SummaryCentral nervous system (CNS) immune privilege is an experimentally defined phenomenon. Tissues that are rapidly rejected by the immune system when grafted in sites, such as the skin, show prolonged survival when grafted into the CNS. Initially, CNS immune privilege was construed as CNS isolation from the immune system by the blood-brain barrier (BBB), the lack of draining lymphatics, and the apparent immunoincompetence of microglia, the resident CNS macrophage. CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounter with CNS antigens. Recent data have dramatically altered this viewpoint by revealing that the CNS is neither isolated nor passive in its interactions with the immune system. Peripheral immune cells can cross the intact BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses, and microglia are immunocompetent but differ from other macrophage/dendritic cells in their ability to direct neuroprotective lymphocyte responses. This newer view of CNS immune privilege is opening the door for therapies designed to harness autoreactive lymphocyte responses and also implies (i) that CNS autoimmune diseases (i.e. multiple sclerosis) may result as much from neuronal and/or glial dysfunction as from immune system dysfunctions and (ii) that the severe neuronal and glial dysfunction associated with neurodegenerative disorders (i.e. Alzheimer's disease) likely alters CNSspecific regulation of lymphocyte responses affecting the utility of immune-based therapies (i.e. vaccines).
Microglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimer's disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA Ò to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells-2 (TREM-2) was among the mRNAs identified as being expressed by unactivated microglia, but down-regulated by lipopolysaccharide/interferon c. In the healthy CNS, not all microglia expressed TREM-2. Microglial expression of TREM-2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood-brain barrier had the lowest percentages of TREM-2-expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM-2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) Tissue-specific inflammation is dependent on more than simply the presence of an antigen within a tissue and an immune response mounted against that antigen. The onset, progression and termination of inflammatory responses are largely dependent on how the resident tissue macrophage/ dendritic cell interacts with both stromal tissue and tissueinfiltrating immune cells (Medzhitov and Janeway 1998;Lo et al. 1999). These interactions can shape antigen-independent and antigen-dependent immune responses toward the production of toxic molecules capable of destroying not only pathogens but also the tissues themselves. Such events have been argued to contribute to catastrophic neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and stroke (Kreutzberg 1996;Stoll and Jander 1999;Becher et al. 2000;Streit 2000;Aloisi 2001;Schwab et al. 2001;Campanella et al. 2002;Togo et al. 2002). Antigen presentation within the CNS by either microglia and/or CNS-infiltrating macrophages/dendritic cells may also mute and may potentially redirect antigen-specific immune responses toward the production of trophic factors (Ford et al. 1996;Raivich et al. 1998;Carson et al. 1999a;Kerschensteiner et al. 1999;Serpe et al. 1999). Such interactions have been suggested to contribute to the generation of immunological privilege and promotion of neuronal survival in the CNS (Schwartz et al. 1999;Streit 2000).The tissue macrophages of the brain are the microglia (Kreutzberg 1996;Streit 2000;Aloisi 2001). They are found in all brain regions, often in close apposition with neurons, and comprise between 5 and 15% of cells in the CNS. Abbreviations used: BBB, blood-brain barrier; Ct, cycle threshold; IRG, interferon response gene; IFN, interferon; LPS, lipolysaccharide; MHC, major histocompatibility complex; SSC, saline sodium citrate buffer; svTREM-2b, splice variant of triggerin...
The heartworm Dirofilaria immitis is an important parasite of dogs. Transmitted by mosquitoes in warmer climatic zones, it is spreading across southern Europe and the Americas at an alarming pace. There is no vaccine, and chemotherapy is prone to complications. To learn more about this parasite, we have sequenced the genomes of D. immitis and its endosymbiont Wolbachia. We predict 10,179 protein coding genes in the 84.2 Mb of the nuclear genome, and 823 genes in the 0.9-Mb Wolbachia genome. The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States. The differential presence of anabolic pathways such as heme and nucleotide biosynthesis hints at the intricate metabolic interrelationship between the heartworm and Wolbachia. Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates. This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness.—Godel, C., Kumar, S., Koutsovoulos, G., Ludin, P., Nilsson, D., Comandatore, F., Wrobel, N., Thompson, M., Schmid, C. D., Goto, S., Bringaud, F., Wolstenholme, A., Bandi, C., Epe, C., Kaminsky, R., Blaxter, M., Mäser, P. The genome of the heartworm, Dirofilaria immitis, reveals drug and vaccine targets.
Sensorineural hearing loss is a common and currently irreversible disorder, because mammalian hair cells (HCs) do not regenerate and current stem cell and gene delivery protocols result only in immature HC-like cells. Importantly, although the transcriptional regulators of embryonic HC development have been described, little is known about the postnatal regulators of maturating HCs. Here we apply a cell type-specific functional genomic analysis to the transcriptomes of auditory and vestibular sensory epithelia from early postnatal mice. We identify RFX transcription factors as essential and evolutionarily conserved regulators of the HC-specific transcriptomes, and detect Rfx1,2,3,5 and 7 in the developing HCs. To understand the role of RFX in hearing, we generate Rfx1/3 conditional knockout mice. We show that these mice are deaf secondary to rapid loss of initially well-formed outer HCs. These data identify an essential role for RFX in hearing and survival of the terminally differentiating outer HCs.
Mice heterozygously deficient in the p0 gene (P0+/−) are animal models for some forms of inherited neuropathies. They display a progressive demyelinating phenotype in motor nerves, accompanied by mild infiltration of lymphocytes and increase in macrophages. We have shown previously that the T lymphocytes are instrumental in the demyelination process. This study addresses the functional role of the macrophage in this monogenic myelin disorder.In motor nerves of P0+/− mice, the number of macrophages in demyelinated peripheral nerves was increased by a factor of five when compared with motor nerves of wild-type mice. Immunoelectron microscopy, using a specific marker for mouse macrophages, displayed macrophages not only in the endoneurium of the myelin mutants, but also within endoneurial tubes, suggesting an active role in demyelination. To elucidate the roles of the macrophages, we crossbred the myelin mutants with a spontaneous mouse mutant deficient in macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe. These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.
Two different macrophage populations contribute to CNS neuroinflammation: CNS-resident microglia and CNS-infiltrating peripheral macrophages. Markers distinguishing these two populations in tissue sections have not been identified. Therefore, we compared gene expression between LPS (lipopolysaccharide)/interferon (IFN)γ-treated microglia from neonatal mixed glial cultures and similarly treated peritoneal macrophages. Fifteen molecules were identified by quantative PCR (qPCR) as being enriched from 2-fold to 250-fold in cultured neonatal microglia when compared with peritoneal macrophages. Only three of these molecules (C1qA, Trem2, and CXCL14) were found by qPCR to be also enriched in adult microglia isolated from LPS/IFNγ-injected CNS when compared with infiltrating peripheral macrophages from the same CNS. The discrepancy between the in vitro and in vivo qPCR data sets was primarily because of induced expression of the ‘microglial’ molecules (such as the tolerance associated transcript, Tmem176b) in CNS-infiltrating macrophages. Bioinformatic analysis of the ∼19000 mRNAs detected by TOGA gene profiling confirmed that LPS/IFNγ-activated microglia isolated from adult CNS displayed greater similarity in total gene expression to CNS-infiltrating macrophages than to microglia isolated from unmanipulated healthy adult CNS. In situ hybridization analysis revealed that nearly all microglia expressed high levels of C1qA, while subsets of microglia expressed Trem2 and CXCL14. Expression of C1qA and Trem2 was limited to microglia, while large numbers of GABA+ neurons expressed CXCL14. These data suggest that (i) CNS-resident microglia are heterogeneous and thus a universal microglia-specific marker may not exist; (ii) the CNS micro-environment plays significant roles in determining the phenotypes of both CNS-resident microglia and CNS-infiltrating macrophages; (iii) the CNS microenvironment may contribute to immune privilege by inducing macrophage expression of anti-inflammatory molecules.
The adhesive cell surface molecule P 0 is the most abundant glycoprotein in peripheral nerve myelin and fulfills pivotal functions during myelin formation and maintenance. Mutations in the corresponding gene cause hereditary demyelinating neuropathies. In mice heterozygously deficient in P 0 (P 0 ϩ/Ϫ mice), an established animal model for a subtype of hereditary neuropathies, T-lymphocytes are present in the demyelinating nerves. To monitor the possible involvement of the immune system in myelin pathology, we cross-bred P 0 ϩ/Ϫ mice with null mutants for the recombination activating gene 1 (RAG-1) or with mice deficient in the T-cell receptor ␣-subunit. We found that in P 0 ϩ/Ϫ mice myelin degeneration and impairment of nerve conduction properties is less severe when the immune system is deficient. Moreover, isolated T-lymphocytes from P 0 ϩ/Ϫ mice show enhanced reactivity to myelin components of the peripheral nerve, such as P 0 , P 2 , and myelin basic protein. We hypothesize that autoreactive immune cells can significantly foster the demyelinating phenotype of mice with a primarily genetically based peripheral neuropathy.
The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection of eukaryotic POL II promoters, experimentally defined by a transcription start site (TSS). Access to promoter sequences is provided by pointers to positions in the corresponding genomes. Promoter evidence comes from conventional TSS mapping experiments for individual genes, or, starting from release 73, from mass genome annotation projects. Subsets of promoter sequences with customized 5′ and 3′ extensions can be downloaded from the EPD website. The focus of current development efforts is to reach complete promoter coverage for important model organisms as soon as possible. To speed up this process, a new class of preliminary promoter entries has been introduced as of release 83, which requires less stringent admission criteria. As part of a continuous integration process, new web-based interfaces have been developed, which allow joint analysis of promoter sequences with other bioinformatics resources developed by our group, in particular programs offered by the Signal Search Analysis Server, and gene expression data stored in the CleanEx database. EPD can be accessed at .
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