Central Nervous System Parenchyma Research Articles

Astrocyte-Derived CXCL10 Drives Accumulation of Antibody-Secreting Cells in the Central Nervous System during Viral Encephalomyelitis

Microbial infections of the central nervous system (CNS) are often associated with local accumulation of antibody (Ab)-secreting cells (ASC). By providing a source of Ab at the site of infection, CNS-localized ASC play a critical role in acute viral control and in preventing viral recrudescence. Following coronavirus-induced encephalomyelitis, the CNS accumulation of ASC is chemokine (C-X-C motif) receptor 3 (CXCR3) dependent. This study demonstrates that CNS-expressed CXCR3 ligand CXCL10 is the critical chemokine regulating ASC accumulation. Impaired ASC recruitment in CXCL10(-/-) but not CXCL9(-/-) mice was consistent with reduced CNS IgG and κ-light chain mRNA and virus-specific Ab. Moreover, the few ASC recruited to the CNS in CXCL10(-/-) mice were confined to the vasculature, distinct from the parenchymal localization in wild-type and CXCL9(-/-) mice. However, neither CXCL9 nor CXCL10 deficiency diminished neutralizing serum Ab, supporting a direct role for CXCL10 in ASC migration. T cell accumulation, localization, and effector functions were also not affected in either CXCL9(-/-) or CXCL10(-/-) mice, consistent with similar control of infectious virus. There was also no evidence for dysregulation of chemokines or cytokines involved in ASC regulation. The distinct roles of CXCL9 and CXCL10 in ASC accumulation rather coincided with their differential localization. While CXCL10 was predominantly expressed by astrocytes, CXCL9 expression was confined to the vasculature/perivascular spaces. These results suggest that CXCL10 is critical for two phases: recruitment of ASC to the CNS vasculature and ASC entry into the CNS parenchyma.

Regulation of Immune Cell Infiltration into the CNS by Regional Neural Inputs Explained by the Gate Theory

The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a “gateway” at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.

Secondary infiltration of the central nervous system in patients with diffuse large B-cell lymphoma

ObjectiveTo investigate the incidence and risk factors of infiltration of the central nervous system after the initial treatment of diffuse large B-cell lymphoma in patients treated at Santa Casa de Misericórdia de São Paulo. MethodsA total of 133 patients treated for diffuse large B-cell lymphoma from January 2001 to April 2008 were retrospectively analyzed in respect to the incidence and risk factors of secondary central nervous system involvement of lymphoma. Intrathecal prophylaxis was not a standard procedure for patients considered to be at risk. This analysis includes patients whether they received rituximab as first-line treatment or not. ResultsNine of 133 (6.7%) patients developed central nervous system disease after a mean observation time of 29 months. The median time to relapse or progression was 7.9 months after diagnosis and all but one patient died despite the treatment administered. Twenty-six (19.5%) patients of this cohort received rituximab as first-line treatment and nine (7.1%) received intrathecal chemoprophylaxis. Of the nine patients that relapsed, seven (77.7%) had parenchymal central nervous system involvement; seven (77.7%) had stage III or IV disease; one (11.1%) had bone marrow involvement; two (22.2%) had received intrathecal chemoprophylaxis; and 3 (33.3%) had taken rituximab. In a multivariate analysis, the risk factors for this infiltration were being male, previous use of intrathecal chemotherapy and patients that were refractory to initial treatment. ConclusionCentral nervous system infiltration in this cohort is similar to that of previous reports in the literature. As this was a small cohort with a rare event, only three risk factors were important for this infiltration

Leishmania amastigotes in the central nervous system of a naturally infected dog

A 4-year-old male Labrador Retriever dog was presented with a 10-day history of tetraplegia, depression, and absent postural reflexes. The cerebrospinal fluid was positive for Leishmania spp. DNA. At necropsy, a 2-cm long mass was observed adhered to C(7) and C(8) left spinal nerves. Microscopically, nerve fiber destruction together with mixed inflammatory infiltration was observed in the spinal nerves. Cervical spinal cord sections showed multifocal, diffuse granulomatous inflammation in the white matter. In the brain, perivascular infiltrates were observed in some areas together with subtle pallor of the parenchyma. Immunohistochemistry for Leishmania infantum confirmed the presence of amastigotes in the spinal nerves, spinal cord, brain parenchyma, and choroid plexuses. The current study describes the presence of Leishmania amastigotes in nervous tissue inciting radiculoneuritis, myelitis, and mild meningoencephalitis, suggesting a likely route by which L. infantum amastigotes reach and affect the central nervous system parenchyma.

Characterization of murine experimental autoimmune encephalomyelitis induced by active immunization with a CD8 epitope of myelin oligodendrocyte glycoprotein

Multiple sclerosis (MS) is an autoimmune, demyelinating and degenerative disease of the central nervous system (CNS). Anti-myelin CD4 T cells are strongly associated with disease development in several animal models of MS such as experimental autoimmune encephalomyelitis (EAE). However, CD8 T cells often outnumber CD4 T cells in the CNS parenchyma of MS patients and recent studies suggest that anti-myelin CD8 T cells may be also implicated. In order to better understand the contribution of pathogenic CD8 T cells, C57Bl/6 female mice were immunized with an epitope of myelin oligodendrocyte protein (MOG) specifically presented by MHC-I to CD8 T cells, as reported by Ford & Evavold in 2005. Only one third of these mice developed EAE with mild clinical signs. In contrast, mice immunized with MOG35-55 developed hindlimb paralysis, as expected for this model. Proliferation and FACS analysis of T cell reactivity using splenocytes isolated from CD8 epitope-immunized mice confirmed the emergence of specific MOG-reactive CD8 T cells in vivo. Immunohistochemical analysis of the spinal cord, cerebellum and optic nerve in mice that developed the first clinical signs indicates that CD8 T cells infiltrate the CNS white matter with a caudo-rostral gradient. Strikingly, the CD8 T cell infiltration is sparse compared with CD4 T cells. Sudan Black staining indicates myelin loss in the CNS white matter of these mice. Further characterization of the CNS T cells in this model is underway. Taken together, these data indicate that anti-myelin CD8 T cells can initiate EAE supporting an early role of CD8 T cells in MS pathogenesis. However, the development or phenotype of autoreactive T cells obtained with this immunization protocol is insufficient to trigger full EAE as compared with the classic EAE model using the CD4 (and CD8) epitope MOG35-55. Supported by Region Pays-de-la-Loire (ABN).

Junctional Adhesion Molecule (JAM)-C Deficient C57BL/6 Mice Develop a Severe Hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C−/− mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C−/− mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C−/− C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C−/− mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3rd ventricle in JAM-C−/− C57BL/6 mice. Taken together, our study suggests that JAM-C−/− C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C.

MCAM Identifies Encephalitogenic TH17 Lymphocytes and Promotes Their Recruitment to the CNS (SC02.001)

Objective: Our hypothesis is that MCAM plays an important role in CNS inflammation by promoting migration of aggressive autoreactive lymphocytes through the BBB into the CNS parenchyma. Background In multiple sclerosis (MS), encephalitogenic CD4 + lymphocytes require adhesion molecules to accumulate into central nervous system (CNS) lesions. Blocking of alpha4beta1 integrin reduces relapses but serious adverse events can arise because of the resulting CNS immunosuppression. Thus, we need to identify new molecules specifically involved in the recruitment through the BBB of highly inflammatory immune cell populations such as T H 17 lymphocytes. We identified expression of melanoma cell adhesion molecule (MCAM), a molecule that can interact with itself, on a subset of human effector memory CD4+ lymphocytes and on blood-brain barrier (BBB) endothelium. Design/Methods: Combination of ex vivo, in vitro and in situ studies using human and mouse material from healthy controls and from MS subjects and from the MS mouse model Experimental Autoimmune Encephalomyelitis (EAE). In vivo studies in EAE. Results: We demonstrate that MCAM is co-expressed by RORgamma + and IL-23Receptor + memory CD4 + lymphocytes, and that MCAM + lymphocytes express more IL-17, IL-22, GM-CSF and Granzyme B than MCAM neg lymphocytes. The proportion of MCAM + CD4 + lymphocytes is higher in the blood and in the CNS of patients affected by MS and in EAE animals, as compared to controls, and MCAM is strikingly up-regulated at the level of the BBB within lesions. Furthermore, MCAM + T H 17 lymphocytes migrate more efficiently than MCAM neg cells and MCAM blockade reduces T H 17 lymphocyte adhesion and transmigration across BBB-ECs in vitro. In vivo , MCAM depletion dampens the clinical and pathological severity of EAE and the infiltration of IL-17 + lymphocytes in the CNS of EAE animals. Conclusions: Our findings indicate that MCAM could serve as a biomarker for T H 17-dependent diseases and represents a valuable target for the treatment of T H 17-dependent CNS inflammation. Supported by: The MSSociety of Canada and the CIHR. Disclosure: Dr. Larochelle has nothing to disclose. Dr. Cayrol has nothing to disclose. Dr. Kebir has nothing to disclose. Dr. Lecuyer has nothing to disclose. Dr. Alvarez has nothing to disclose. Dr. Arbour has nothing to disclose. Dr. Prat has nothing to disclose.

Microglial physiopathology: how to explain the dual role of microglia after acute neural disorders?

Microglia are the resident macrophages of the central nervous system (CNS). In physiological conditions, resting microglia maintain tissue integrity by scanning the entire CNS parenchyma through stochastic and complex movements of their long processes to identify minor tissue alterations. In pathological conditions, over-activated microglia contribute to neuronal damage by releasing harmful substances, including inflammatory cytokines, reactive oxygen species, and proteinases, but they can provide tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. The reasons for this apparent paradox are unknown. In this paper, we first review the physiological role as well as both detrimental and beneficial actions of microglial during acute CNS disorders. Further, we discuss the possible reasons for this microglial dual role following CNS insults, considering that the final microglial phenotype is a direct consequence of both noxious and beneficial stimuli released into the extracellular space during the pathological insult. The nature of these micro-glial ligands is unknown, but we hypothesize that harmful and beneficial stimuli may be preferentially located at specific anatomical niches along the pathological environment triggering both beneficial and deleterious actions of these glial cells. According to this notion, there are no natural populations of detrimental microglia, but is the pathological environment that determines the final microglial phenotype.

Type17 T-cells in Central Nervous System Autoimmunity and Tumors

Interleukin-17 (IL-17) producing Type17 T-cells, specifically T-helper (Th)17 cells reactive to central nervous system (CNS) autoantigens, manifest a higher migratory capability to the CNS parenchyma compared with other T-cell subpopulations due to their ability to penetrate the blood brain barrier (BBB). In the field of cancer immunotherapy, there are now a number of cell therapy approaches including early studies using T-cells transduced with chimeric antigen receptors in hematologic malignancy, suggesting that the use of T-cells or genetically modified T-cells could have a significant role in effective cancer therapy. However, the successful application of this strategy in solid tumors, such as CNS tumors, requires careful consideration of critical factors to improve the tumor-homing of T-cells. The current review is dedicated to discuss recent findings on the role of Type17 T-cells in CNS autoimmunity and cancer. The insight gained from these findings may lead to the development of novel therapeutic and prophylactic strategies for CNS autoimmunity and tumors.

A Case of Central Nervous System Lymphoma Manifesting as Multiple Patchy White Matter Lesions with a Past History of Tonsil Lymphoma

Lymphoma of the central nervous system (CNS) parenchyma is known to present as a well-demarcated mass with strong and homogenous gadolinium enhancement in the periventricular and/or superficial region. We report a case of central nervous system lymphoma (CNSL) manifesting as multiple white matter lesions with non-tumorous patchy or ring-like enhancement and partial spontaneous resolution on magnetic resonance imaging (MRI). Such findings are unusual and could lead to misdiagnosis without pathological evaluation.

In vivo imaging of lymphocytes in the CNS reveals different behaviour of naïve T cells in health and autoimmunity

BackgroundTwo-photon laser scanning microscopy (TPLSM) has become a powerful tool in the visualization of immune cell dynamics and cellular communication within the complex biological networks of the inflamed central nervous system (CNS). Whereas many previous studies mainly focused on the role of effector or effector memory T cells, the role of naïve T cells as possible key players in immune regulation directly in the CNS is still highly debated.MethodsWe applied ex vivo and intravital TPLSM to investigate migratory pathways of naïve T cells in the inflamed and non-inflamed CNS. MACS-sorted naïve CD4+ T cells were either applied on healthy CNS slices or intravenously injected into RAG1 -/- mice, which were affected by experimental autoimmune encephalomyelitis (EAE). We further checked for the generation of second harmonic generation (SHG) signals produced by extracellular matrix (ECM) structures.ResultsBy applying TPLSM on living brain slices we could show that the migratory capacity of activated CD4+ T cells is not strongly influenced by antigen specificity and is independent of regulatory or effector T cell phenotype. Naïve T cells, however, cannot find sufficient migratory signals in healthy, non-inflamed CNS parenchyma since they only showed stationary behaviour in this context. This is in contrast to the high motility of naïve CD4+ T cells in lymphoid organs. We observed a highly motile migration pattern for naïve T cells as compared to effector CD4+ T cells in inflamed brain tissue of living EAE-affected mice. Interestingly, in the inflamed CNS we could detect reticular structures by their SHG signal which partially co-localises with naïve CD4+ T cell tracks.ConclusionsThe activation status rather than antigen specificity or regulatory phenotype is the central requirement for CD4+ T cell migration within healthy CNS tissue. However, under inflammatory conditions naïve CD4+ T cells can get access to CNS parenchyma and partially migrate along inflammation-induced extracellular SHG structures, which are similar to those seen in lymphoid organs. These SHG structures apparently provide essential migratory signals for naïve CD4+ T cells within the diseased CNS.

Multiple radiculopathy as the presenting manifestation of primary spinal leptomeningeal B cell lymphoma detected by flow cytometry of cerebrospinal fluid

Primary leptomeningeal lymphoma is a rare syndrome characterized by lymphomatous meningeal infiltration without identification of systemic lymphoma or parenchymal central nervous system lymphoma. We report a case of a 62-year-old immunocompetent woman with primary spinal leptomeningeal lymphoma presenting as cervical and lumbar radiculopathy who is rare because of particularly unusual onset site of B cell lymphoma. Interestingly, the diagnosis was possible only by cerebrospinal fluid flow cytometry.

CXCR3-Dependent Plasma Blast Migration to the Central Nervous System during Viral Encephalomyelitis

Immunoglobulin in cerebral spinal fluid and antibody secreting cells (ASC) within the central nervous system (CNS) parenchyma are common hallmarks of microbial infections and autoimmune disorders. However, the signals directing ASC migration into the inflamed CNS are poorly characterized. This study demonstrates that CXCR3 mediates CNS accumulation of ASC during neurotropic coronavirus-induced encephalomyelitis. Expansion of CXCR3-expressing ASC in draining lymph nodes prior to accumulation within the CNS was consistent with their recruitment by sustained expression of CXCR3 ligands during viral persistence. Both total and virus-specific ASC were reduced greater than 80% in the CNS of infected CXCR3(-/-) mice. Similar T cell CNS recruitment and local T cell-dependent antiviral activity further indicated that the ASC migration defect was T cell independent. Furthermore, in contrast to the reduction of ASC in the CNS, neither virus-specific ASC trafficking to bone marrow nor antiviral serum antibody was reduced relative to levels in control mice. Impaired ASC recruitment into the CNS of infected CXCR3(-/-) mice coincided with elevated levels of persisting viral RNA, sustained infectious virus, increased clinical disease, and mortality. These results demonstrate that CXCR3 ligands are indispensable for recruitment of activated ASC into the inflamed CNS and highlight their local protective role during persistent infection.

IFNγ regulates CXCL12 expression and cell trafficking during WNV infection (105.39)

Abstract West Nile Virus (WNV), a mosquito-transmitted neurotropic flavivirus, causes severe neuroinvasive disease in the elderly and immuno-compromised. For viral clearance and survival, it is essential that virus-specific T cells enter into the central nervous system (CNS) parenchyma in both human and murine subjects. The chemokine CXCL12 is a potent immune factor that dictates homing and motility of lymphocytes to specific microenvironments. In the context of WNV encephalitis, we have shown that CXCL12-mediated localization of lymphocytes to the perivascular space modulates their ability to efficiently control infection. This localization regulates the parenchymal entry of infiltrating leukocytes during neuroinflammatory diseases. However, the means by which CXCL12 is regulated and how this regulation influences cell trafficking during WNV remains unclear. We show that CXCL12 is up-regulated within the spleen and down-regulated in the CNS on day 8 post-WNV infection. However, in the absence of IFN-γ, there is an increase in CXCL12 expression in the CNS of WNV-infected mice. We propose that during WNV infection, IFN-γ regulates CXCL12 expression both in the periphery and in the CNS, which has an effect on the localization of leukocytes and therefore influences the function of these cells to efficiently control infection.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) is effective therapy for patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) involvement

Abstract Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

Behçet’s Disease

Neurologic involvement in Behçet's disease (BD) is seen in about 5% to 10% of all BD patients. Clinical and imaging data suggest that neurologic involvement in BD presents in two major forms. The first, central nervous system (CNS) parenchymal involvement with a predilection to brainstem-diencephalic regions, is seen in the majority of patients with neuro-BD (NBD). The second form is cerebral venous sinus thrombosis (CVST), which is seen in up to 20% of cases. BD is very rare in children, but when it does occur, the patterns are reversed: most children with NBD present with CVST. Other syndromes such as spinal cord involvement, arterial CNS involvement, optic neuritis, aseptic meningitis, and peripheral neuropathies may be seen, but are rare. Venous sinus thrombosis in BD has a significantly better neurologic prognosis than parenchymal CNS involvement. There is no Class I evidence regarding treatment of parenchymal CNS involvement or CVST in BD. Current treatment applications are based largely on expert opinion; none are evidence-based. Acute parenchymal CNS involvement should be treated with high-dose intravenous methylprednisolone (IVMP), 1g per day, for 5 to 10days, followed by either a prolonged oral taper or intermittent IVMP pulses with a low oral dose between the pulses, over 6months. After treatment of the acute attack, long-term maintenance with immunosuppressive agents should be considered in patients with parenchymal CNS involvement, as this form may follow a relapsing or secondary progressive course and may result in significant physical and cognitive deficits leading to severe neurologic disability. A number of randomized controlled studies have tested treatments for systemic manifestations of BD. Colchicine was found to be effective for mucocutaneous symptoms, thalidomide was found to be effective in erythema nodosum-like skin lesions, azathioprine and cyclosporine were shown to be effective in BD uveitis, and cyclophosphamide was shown to be effective for major vascular involvement. More recently, interferon alfa and anti-TNF agents were also shown to be effective in BD uveitis. Although randomized controlled studies have not been performed in NBD, the most widely used long-term therapeutic agent is azathioprine. Recent observations suggest that the addition and long-term use of azathioprine in NBD could be associated with a more favorable course. A growing number of case reports in recent years suggest that anti-TNF agents may be an effective alternative in NBD, but current experience with these agents is limited. CVST in BD is also treated with steroids. The addition to glucocorticoids of anticoagulation, including short-term fractionated heparin, is controversial, as these patients have a higher probability of harboring pulmonary or other aneurysms, which may be associated with an increased risk of bleeding. Long-term oral anticoagulation is unnecessary. Interestingly, the prognosis of CVST due to BD seems to be much more favorable than the prognosis of CVST due to other causes, with much less tendency for venous infarcts and seizures. However, as recurrences may occur, long-term treatment with azathioprine is recommended.

CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity

Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood-brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1β increased, whereas interferon-γ decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS.

Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle

Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the outer walls of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the castle moat, namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the castle moat is bordered by a second wall, the glia limitans, composed of astrocytic foot processes and a parenchymal basement membrane. Inside the castle, that is the CNS parenchyma proper, the royal family of sensitive neurons resides with their servants, the glial cells. Within the CSF-drained castle moat, macrophages serve as guards collecting all the information from within the castle, which they can present to the immune-surveying T cells. If in their communication with the castle moat macrophages, T cells recognize their specific antigen and see that the royal family is in danger, they will become activated and by opening doors in the outer wall of the castle allow the entry of additional immune cells into the castle moat. From there, immune cells may breach the inner castle wall with the aim to defend the castle inhabitants by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the castle inhabitants, this may allow for continuous entry of immune cells into the castle and lead to the death of the castle inhabitants, and finally members of the royal family, the neurons. This review will summarize the molecular traffic signals known to allow immune cells to breach the outer and inner walls of the CNS castle moat and will highlight the importance of the CSF-drained castle moat in maintaining immune surveillance and in mounting immune responses in the CNS.

18F]Fluorothymidine PET imaging in the diagnosis of leptomeningeal involvement with diffuse large B-cell lymphoma

The diagnosis of leptomeningeal carcinomatosis remains difficult despite improvement in central nervous system (CNS) imaging and cytologic examination of the cerebral spinal fluid. False-negative results are common, providing obstacles in assessing both prophylactic and therapeutic efforts. As a result of increased survival of patients with a variety of systemic neoplasms it is likely that central nervous involvement will need to be addressed more often. This article presents a patient with a diffuse large B-cell lymphoma with polymorphic features. Imaging using 18F-labeled fluorodeoxythymidine (FLT) proved useful in demonstrating both parenchymal and leptomeningeal CNS involvement. The potential for FLT to identify proliferative tissue may make it uniquely suitable for detection of CNS malignant disease.

Glial cells in non-germinal territories: insights into their stem/progenitor properties in the intact and injured nervous tissue.

In the adult murine central nervous system (CNS), the germinal astroglia residing in the subependymal zone of the lateral ventricles and in the subgranular layer of the hippocampal dentate gyrus behaves as neural stem cells actively undergoing neurogenesis and gliogenesis. Although neurogenesis does not normally occur outside the germinal niches, two types of parenchymal glial cells, namely astrocytes and NG2-expressing cells, display distinct progenitor activities in the intact brain or upon injury. Importantly, in defined experimental conditions both cell types reveal the potential to behave as multipotent stem cells suggesting that the mature CNS parenchyma may retain a latent stem cell potential, normally inhibited in vivo that, if properly evoked, might be exploited in situ for endogenous cell replacement following injury. In this review we scrutinise recent studies focussing on (i) the molecular and functional relationships between precursors in germinal niches and non-germinal areas; (ii) the ability of adult parenchymal glia to undergo lineage transgressions and neurogenesis in the intact brain and upon CNS injury. We also compare evidence for lineage plasticity in astrocytes or NG2+ cells, and discuss possible approaches for the implementation of stem/progenitor cell capabilities in non-germinal glial cells.