the role of TrkB ligands in these cells remains to be clarified, the present findings provide further evidence for the supposed role of neurotrophins in immune system homeostasis.

Expression of the TrkB neurotrophin receptor by thymic macrophages.

Increasing evidence suggests that some members of the neurotrophic factor family of neurotrophins could be implicated in the regulation of immune responses. Neurotrophins, as well as their tyrosine kinase signal-transducing receptors (the so-called Trk neurotrophin receptors), have been detected in different lymphoid tissues, although their cellular localization is not well known. In this study we used single and double immunohistochemistry to localize TrkB in situ in the rat thymus (in animals from 0 days to 2 years of age), in cytospin preparations of rat thymic cells, and in two mouse monocyte-macrophage cell lines (RAW 264.7 and J774A.1). We found TrkB protein expression in a subpopulation of cells in the corticomedullary junction, which simultaneously expressed the rat macrophage marker ED1. The density of TrkB-expressing cells increased with age, reaching maximal values at 2 years. Conversely, no evidence of TrkB protein expression could be found in dendritic cells, epithelial cells or thymocytes. Thymic macrophages in cytospin preparations, as well as in the mouse monocyte macrophage cell lines, also expressed TrkB protein. Although the possible function of TrkB in the thymic macrophage remains to be clarified, present findings add further evidence to the proposed role of neurotrophins in the immune system.

Neurotrophins and their receptors in the pigeon caecal tonsil. An immunohistochemical study.

Neurotrophins are growth factors which bind to signal-transducing receptors called Trk proteins. The neurotrophins and their receptor proteins are present in the mammalian and avian lymphoid organs, thus suggesting that these factors could act upon cells of the immune system. Nevertheless, little is known about the cellular distribution of neurotrophins and their receptor proteins in avian lymphoid tissues. In this study we use immunohistochemistry to detect the cellular localisation of neurotrophins and their receptor proteins in the pigeon caecal tonsil, used as a model for avian secondary lymphoid organs. Rabbit polyclonal antibodies against neurotrophins (nerve growth factor -NGF-, brain-derived neurotrophic factor -BDNF- and neurotrophin -3 NT-3-) and against specific epitopes of TrkA, TrkB and TrkC proteins were used. Cytokeratins, vimentin, S-100 protein and chromogranin A were studied in parallel to identify cells which seemed to express neurotrophins and Trk proteins. TrkA-like protein was seen in the intestinal epithelium, whereas TrkB-like and TrkC-like proteins was found in cells which we identified as dendritic cells and macrophages. BDNF-like and NT-3-like reactivity was localised in intestinal epithelial cells, especially endocrine cells. Present results add further evidence to the presumptive immune role of neurotrophins and their receptors and the possible functions of these peptides in the caecal tonsil are discussed.

Neurotrophin receptor-like protein immunoreactivity in human lymph nodes.

BACKGROUND: Trk proteins are essential constituents of the high-affinity signal-transducing neurotrophin receptors. They are expressed in a variety of non-neuronal tissues, including lymphoid organs, but their cellular localization in these remains to be established, as does the exact role of neurotrophins in the immune system. In this study we used immunohistochemical methods to analyze the cellular distribution of TrkA, TrkB, TrkC, and p75 (the low-affinity pan-neurotrophin receptor) proteins in normal human lymph nodes. METHODS: Formaldehyde-fixed, paraffin-embedded human lymph nodes were processed for indirect immunoperoxidase labelling, using antibodies against each Trk protein, human p75, and a panel of antibodies against B-lymphocytes (CD20), macrophages (MAC387), dendritic cells (S-100 protein). RESULTS: Immunoreactivity (IR) for p75 was observed in follicular dendritic cells of lymphoid follicles, and possibly in B cells. TrkA-like IR was seen in dendritic cells and also in some follicular dendritic cells, and in blood vessel walls. TrKB-like IR labelled scattered cells, mostly in the T cell zones, identified as macrophages, while specific TrkC-like IR could not be observed in immunocompetent cells. In no case was Trk-like IR seen in lymphocytes. CONCLUSIONS: These results demonstrate the occurrence of Trk-like proteins in normal human lymph nodes and describe their cellular localization, favoring the notion that neurotrophins have a physiological role in the immune system, possibly acting through accessory cells and not directly on lymphocytes.

Neurotrophin receptor-like proteins in Peyer's patches.

BACKGROUND: The neurotrophins are a family of growth factors that act on responsive cells through specific high-affinity signal-transducing receptors called Trk (A, B, and C) proteins. The neurotrophin receptor proteins are widely distributed in both nervous and nonnervous tissues, including the lymphoid organs. The expression of these receptor proteins by a cell population is an indication of responsiveness to the respective binding neurotrophin. The present study investigated the presence and cellular localization of high-affinity neurotrophin receptor proteins in equine and bovine Peyer's patches. METHODS: Peyer's patches from horse and cow intestine were fixed in Bouin's fixative, embedded in paraffin cut 10 microns thick, and studied immunohistochemically using rabbit polyclonal antibodies against specific epitopes of the intracellular domain of the Trk receptor proteins. RESULTS: Immunoreactivity (IR) for Trk-like proteins was found in specific cell populations in Peyer's patches. TrkA-IR in the horse was localized in dendritic cells of the interfollicular T-cell zones and in follicular dendritic cells of the lymphoid follicles; in the cow, TrkA-ir was present in reticulum cells. TrkB-like IR was present in cells found inside lymphoid follicles of the horse, probably reticulum cells. Furthermore, in both species, TrkB-IR was found in interstitial dendritic cells and/or macrophages of the intestinal lamina propria. No specific TrkC-like immunostaining was found in immunocompetent cells of Peyer's patches. CONCLUSIONS: Present findings demonstrate that, as in other lymphoid organs, the accessory nonlymphoid cells express immunoreactivity for high-affinity neurotrophin receptor proteins. These results seem to favor the notion that neurotrophins, especially nerve growth factor, could have a physiological role in secondary lymphoid organs, possibly acting on accessory cells and not directly on lymphocytes.

TrkA neutrophin receptor protein in the rat and human thymus.

BACKGROUND: Increasing evidence suggests that nerve growth factor (NGF), and probably other neurotrophins, are involved in the control of lymphoid organs and immunocompetent cells that express neurotrophins and/or their receptors. In the rat thymus, mRNA for TrkA (an essential component of the NGF signal transducing receptor) has been found primarily in stromal cells. The present study was undertaken to analyze the occurrence and localization of TrkA in the rat and human thymus, using Western blot and immunohistochemical techniques. METHODS: Thymuses from human fetuses (estimated gestational ages of 29 and 32 weeks) and newborns (3 and 4 weeks old), as well as from 3-month-old rats were used. Human and rat samples were fixed in buffered 10% formaldehyde, paraffin-embedded, and processed for immunohistochemistry. Moreover, rat thymus samples were processed for Western blot analysis. RESULTS: A protein band consistent with full-length TrkA (approximately 140 kDa) was detected in the rat thymus. Immunoreactivity (IR) for TrkA was exclusively found in thymic epithelial cells of both rat and human, identified because they also displayed cytokeratin IR. Interestingly, species-specific differences were noted for the expression of TrkA in different subtypes of thymic epithelial cells. Apparently, no immunolabelling was observed in other stromal cells or in lymphocytes. CONCLUSIONS: These results suggest that TrkA ligands may be involved in the control of thymic epithelial cells. This could be of potential importance because of the involvement of these cells in providing an appropriate microenvironment for maturation and selection of T lymphocytes.

Localization of Trk neurotrophin receptor-like proteins in avian primary lymphoid organs (thymus and bursa of Fabricius).

The avian thymus and bursa of Fabricius are the specific organs where the maturation and differentiation of T- and B-lymphocytes, respectively, take place. In the mammalian lymphoid organs mRNAs of the neurotrophins and their receptors have been identified but their localization at the protein level remains still unknown. This study was undertaken to analyze the localization of the Trk family of tyrosine kinase receptors in the avian primary lymphoid organs (thymus and bursa of Fabricius) during the posthatching development using immunohistochemistry. These proteins serve as essential constituents of the high affinity receptors for neurotrophins. In the thymus of all groups of age specific immunoreactivity (IR) was observed for all three Trks: TrkA-like IR was found labelling medullary epithelial cells and a subpopulation of cortical epithelial cells; TrkB-like IR was found in the medullar dendritic cells and cortical macrophages; TrkC-like IR labelled the cortical epithelial cells and scattered medullar clusters of epithelial cells (including Hassal's corpuscles). Quantitative analysis revealed age-dependent decrease in the area occupied by TrkA-like IR in the cortex, and age-dependent increase in the medulla; no changes were detected in the area occupied by TrkB-like IR; the TrkC-like immunoreactive cells increase from 7 to 30 days and then decrease. Regarding to the bursa of Fabricius, TrkA-and TrkC-like IR were exclusively found in the epithelial cells of the follicle associated and the interfollicular epithelia, as well as TrkC-like IR in some medullary reticular epithelial cells of adult animals. Nevertheless, TrkB-like IR labelled extrafollicular unidentified cells in 7 days old animals, and the follicular secretory dendritic cells at 30 and 60 post-hatching. The area occupied by the medullary TrkB-like IR cells increased between 30 and 60 days. No immunostaining of lymphocytes was observed for any of the assessed antigens. The blood vessels of both the thymus and the bursa of Fabricius were immunoreactive for TrkA- and TrkC-like proteins. The present results provide evidence for the localization of Trks in the non-lymphoid cells (epithelial and dendritic) of the avian primary lymphoid organs, suggesting a role for neurotrophins in these cells. Moreover, the selective cell localization of each Trk protein, and the absence of apparent overlapping, claims for a differential role of the specific Trk ligands. Whether or not these findings have functional relevance for T- and B-lymphocytes processing in avian primary lymphoid organs is discussed.

Distribution of neurotrophin receptors in human palatine tonsils: an immunohistochemical study.

Increasing evidence indicates that nerve growth factor (NGF) exerts effects on cells of the immune system, but the possible immunomodulatory effect of other neurotrophins (brain-derived neurotrophic factor, BDNF; neurotrophin-3, NT-3; and NT-4/5) has not been studied. Neurotrophins act on responsive cells by binding a low-affinity pan-neurotrophin receptor (p75), and more specific high-affinity receptors (gp140trkA, gp145trkB and gp145trkC considered as preferred signaling transduction receptors for NGF, BDNF and NT-3, respectively). The expression of neurotrophin receptor proteins may be considered, therefore, as a potential indication of neurotrophin activity. In the present study we investigated the distribution of both types of neurotrophin receptors in the human palatine tonsils using immunohistochemical methods. In the follicular germinal centers both lymphocytes and follicular dendritic cells (FDC) displayed gp75 IR, but not IR for trk neurotrophin receptor proteins. gp140trkA-like IR and gp145trkC-like IR were encountered on paracortical interdigitating cells (PIC), and in the high endothelial venule cells. gp145trkB-like IR was found in a cell subpopulation which probably represented macrophages. Present results suggest that NGF, NT-3 and NT-4/5 may act in PIC and indirectly in lymphocytes, whereas BDNF and NT-4/5 could control macrophages. The role of p75 on lymphocytes and FDC and whether trk neurotrophin receptor proteins present in lymphoid tissues are functional receptors for neurotrophins remains to be elucidated.

Neurotrophin receptor proteins immunoreactivity in human gastrointestinal endocrine cells.

The distribution of neurotrophin receptors (p75, trkA-, trkB-, and trkC-receptor proteins) was studied by immunohistochemistry on sections of human gastrointestinal tract mucosa from esophagus through rectum. Moreover, chromogranin A (CgA) was studied in parallel to identify endocrine cells (EC). In all of the analyzed samples there was specific immunoreactivity (IR) for trkB-receptor protein in EC, the percentage of which varied between 26 +/- 0.6% for the duodenum and 78 +/- 3% for the sigmoid colon. EC displaying trkC-receptor protein IR were also encountered, in some cases, in EC of the gastric fundus (9%), duodenum (12%), jejune (23%), and colon (12%); trkA-receptor protein IR was occasionally present labelling EC in the jejune (52%), ileum (25%), and sigmoid colon (18%); finally, p75 was in 21% of EC exclusively in one case in the ileum. In addition to EC, IR for all assessed antigens was also present in the submucous blood vessels. Our results provide evidence for the occurrence of neurotrophin receptor proteins in nonneuronal tissues and suggest that neurotrophins, especially that binding trkB receptor proteins, can regulate a subpopulation of EC cells. However, whether EC expressing different trk receptor proteins represent neurochemical subtypes of EC, and whether the identified trk receptor proteins correspond to functional receptors, remain to be elucidated.