The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival

The French scientist Charles Benjamin Rouget identified the pericyte nearly 140 years ago. Since that time the role of the pericyte in vascular function has been difficult to elucidate. It was not until the development of techniques to isolate and culture pericytes that scientists have begun to understand the true impact of this unique cell in the maintenance of tissue homeostasis. In the brain the pericyte is an integral cellular component of the blood-brain barrier and, together with other cells of the neurovascular unit (endothelial cells, astrocytes and neurons) the pericyte makes fine-tuned regulatory adjustments and adaptations to promote tissue survival. These regulatory changes involve trans-cellular communication networks between cells. In this review we consider evidence for cell-to-cell crosstalk between pericytes and astrocytes during development and in adult brain

Case report: Use of granulocyte-colony stimulating factor as an immunomodulatory therapy in a patient with neuromyelitis optica spectrum disorder and comorbid immunodeficiency

BackgroundAutoimmune diseases can coexist with immunodeficiency. We describe a treatment approach in which granulocyte-colony stimulating factor (G-CSF) is used to restore immune competence without worsening autoimmunity. G-CSF is a polyfunctional cytokine that influences survival, proliferation, and differentiation of hematopoietic stem cells, and has immunomodulatory effects on the innate and adaptive immune systems.ObjectiveTo report a case of neuromyelitis optica spectrum disorder (NMOSD) with comorbid immunodeficiency and frequent infections.MethodsCase report and review of literature.ResultsA 23 years-old man presented with a focal onset seizure with impaired awareness at age 12. At age 18, he developed headaches, recurrent multifocal seizures, and non-convulsive status epilepticus. Brain magnetic resonance imaging (MRI) showed extensive T2 hyperintense and gadolinium-enhancing periventricular and corpus callosum lesions. Serum aquaporin 4 antibody was positive 1:10,000 (normal value <1.5 titer), hence he was diagnosed with NMOSD. As a complication, patient developed mucormycotic pneumonia with cavitation, requiring thoracotomy precluding use of immunosuppressants. Gene testing demonstrated a mutation in MT-ND4 gene encoding for NADH dehydrogenase 4 in mitochondrial complex 1. Eventually, he began a treatment with filgrastim, a G-CSF analog, in addition to intravenous immunoglobulins and prednisone. Patient’s NMOSD has been in remission without relapses, or coexistent infections ever since.ConclusionG-CSF is a polyfunctional cytokine with important immunomodulatory effects, which makes it an interesting therapeutic option when autoimmunity coexists with immunodeficiency and was used successfully in this case

Suppressor of Cytokine Signaling 1 Expression Protects Oligodendrocytes from the Deleterious Effects of Interferon-

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine produced by T cells and natural killer cells that has been implicated as a deleterious factor in the immune-mediated demyelinating disorder multiple sclerosis. In vitro, purified developing and mature oligodendrocytes have been shown to die in the presence of IFN-gamma by apoptosis and necrosis, respectively. Moreover, transgenic expression of IFN-gamma in the CNS of mice during development results in tremor, hypomyelination, and oligodendrocyte cell loss, and IFN-gamma expression in adult animals after demyelinating insults inhibits remyelination. To examine the molecular mechanisms of IFN-gamma-induced oligodendrocyte injury, we generated a transgenic mouse line [PLP/SOCS1 (proteolipid protein/suppressor of cytokine signaling 1)] that exhibits diminished oligodendrocyte responsiveness to IFN-gamma attributable to the targeted expression of SOCS1 in these cells. We demonstrate that oligodendrocytes in the PLP/SOCS1 transgenic mice are protected against the injurious effect of IFN-gamma. Our data indicate that IFN-gamma exerts a direct deleterious effect on developing oligodendrocytes. The capacity of SOCS1 to inhibit the effects of IFN-gamma suggests a therapeutic approach toward protection of myelinating oligodendrocytes against the harmful effects of inflammation

Interferon- -Oligodendrocyte Interactions in the Regulation of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human demyelinating disorder multiple sclerosis (MS). The immune cytokine interferon-gamma (IFN-gamma) is believed to participate in disease pathogenesis in both EAE and MS. In the present study, we examined the significance of IFN-gamma-oligodendrocyte interactions in the course of EAE. For the purpose of our study, we used the previously described [proteolipid protein/suppressor of cytokine signaling 1 (PLP/SOCS1)] transgenic mouse line that displays suppressed oligodendrocyte responsiveness to IFN-gamma. PLP/SOCS1 mice developed EAE with an accelerated onset associated with enhanced early inflammation and markedly increased oligodendrocyte apoptosis. Moreover, we found that IFN-gamma pretreatment of mature oligodendrocytes in vitro had a protective effect against oxidative stress and the inhibition of proteasome activity and resulted in upregulation in expression of a number of chemokines, including CXCL10 (IP10), CCL2 (MCP-1), CCL3 (MCP-1alpha), and CCL5 (RANTES). These results suggest that IFN-gamma-oligodendrocyte interactions are of significance to the clinical and pathological aspects of EAE. In addition, the present study suggests that oligodendrocytes are not simply targets of inflammatory injury but active participants of the neuroimmune network operating during the course of EAE

www.mdpi.com/journal/ijms Molecular Mechanisms of Oligodendrocyte Injury in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Abstract: New evidence has emerged over the last decade indicating that oligodendrocyte injury in multiple sclerosis (MS) is not a single unified phenomenon but rather a spectrum of processes ranging from massive immune destruction to a subtle cell death in the absence of significant inflammation. Experimentally, protection of oligodendrocytes against inflammatory injury results in protection against experimental autoimmune encephalitis, the animal model of multiple sclerosis. In this review, we will discuss the molecular mechanisms regulating oligodendrocyte injury and inflammatory demyelination. We draw attention to the injurious role of IFN-γ signaling in oligodendrocytes and the pro-inflammatory effect of their death. In conclusion, studying the molecular mechanisms of oligodendrocyte injury is likely to provide new perspective on the pathogenesis of MS and a rationale for cell protective therapies

Treatment of natalizumab‐associated PML with filgrastim

Abstract Objective There is no consensus on the treatment of progressive multifocal leukoencephalopathy (PML) occurring in multiple sclerosis (MS) patients treated with natalizumab (Nz). We report novel immune activating treatment with filgrastim of Nz‐associated PML in MS patients treated at Rush University Medical Center. Methods We retrospectively analyzed 17 Nz‐PML patients treated at this single tertiary referral center between 2010 and 2017. We reviewed the clinical symptoms, diagnostic methods, survival, outcome and MS modifying therapy (MSMT) after Nz‐PML. Results PML occurred after an average of 49 Nz infusions. To facilitate JCV elimination by accelerating immune reconstitution inflammatory syndrome (IRIS), all patients received subcutaneous filgrastim upon PML diagnosis and discontinuation of Nz; eight received plasma exchange (PLEX). Earlier than previously published, PML‐IRIS occurred in 15 of 17 (88.2%) patients within a mean of 57.4 days (SD 21.20) after the last Nz infusion. Seven patients recovered to or near baseline. There were no PML/IRIS–related fatalities but one patient committed suicide 2.5 years later. PLEX had no impact on PML outcome. Of 17 patients, 3 (18%) had MS relapses within 1 year after PML, and 5 (29%) beyond 1 year of PML onset, which is lower than expected in highly active MS patients. Eight patients started MSMTs after Nz‐PML on an average of 26 months after Nz withdrawal. Interpretation Our findings indicate that immunoactivation with filgrastim during PML and careful management of subsequent IRIS is likely beneficial in patients with Nz‐PML, without worsening MS. The clinical course of MS may be ameliorated by PML

Data_Sheet_1_Case report: Use of granulocyte-colony stimulating factor as an immunomodulatory therapy in a patient with neuromyelitis optica spectrum disorder and comorbid immunodeficiency.PDF

BackgroundAutoimmune diseases can coexist with immunodeficiency. We describe a treatment approach in which granulocyte-colony stimulating factor (G-CSF) is used to restore immune competence without worsening autoimmunity. G-CSF is a polyfunctional cytokine that influences survival, proliferation, and differentiation of hematopoietic stem cells, and has immunomodulatory effects on the innate and adaptive immune systems.ObjectiveTo report a case of neuromyelitis optica spectrum disorder (NMOSD) with comorbid immunodeficiency and frequent infections.MethodsCase report and review of literature.ResultsA 23 years-old man presented with a focal onset seizure with impaired awareness at age 12. At age 18, he developed headaches, recurrent multifocal seizures, and non-convulsive status epilepticus. Brain magnetic resonance imaging (MRI) showed extensive T2 hyperintense and gadolinium-enhancing periventricular and corpus callosum lesions. Serum aquaporin 4 antibody was positive 1:10,000 (normal value ConclusionG-CSF is a polyfunctional cytokine with important immunomodulatory effects, which makes it an interesting therapeutic option when autoimmunity coexists with immunodeficiency and was used successfully in this case.</p

Long-Term Effectiveness and Safety of Natalizumab in African American and Hispanic/Latino Patients with Early Relapsing–Remitting Multiple Sclerosis: STRIVE Data Analysis

Abstract Introduction In STRIVE, natalizumab treatment demonstrated effectiveness in clinical, magnetic resonance imaging (MRI), and patient-reported outcomes (PROs) in patients with early relapsing–remitting multiple sclerosis (RRMS). This post hoc analysis examined the effectiveness and safety of natalizumab in patients who self-identified as either Black/African American (AA) or Hispanic/Latino. Methods Clinical, MRI, and PROs were assessed for the Black/AA subgroup (n = 40) and compared with the non-Hispanic White subgroup (n = 158). As a result of the very small sample size, outcomes for the Hispanic/Latino subgroup (n = 18) were assessed separately, including a sensitivity analysis with Hispanic/Latino patients who completed the 4-year study on natalizumab. Results Clinical, MRI, and PROs were comparable between the Black/AA and non-Hispanic White subgroups except for MRI outcomes at year 1. A higher proportion of non-Hispanic White than Black/AA patients achieved MRI no evidence of disease activity (NEDA; 75.4% vs. 50.0%, p = 0.0121) and no new or newly enlarging T2 lesions (77.6% vs. 50.0%, p = 0.0031) at year 1; these differences were not observed in years 2–4 of the study. For the Hispanic/Latino subgroup in the intent-to-treat population, 46.2% and 55.6% achieved NEDA at years 1 and 2; 66.7% and 90.0% achieved clinical NEDA at years 3 and 4. Annualized relapse rate was reduced by 93.0% at year 1 versus the year before natalizumab initiation; this reduction was maintained throughout the study. Over 4 years, 37.5–50.0% of patients had a clinically meaningful improvement in their Symbol Digit Modalities Test score, and 81.8–100.0% and 90.9–100.0% had stable/improved Multiple Sclerosis Impact Scale-29 physical and psychological scores, respectively. Similar results were observed in the sensitivity analysis with Hispanic/Latino subgroup of the 4-year natalizumab completers. Conclusion These results highlight the effectiveness and safety of natalizumab in patients with early RRMS who self-identified as Black/AA or Hispanic/Latino. ClinicalTrials.gov NCT01485003