Direct antigen presentation by a xenograft induces immunity independently of secondary lymphoid organs

The location of immune activation is controversial during acute allograft rejection and unknown in xenotransplantation. To determine where immune activation to a xenograft occurs, we examined whether splenectomized alymphoplastic mice that possess no secondary lymphoid organs can reject porcine skin xenografts. Our results show that these mice rejected their xenografts, in a T cell-dependent fashion, at the same tempo as wild-type recipients, demonstrating that xenograft rejection is not critically dependent on secondary lymphoid organs. Furthermore, we provide evidence that immune activation in the bone marrow did not take place during xenograft rejection. Importantly, immunity to xenoantigens was only induced after xenotransplantation and not by immunization with porcine spleen cells, as xenografted mutant mice developed an effector response, whereas mutant mice immunized by porcine spleen cells via i.p. injection failed to do so. Moreover, we provide evidence that antixenograft immunity occurred via direct and indirect Ag presentation, as recipient T cells could be stimulated by either donor spleen cells or recipient APCs. Thus, our data provide evidence that direct and indirect Ag presentation by a xenograft induces immunity in the absence of secondary lymphoid organs. These results have important implications for developing relevant xenotransplantation protocols.     

Interactions between central nervous system and peripheral metabolic organs

Science China Life Sciences - According to Descartes, minds and bodies are distinct kinds of “substance”, and they cannot have causal interactions. However, in neuroscience, the two-way...     

Modeling immune reactivity in secondary lymphoid organs

Models of the dynamical interactions important in generating immune reactivity have generally assumed that the immune system is a single well-stirred compartment. Here we explicitly take into account the compartmentalized nature of the immune system and show that qualitative conclusions, such as the stability of the immune steady state, depend on architectural details. We examine a simple model idiotypic network involving only two types of B cells and antibody molecules. We show, for model parameters used by De Boeret al. (1990,Chem. Eng. Sci. 45, 2375–2382), that the immune steady state is unstable in a one compartmental model but stable in a two compartment model that contains both a lymphoid organ, such as the spleen, and the circulatory system. This work was performed under the auspices of the U.S. Department of Energy.     

Asymmetries in the sense organs and central nervous system of the squid Histioteuthis

The visual system of Histioteuthis is markedly asymmetrical, in that the eyes and optic lobes are considerably larger on the left side, and the lens of the left eye is often yellower in colour than that of the right eye. At the histological level, the rhabdomes of the retinas of both eyes show the usual rectilinear pattern typical of cephalopods. Unlike other species described, however, the orientation of the pattern is not uniform over the retina. The optic lobes are well developed on both sides, again following the typical squid pattern, although the plexiform and inner granular layers are thicker on the left side. In life it is likely that the animals orient at an oblique angle with the arms downward, and the left eye pointing upwards and the right eye downwards, and the asymmetries of the visual system are probably related to this posture. No corresponding asymmetries in the statocysts or other parts of the central nervous system have, however, been detected     

Prion pathogenesis and secondary lymphoid organs (SLO)

Prion diseases are subacute neurodegenerative diseases that affect humans and a range of domestic and free-ranging animal species. These diseases are characterized by the accumulation of PrP^Sc, an abnormally folded isoform of the cellular prion protein (PrP^C), in affected tissues. The pathology during prion disease appears to occur almost exclusively within the central nervous system. The extensive neurodegeneration which occurs ultimately leads to the death of the host. An intriguing feature of the prion diseases, when compared with other protein-misfolding diseases, is their transmissibility. Following peripheral exposure, some prion diseases accumulate to high levels within lymphoid tissues. The replication of prions within lymphoid tissue has been shown to be important for the efficient spread of disease to the brain. This article describes recent progress in our understanding of the cellular mechanisms that influence the propagation of prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. A thorough understanding of these events will lead to the identification of important targets for therapeutic intervention, or alternatively, reveal additional processes that influence disease susceptibility to peripherally-acquired prion diseases.     

MAIDS resistance-associated gene expression patterns in secondary lymphoid organs

Murine acquired immunodeficiency syndrome (MAIDS) is caused by exposure to murine leukemia virus and serves as a model to study human AIDS. In MAIDS-susceptible C57BL/6 mice, virus exposure leads to progressive immune deficiency, while resistant strains such as BALB/c recover from infection and develop protective immunity. The goal of this study was to identify early gene expression patterns that may be important in establishing this strain-specific differential response. Total RNA was isolated from spleens and pooled lymph nodes of both mouse strains at 3 and 7 days post virus infection. The complementary DNA generated from this RNA was hybridized to mouse oligonucleotide DNA microarrays using a strategy that controlled for inherent variability and highlighted only virus-induced changes. Fluorescent intensities were normalized and analyzed for statistically significant differential expression between strains across both time points and lymphoid organs. The majority of the resistance-associated genes was identified at day 3 post-infection and demonstrated the highest fold differences between strains, while more susceptibility-associated sequences were seen at 7 days post-infection. Among the most highly differentially expressed sequences seen at the earlier time point were genes related to protein metabolism, especially serine proteases. Differential patterns of chemokine-related genes were observed at the later time point. The overall pattern of expression suggests strain-specific differences in proteases and chemokines within secondary lymphoid organs shortly after infection influence the likelihood of disease progression.     

Calcitonin gene-related peptide-like immunoreactivity in the central nervous system and peripheral organs of rats

The concentrations of rat calcitonin gene-related peptide-like immunoreactivity (rCGRP-LI) in various organs of male rats as well as the molecular heterogeneity of rCGRP-LI in tissue extracts was examined using a specific radioimmunoassay (RIA) for rCGRP and gel-filtration chromatography. rCGRP-LI was high in extracts of the spinal cord (202 +/- 22.6 pg/mg wet wt. of tissue; mean +/- S.E.M.) and of the thyroid (229 +/- 62.3 pg/mg). rCGRP-LI was detectable in the brainstem, hypothalamus, stomach, duedenum, pancreas and kidney. The elution pattern of the extracts on a Sephadex G-50 column showed 3 peaks of rCGRP-LI irrespective of organs and tissues. The first peak corresponded to authentic rCGRP-(1-37). The second and third rCGRP-LI peaks probably consisted of C-terminal fragments of rCGRP, because they had a lower molecular weight than rCGRP-(1-37) and because our antiserum cross-reacts with a synthetic C-terminal fragment. The ratio of 3 rCGRP-LI molecules, however, differed between neural tissue extracts and others. The main component of rCGRP-LI in neural tissue was authentic rCGRP-(1-37), while the smaller fragments of rCGRP were chiefly contained in other tissues like the stomach, pancreas and thyroid. The relative ratio of rCGRP-LI molecules with different size in respective tissue extracts was not changed after leaving the dissected tissues for 2 h at room temperature. These findings indicate that rCGRP-LI is abundantly present in the thyroid as well as the spinal cord and it is detected in lower amounts in the alimentary tract and central nervous system. rCGRP-LI in the extracts consists of 3 different components, the proportions of which vary from one tissue to another, probably reflecting tissue-specific differences in the processing of CGRP.     

Morphofunctional restructuring of the nervous system of the lymphoid organs during electrostimulation of the hypothalamus

The intramural nervous apparatus of rabbit lymphoid organs was examined after 15 and 30 sessions of electric stimulation of the posterior hypothalamus. The function of nerve cells was evaluated by cytophotometry according to the content of catecholamines and acetylcholinesterase (ACE) activity. In the mesenteric lymph nodes, stimulation led to a decrease in the activity of both adrenergic and ACE-containing nerve cells. The spleen demonstrated a reduction in the catecholamine content in the perivascular nerve plexuses, with a simultaneous rise of the catecholamine content in the fibers located in the parenchyma, which evidences inhibition of the neurogenous mechanisms of vasomotor control and possible selective activation of the sympathetic mechanisms involved in the regulation of the immunogenesis. Thymic preparations impregnated with silver salts manifested high argyrophilia of the nerve cells, characteristic of the reactive phase of the destructive process. The problems of the hypothalamic effects on the blood supply and functions of the immune system organs are discussed.     

The stromal and haematopoietic antigen-presenting cells that reside in secondary lymphoid organs

T cells encounter their cognate antigens in specialized compartments of secondary lymphoid organs (SLOs). There, dendritic cells (DCs) present self and non-self antigens to T cells, and promote immunity or tolerance depending on the availability of danger signals. Resident stromal cells orchestrate the interaction between T cells and DCs by recruiting them to T cell zones and guiding their migration within SLOs. Recent studies have shown that SLO-resident stromal cells also have a crucial role in tolerance induction in the periphery. In this Review, we discuss the roles of SLO-resident DCs and stromal cells in shaping T cell responses.     

Developmental study of tripeptidyl peptidase I activity in the mouse central nervous system and peripheral organs

Tripeptidyl peptidase I (TPPI) — a lysosomal serine protease — is encoded by the CLN2 gene, mutations that cause late-infantile neuronal ceroid lipofuscinosis (LINCL) connected with profound neuronal loss, severe clinical symptoms and early death at puberty. Developmental studies of TPPI activity levels and distribution have been done in the human and rat central nervous systems (CNS) and visceral organs. Similar studies have not been performed in mouse. In this paper, we follow up on the developmental changes in the enzyme activity and localization pattern in the CNS and visceral organs of mouse over the main periods of life — embryonic, neonate, suckling, infantile, juvenile, adult and aged — using biochemical assays and enzyme histochemistry. In the studied peripheral organs (liver, kidney, spleen, pancreas and lung) TPPI is present at birth but further its pattern is not consistent in different organs over different life periods. TPPI activity starts to be expressed in the brain at the 10th embryonic day but in most neuronal types it appears at the early infantile period, increases during infancy, reaches high activity levels in the juvenile period and is highest in adult and aged animals. Thus, in mice TPPI activity becomes crucial for the neuronal functions later in development (juvenile period) than in humans and does not decrease with aging. These results are essential as a basis for comparison between normal and pathological TPPI patterns in mice. They can be valuable in view of the use of animal models for studying LINCL and other neurodegenerative disorders.     

Differential regulation of primary and secondary CD8+ T cells in the central nervous system

T cell accumulation and effector function following CNS infection is limited by a paucity of Ag presentation and inhibitory factors characteristic of the CNS environment. Differential susceptibilities of primary and recall CD8+ T cell responses to the inhibitory CNS environment were monitored in naive and CD8+ T cell-immune mice challenged with a neurotropic coronavirus. Accelerated virus clearance and limited spread in immunized mice was associated with a rapid and increased CNS influx of virus-specific secondary CD8+ T cells. CNS-derived secondary CD8+ T cells exhibited increased cytolytic activity and IFN-gamma expression per cell compared with primary CD8+ T cells. However, both Ag-specific primary and secondary CD8+ T cells demonstrated similar contraction rates. Thus, CNS persistence of increased numbers of secondary CD8+ T cells reflected differences in the initial pool size during peak inflammation rather than enhanced survival. Unlike primary CD8+ T cells, persisting secondary CD8+ T cells retained ex vivo cytolytic activity and expressed high levels of IFN-gamma following Ag stimulation. However, both primary and secondary CD8+ T cells exhibited reduced capacity to produce TNF-alpha, differentiating them from effector memory T cells. Activation of primary and secondary CD8+ T cells in the same host using adoptive transfers confirmed similar survival, but enhanced and prolonged effector function of secondary CD8+ T cells in the CNS. These data suggest that an instructional program intrinsic to T cell differentiation, rather than Ag load or factors in the inflamed CNS, prominently regulate CD8+ T cell function.     

Studies on autoimmune encephalomyelitis in the guinea pig--III. A comparative study of two autoantigens of central nervous system myelin.

Abstract— A new CNS myelin autoantigen(s) (referred to as M2), different from the encephalitogenic basic protein (BP), can be detected with guinea-pig demyelinating and complement fixing (CF) sera raised against guinea pig CNS tissue or myelin (Lebar et al., 1976). M2 and BP were present in mouse, rat, rabbit, bovine and human CNS tissues when tested with guinea-pig homologous specific antisera; they were not present in non-CNS tissues. Both autoantigens were also detected in newborn guinea-pig myelin and myelin-like fractions. The CF activity of myelin with demyelinating (anti-M2) sera was not altered by trypsin; however, absorption experiments showed that M2 was partly trypsin sensitive. Both antibodies against the trypsin sensitive and the trypsin resistant determinants of M2 were demyelinating. Both determinants of M2 were preselit in mouse, rat, rabbit, bovine‘and human CNS tissues and in guinea-pig newborn myelin. CF BP activity of myelin was partially or even totally abolished by trypsin, but the persistent encephali-togenicity of trypsin-treated myelin could be attributed to non-CF encephalitogenic peptides from BP. In accordance with recent work our results tend to support an inner localization of BP in myelin; M2, on the other hand, would be a surface antigen(s).     

Erythropoietin processing in erythropoietic system and central nervous system

We describe possible functions of carbohydrates attached to growth factors and strategies to examine the functions, concentrating on erythropoietin, a major regulator of erythropoiesis. Erythropoietin in erythropoiesis functions as an endocrine hormone; it is produced by kidney cells and transferred into the circulation to hemopoietic sites. In the brain, erythropoietin acts on neurons in a paracrine fashion. Comparison of glycosylation has been made between kidney and brain erythropoietins.Abbreviations BHK Baby Hamster Kidney - Epo Erythropoietin - Epo-R erythropoietin receptor     

中枢神经系统谷氨酸转运体的研究进展

在中枢神经系统,谷氨酸转运体在谷氨酸一谷氨酰胺循环中发挥着重要作用。谷氨酸转运体有高亲和力转运体,即兴奋性氨基酸转运体（excitatory amino acid transporters,EAATs）和低亲和力转运体,即囊泡谷氨酸转运体（vesicular glutamate transporters,VGLUTs）两种类型。其中,VGLUTs的功能是特异地将突触囊泡外的谷氨酸转运进入突触囊泡内,它包括三个成员,分别是VGLUT1、VGLUT2和VGLUT3。一方面,VGLUT1和VGLUT2标记了所有的谷氨酸能神经元,是谷氦酸能神经元和它们轴突末端高度特异的标志;另一方面,VGLUT1标志着皮质一皮质投射,而VGLUT2则标志着丘脑一皮层投射,VGLUT3则位于抑制性突触末端。     

Emergence in the central nervous system

“Emergence” is an idea that has received much attention in consciousness literature, but it is difficult to find characterizations of that concept which are both specific and useful. I will precisely define and characterize a type of epistemic (“weak”) emergence and show that it is a property of some neural circuits throughout the CNS, on micro-, meso- and macroscopic levels. I will argue that possession of this property can result in profoundly altered neural dynamics on multiple levels in cortex and other systems. I will first describe emergent neural entities (ENEs) abstractly. I will then show how ENEs function specifically and concretely, and demonstrate some implications of this type of emergence for the CNS.     

Insulin and the central nervous system

Data from literature concerning the neurobiological, electrical and metabolic effects of insulin are reviewed. Emphasis is laid on insulin distribution in the CNS, on distribution and localization of the insulin brain receptors, on insulin transport through the hemato-encephalic barrier. Data concerning insulin effect on the electrical activity of various CNS neurons, particularly, on those of the feeding and satiety centres. The effects of insulin on the brain metabolism are discussed. Insulin shares many properties with the nerve growth factor and may be considered as specific neurotransmitter and neuromodulator.     

Ergothioneine and central nervous system diseases

Neurochemical Research - Ergothioneine (ERGO) is a thiol contained in the food that exhibits an excellent antioxidant effect similar to that of glutathione. Although mammals lack a biosynthetic...