Institute of Neuroimmunology

Multiple sclerosis is characterized by CNS infiltration of autoreactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8+ antineural T cells in the neurodegeneration that underlies irreversible clinical progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8+ T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8+ T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8+ T cell–mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer–based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8+ T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8+ T cell–mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8+ T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.

To investigate the clinical spectrum, diagnostic implications and treatment outcomes of laboratory positive Myelin Oligodendrocyte Glycoprotein (MOG) IgG antibody in a real-world cohort of patients.

CD8+ T cells outnumber CD4+ cells in multiple sclerosis (MS) lesions associated with disease progression, but the pathogenic role and antigenic targets of these clonally expanded effectors are unknown. Based on evidence that demyelination is necessary but not sufficient for disease progression in MS, we previously hypothesized that CNS-infiltrating CD8+ T cells specific for neuronal antigens directly drive the axonal and neuronal injury that leads to cumulative neurologic disability in patients with MS. We now show that demyelination induced expression of MHC class I on neurons and axons and resulted in presentation of a neuron-specific neoantigen (synapsin promoter-driven chicken ovalbumin) to antigen-specific CD8+ T cells (anti-ovalbumin OT-I TCR-transgenic T cells). These neuroantigen-specific effectors surveilled the CNS in the absence of demyelination but were not retained. However, upon induction of demyelination via cuprizone intoxication, neuroantigen-specific CD8+ T cells proliferated, accumulated in the CNS, and damaged neoantigen-expressing neurons and axons. We further report elevated neuronal expression of MHC class I and β2-microglobulin transcripts and protein in gray matter and white matter tracts in tissue from patients with MS. These findings support a pathogenic role for autoreactive anti-axonal and anti-neuronal CD8+ T cells in MS progression.

<h3>Objective:</h3> Evaluate the association between upper cervical cord (UCC) volume and common brain metrics of MS. <h3>Background:</h3> Based on their higher availability than cord MRIs, UCC atrophy assessed from brain MRIs is frequently used as an imaging biomarker in MS. Compared to the measurements from the whole cervical cord, UCC atrophy may not be as sensitive, but it seems to correlate well with MS disability metrics. UCC may also be associated with other imaging metrics of MS. <h3>Design/Methods:</h3> 89 consecutive patients with MS (63F/26M, 72 relapsing/17 progressive) were prospectively enrolled from a single center. For brain structure volumes, automated LesionQuant (Cortechs Labs) was used. For lower brainstem and UCC volumes, a novel automated method was used. To propagate a mask of lower brainstem and UCC regions from the atlas template space to each T1-weighted brain MRI, Advanced Normalization Tools nonlinear registration was utilized. Volumes were calculated as the image’s voxel volume multi plied by the sum of voxels in the masks. Automated volumes from each anatomical level (aMedulla, aCervicomedullaryJunction-aCMJ, aC1, aC2) and total volumes from medulla to C2 (aMedulla+UCC) and from CMJ to C2 (aUCC) were identified. <h3>Results:</h3> 130 brain MRIs were analyzed. Age at MRI was 46.0±12.3 years. Individual aCMJ, aC1 and aC2 volumes and total volumes (aMedulla+UCC and aUCC) associated with whole brain and thalamus volumes(p&lt;0.05). The strongest correlations were between aMedulla and whole brain (unadjusted r=0.67p&lt;0.001; adjusted for age&amp;sex r=0.59 p&lt;0.001) and thalamus volumes (unadjusted r=0.53 p&lt;0.001; adjusted for age&amp;sex r=0.46 p&lt;0.001). <h3>Conclusions:</h3> Besides the whole brain and thalamus volumes, brain imaging is also used to evaluate UCC atrophy in MS. These common imaging metrics are often considered as independent variables; however, they also seem to interact with each other. Therefore, in MS trials, a composite metric, especially accounting for thalamus and UCC volumes, could serve as a complementary imaging outcome. <b>Disclosure:</b> Dr. Neyal has nothing to disclose. Dr. Son has nothing to disclose. Christopher Schwarz has received personal compensation for serving as an employee of Mayo Clinic. The institution of Christopher Schwarz has received research support from NIH. Elizabeth Atkinson has nothing to disclose. Ms. Morrison has nothing to disclose. The institution of John D. Port has received research support from NIH. The institution of Dr. Kantarci has received research support from Eli Lilly. The institution of Dr. Kantarci has received research support from NIH. The institution of Dr. Kantarci has received research support from ADDF. Dr. Kantarci has nothing to disclose. The institution of Dr. Zeydan has received research support from National Institutes of Health.

&lt;p&gt;Supplementary Table S1. Index of genes upregulated or downregulated in basal-TIC tumors relative to luminal-TIC tumors. Supplementary Table S2. WNT5A CNV by PAM50 molecular subtype from samples with both RNAseq expression data and CNV (n=807). Figure S1: Verification of Illumina Array by reverse transcription real-time PCR analysis (Supplementary for Figure 1). Figure S2: Allelic loss of WNT5A led to decreased WNT5A expression in human breast-cancer specimens and mouse luminal epithelial cells. Figure S3: Schematic depiction of the purification procedure for different populations of mammary epithelial cells. Figure S4: Supplementary information of Figure 4. Figure S5: Heterozygous deletion of Wnt5a has no impact on normal mammary gland development. Figure S6: WNT5A induces the phosphorylation of SMAD2. Figure S7: Differential expression of canonical and noncanonical Wnt receptors in basal and luminal epithelial cells. Figure S8: RYK or SMAD2 expression does not correlate with metastasis-free survival. Figure S9: Schematic depiction of the major conclusions and explained in detail in the Discussion section.&lt;/p&gt;

Abstract The microtubule-associated protein tau forms disease-specific filamentous aggregates in several different neurodegenerative diseases. In order to understand how tau undergoes misfolding into a specific filament type and to control this process for drug development purposes, it is crucial to studyin vitrotau aggregation methods and investigate the structures of the obtained filaments at the atomic level. Here, we used the tau fragment dGAE, which aggregates spontaneously, to seed the formation of full-length tau filaments. The structures of dGAE and full-length tau filaments were investigated by solid-state MAS NMR, showing that dGAE allows propagation of a chronic traumatic encephalopathy (CTE)-like fold to the full-length tau. The obtained filaments efficiently seeded tau aggregation in HEK293T cells. This work demonstrates thatin vitropreparation of disease-specific types of full-length tau filaments is feasible.

Multisite machine-learning neuroimaging studies, such as those conducted by the ENIGMA Consortium, need to remove the differences between sites to avoid effects of the site (EoS) that may prevent or fraudulently help the creation of prediction models, leading to impoverished or inflated prediction accuracy. Unfortunately, we have shown earlier that current Methods Aiming to Remove the EoS (MAREoS, e.g., ComBat) cannot remove complex EoS (e.g., including interactions between regions). And complex EoS may bias the accuracy. To overcome this hurdle, groups worldwide are developing novel MAREoS. However, we cannot assess their effectiveness because EoS may either inflate or shrink the accuracy, and MAREoS may both remove the EoS and degrade the data. In this work, we propose a strategy to measure the effectiveness of a MAREoS in removing different types of EoS. FOR MAREOS DEVELOPERS, we provide two multisite MRI datasets with only simple true effects (i.e., detectable by most machine-learning algorithms) and two with only simple EoS (i.e., removable by most MAREoS). First, they should use these datasets to fit machine-learning algorithms after applying the MAREoS. Second, they should use the formulas we provide to calculate the relative accuracy change associated with the MAREoS in each dataset and derive an EoS-removal effectiveness statistic. We also offer similar datasets and formulas for complex true effects and EoS that include first-order interactions. FOR MACHINE-LEARNING RESEARCHERS, we provide an extendable benchmark website to show: a) the types of EoS they should remove for each given machine-learning algorithm and b) the effectiveness of each MAREoS for removing each type of EoS. Relevantly, a MAREoS only able to remove the simple EoS may suffice for simple machine-learning algorithms, whereas more complex algorithms need a MAREoS that can remove more complex EoS. For instance, ComBat removes all simple EoS as needed for predictions based on simple lasso algorithms, but it leaves residual complex EoS that may bias the predictions based on standard support vector machine algorithms.

We present three patients with insidious onset of high-frequency atypical seizures, in association with atypical autoantibodies, with significant improvement with immunotherapy.

Abstract PD-1 restricts T cell effector functions, regulates T cell tolerance, and maintains immune homeostasis, thereby playing pivotal roles in cancer, autoimmune and infectious diseases. Our studies and others show that PD-1 can restrain Treg suppressive function in autoimmunity and cancer. Here, we investigate the role of Treg intrinsic PD-1 in regulating pathogenic and protective CD4+ T cell responses in experimental autoimmune encephalomyelitis (EAE) by inducing PD-1 deletion on FoxP3+ cells prior to disease development. This deletion of PD-1 only in Treg protects mice from severe disease, and both flow cytometry and transcriptional analysis of central nervous system (CNS) CD4+ T cells show enrichment of tissue effector Treg (eTreg) subsets at peak of disease. We find that PD-1 restrains the generation and suppressive function of these effector Treg. This tissue eTreg signature is also observed in human and mouse Treg subsets from the tumor microenvironment, and are potent suppressor populations. Further studies are underway to determine how PD-1 impacts TCR signaling and FoxP3 transcriptional co-activators in Treg cells. Our study provides deeper insights into how PD-1 regulates T cell tolerance, underscoring the important role of PD-1 in regulating Treg differentiation and suppressive function during autoimmune diseases, and provide mechanistic insights for PD-1 modulation in cancer and autoimmunity. Supported by NIH P01AI108545