A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

Objective: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL.

Prevalence, Demographic, and Clinical Factors Associated With Cognitive Dysfunction in Patients With Neuromyelitis Optica Spectrum Disorder.

Background And Objectives: Neuromyelitis optica spectrum disorder (NMOSD) is a chronic CNS demyelinating autoimmune disorder targeting the astrocyte antigen aquaporin-4 (AQP4), typically presenting with optic neuritis, transverse myelitis, and brain syndromes. Cognitive dysfunction (CD) in NMOSD is under-recognized and poorly understood. The purpose of this study was to evaluate the prevalence and clinical variables associated with CD in NMOSD.

A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis.

Objective: We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues.

Background: ALD is caused by mutations in the gene encoding a peroxisomal transporter.

Immune cell subset profiling in multiple sclerosis after fingolimod initiation and continued treatment: The FLUENT study.

Background: Fingolimod is a sphingosine 1-phosphate receptor modulator approved for relapsing MS. Long-term effects on the immunological profile are not fully understood.

Objective: Investigate fingolimod's temporal effects on immune cell subsets, and safety outcomes.

Visualizing Sphingosine-1-Phosphate Receptor 1(S1P) Signaling During Central Nervous System De- and Remyelination.

Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) mediated by aberrant auto-reactive immune responses. The current immune-modulatory therapies are unable to protect and repair immune-mediated neural tissue damage. One of the therapeutic targets in MS is the sphingosine-1-phosphate (S1P) pathway which signals via sphingosine-1-phosphate receptors 1-5 (S1P).

New Therapeutic Landscape in Neuromyelitis Optica.

Purpose Of Review: This review discusses the current treatment trends and emerging therapeutic landscape for patients with neuromyelitis optica spectrum disorder (NMOSD).

Recent Findings: Conventional immune suppressive therapies, such as B cell depletion, have been used for long-term treatment. However, the availability of recent FDA-approved and investigational drugs has made therapeutic choices for NMOSD more complex.

Pericytes regulate vascular immune homeostasis in the CNS.

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood-brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice ( ), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation.

Revealing architectural order with quantitative label-free imaging and deep learning.

We report quantitative label-free imaging with phase and polarization (QLIPP) for simultaneous measurement of density, anisotropy, and orientation of structures in unlabeled live cells and tissue slices. We combine QLIPP with deep neural networks to predict fluorescence images of diverse cell and tissue structures. QLIPP images reveal anatomical regions and axon tract orientation in prenatal human brain tissue sections that are not visible using brightfield imaging.

The impact of COVID-19 on patients with neuromyelitis optica spectrum disorder; a pilot study.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS neuroinflammatory disorder, mediated by the pathogenic autoantibody aquaporin-4 (AQP4-IgG). Current treatment includes long-term use of immunomodulatory therapies, leading to increased rates of infections among this population. It is of interest therefore, to study how the COVID-19 pandemic affects NMOSD patients in terms of their disease activity.

Emergence of rheumatoid arthritis following exposure to natalizumab.

We report a patient with relapsing-remitting multiple sclerosis, who developed rheumatoid arthritis after exposure to natalizumab. While some multiple sclerosis therapies are known to unmask autoimmune conditions, natalizumab is rarely implicated as a cause of alternative autoimmunity. This case illustrates an unusual clinical scenario which may support recent scientific work suggesting that, when natalizumab blocks T helper 1 cells from entering the central nervous system, T helper 17 cells may continue to migrate into immune-privileged spaces and cause pathologic inflammation.

A case of GFAP-astroglial autoimmunity presenting with reversible parkinsonism.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a newly recognized autoimmune central nervous system (CNS) inflammatory disorder, presenting with an array of neurological symptoms in association with autoantibodies against GFAP, a hallmark protein expressed on astrocytes. Limited knowledge is available on the disease pathogenesis and clinical outcome. Here, we report a case of autoimmune GFAP astrocytopathy presenting with encephalomyelitis and parkinsonism.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment.

Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks.

Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.

Immunological Aspects of Approved MS Therapeutics.

Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease.

MR susceptibility contrast imaging using a 2D simultaneous multi-slice gradient-echo sequence at 7T.

Purpose: To develop a 7T simultaneous multi-slice (SMS) 2D gradient-echo sequence for susceptibility contrast imaging, and to compare its quality to 3D imaging.

Methods: A frequency modulated and phase cycled RF pulse was designed to simultaneously excite multiple slices in multi-echo 2D gradient-echo imaging. The imaging parameters were chosen to generate images with susceptibility contrast, including T2*-weighted magnitude/phase images, susceptibility-weighted images and quantitative susceptibility/R2* maps.

Myeloid sphingosine-1-phosphate receptor 1 is important for CNS autoimmunity and neuroinflammation.

The critical role of sphingosine-1-phosphate (S1P) signaling in lymphocyte trafficking is well recognized, however, the contribution of myeloid cell-S1P signaling in neuroimmunity is less well understood. We previously reported that C57BL/6J mice harboring phosphorylation defective S1P receptor 1 (S1P) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P(S5A)] developed severe, T17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P-mediated T17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P signaling in myeloid cells.

The FLUENT study design: investigating immune cell subset and neurofilament changes in patients with relapsing multiple sclerosis treated with fingolimod.

Background: Fingolimod is a sphingosine 1-phosphate receptor modulator for the treatment of patients with relapsing forms of multiple sclerosis (RMS). Fingolimod sequesters lymphocytes within lymphoid tissue thereby reducing the counts of circulating lymphocytes. However, fingolimod's effects on the innate and adaptive components of the immune system are incompletely understood.

Molecular signature of Epstein-Barr virus infection in MS brain lesions.

Objective: We sought to confirm the presence and frequency of B cells and Epstein-Barr virus (EBV) (latent and lytic phase) antigens in archived MS and non-MS brain tissue by immunohistochemistry.

Methods: We quantified the type and location of B-cell subsets within active and chronic MS brain lesions in relation to viral antigen expression. The presence of EBV-infected cells was further confirmed by in situ hybridization to detect the EBV RNA transcript, EBV-encoded RNA-1 (EBER-1).

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage.

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination.

Phosphorylation of αB-crystallin supports reactive astrogliosis in demyelination.

The small heat shock protein αB-crystallin (CRYAB) has been implicated in multiple sclerosis (MS) pathogenesis. Earlier studies have indicated that CRYAB inhibits inflammation and attenuates clinical disease when administered in the experimental autoimmune encephalomyelitis model of MS. In this study, we evaluated the role of CRYAB in primary demyelinating events.

Integrative proteomics, genomics, and translational immunology approaches reveal mutated forms of Proteolipid Protein 1 (PLP1) and mutant-specific immune response in multiple sclerosis.

In order to gain mechanistic insights into multiple sclerosis (MS) pathogenesis, we utilized a multi-dimensional approach to test the hypothesis that mutations in myelin proteins lead to immune activation and central nervous system autoimmunity in MS. Mass spectrometry-based proteomic analysis of human MS brain lesions revealed seven unique mutations of PLP1; a key myelin protein that is known to be destroyed in MS. Surprisingly, in-depth genomic analysis of two MS patients at the genomic DNA and mRNA confirmed mutated PLP1 in RNA, but not in the genomic DNA.

Exosomal proteome analysis of cerebrospinal fluid detects biosignatures of neuromyelitis optica and multiple sclerosis.

Quantitative proteomic analysis of exosomes isolated from cerebrospinal fluid (CSF) of neuromyelitis optica (NMO) patients detected signature proteins differentiating NMO from multiple sclerosis (MS) and idiopathic longitudinally extensive transverse myelitis. Exosomes with good yields were obtained using ultracentrifugation from pooled CSF assisted by chemokine-based clustering strategy, which improved target molecule identification by providing amplified fold change values. 442 significant proteins generated a list of signature molecules of diseases validated primarily by the identification of known markers such as glial fibrillary acidic protein (GFAP) and fibronectin specific to NMO and MS respectively.