May Han, MD

All Publications

• A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets. Annals of neurology Hashemi, E., Srivastava, I. N., Aguirre, A., Yoseph, E. T., Kaushal, E., Awani, A., Ryu, J. K., Akassoglou, K., Talebian, S., Chu, P., Pisani, L., Musolino, P., Steinman, L., Doyle, K., Robinson, W. H., Sharpe, O., Cayrol, R., Orchard, P. J., Lund, T., Vogel, H., Lenail, M., Han, M. H., Bonkowsky, J. L., Van Haren, K. P. 2024

  Abstract

  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.We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024.

  View details for DOI 10.1002/ana.27117

  View details for PubMedID 39467011

• Prevalence, Demographic, and Clinical Factors Associated With Cognitive Dysfunction in Patients With Neuromyelitis Optica Spectrum Disorder (vol 102, e207965, 2024) NEUROLOGY Vlahovic, L., McDonald, J., Hinman, J., Tomczak, A., Lock, C., Palmer, C. A., Cook, L. J., Yeaman, M. R., Burnett, M. K., Deutsch, G. K., Nelson, L. M., Han, M. H., CIRCLES Study Grp 2024; 103 (3)

  View details for DOI 10.1212/WNL.0000000000209215

  View details for Web of Science ID 001262358400001

• Permittivity tensor imaging: modular label-free imaging of 3D dry mass and 3D orientation at high resolution. Nature methods Yeh, L. H., Ivanov, I. E., Chandler, T., Byrum, J. R., Chhun, B. B., Guo, S. M., Foltz, C., Hashemi, E., Perez-Bermejo, J. A., Wang, H., Yu, Y., Kazansky, P. G., Conklin, B. R., Han, M. H., Mehta, S. B. 2024

  Abstract

  The dry mass and the orientation of biomolecules can be imaged without a label by measuring their permittivity tensor (PT), which describes how biomolecules affect the phase and polarization of light. Three-dimensional (3D) imaging of PT has been challenging. We present a label-free computational microscopy technique, PT imaging (PTI), for the 3D measurement of PT. PTI encodes the invisible PT into images using oblique illumination, polarization-sensitive detection and volumetric sampling. PT is decoded from the data with a vectorial imaging model and a multi-channel inverse algorithm, assuming uniaxial symmetry in each voxel. We demonstrate high-resolution imaging of PT of isotropic beads, anisotropic glass targets, mouse brain tissue, infected cells and histology slides. PTI outperforms previous label-free imaging techniques such as vector tomography, ptychography and light-field imaging in resolving the 3D orientation and symmetry of organelles, cells and tissue. We provide open-source software and modular hardware to enable the adoption of the method.

  View details for DOI 10.1038/s41592-024-02291-w

  View details for PubMedID 38890427

  View details for PubMedCentralID 6922317

• Antipsychotic medications associated with increased length of hospital stay in autoimmune encephalitis and multiple sclerosis: A retrospective study. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Sai Folmsbee, S., Hui, G., Yuan, Y., Gombar, S., Han, M., Le, S. 2024; 124: 87-93

  Abstract

  Antipsychotic medications (APMs) and selective serotonin reuptake inhibitors (SSRIs) are frequently utilized in patients with neuroinflammatory disorders, such as autoimmune encephalitis and multiple sclerosis (MS). This retrospective study investigates how in-hospital treatment with APMs and SSRIs in patients with these neuroinflammatory diseases are associated with differences in hospital length-of-stay (LOS) and mortality.We evaluated all the inpatients in the Stanford University Hospital from 2008 to 2023 diagnosed with either non-infectious encephalitis or MS and subdivided them into those who did or did not receive APMs or SSRIs while hospitalized. We then analyzed whether hospital LOS and mortality differed with these medications.Among inpatients with non-infectious encephalitis (n = 114), those who were exposed to APMs had a significantly increased mean LOS (11.8 vs 20.9 days, p < 0.01). For inpatients with MS (n = 1095), treatment with an APM was associated with a significant increase in mean LOS (2.8 vs. 7.1, p < 0.00001). When comparing typical to atypical APMs given to subjects with MS, those who received atypical APMs showed a significant increase in LOS (4.3 vs 10.5, p < 0.01), although typical APMs showed significantly increased risk of mortality (p < 0.05). For inpatients with MS and SSRI use, there was a significant increase in mean hospital LOS (3.5 vs 5.3, p < 0.01), with a significant difference found in those who received fluoxetine or citalopram, but not sertraline or escitalopram. Finally, several healthcare disparities were found, including that Black patients were more likely to receive APMs, and those with MS were more likely to receive typical rather than atypical APMs. Conversely, Black patients with MS were less likely to receive SSRI treatment.There was a statistically significant increase in LOS associated with APM use in non-infectious encephalitis and MS, as well as with SSRI use in MS. These data reflect the importance of these medications in these neuroinflammatory disorders and suggest that further investigation into their risks and benefits would be warranted.

  View details for DOI 10.1016/j.jocn.2024.04.021

  View details for PubMedID 38677201

• Clinical Features of Neurotoxicity Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma. Blood advances Nie, E. H., Su, Y. J., Baird, J. H., Agarwal, N., Bharadwaj, S., Weng, W. K., Smith, M., Dahiya, S., Han, M. H., Dunn, J. E., Kipp, L. B., Miklos, D. B., Scott, B. J., Frank, M. J. 2024

  Abstract

  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 following CD19 CAR T-cell therapy in patients with MCL. All patients (n = 26) who received standard of care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (≥ grade 3) ICANS. All ICANS patients had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. 92% of EEGs revealed interictal changes; no patients experienced frank seizures due to ICANS. 86% of severe ICANS patients with post-infusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of post-infusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in severe ICANS patients, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

  View details for DOI 10.1182/bloodadvances.2023011896

  View details for PubMedID 38295285

• Prevalence, Demographic, and Clinical Factors Associated With Cognitive Dysfunction in Patients With Neuromyelitis Optica Spectrum Disorder. Neurology Vlahovic, L., McDonald, J., Hinman, J., Tomczak, A., Lock, C., Palmer, C. A., Cook, L. J., Yeaman, M. R., Burnett, M. K., Deutsch, G. K., Nelson, L. M., Han, M. H. 2024; 102 (1): e207965

  Abstract

  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.This observational retrospective study with longitudinal follow-up describes a clinical cohort seen in the Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Serial Montreal Cognitive Assessments (MoCAs) were performed upon enrollment and at 6-month intervals to evaluate longitudinal cognitive function relative to demographic and disease-related factors. We used 2-tailed t test, analysis of variance, the χ2 test, linear regression for univariable and adjusted analyses and simultaneous linear regression and mixed-effects model for multivariable analyses.Thirty-four percent (75/219) of patients met criteria for CD (MoCA <26); 29% (64/219) showed mild dysfunction (MoCA 20-26/30), and 5% (11/219) showed moderate (MoCA <20/30) dysfunction. Patients with less neurologic disability and lower pain scores had higher MoCA scores (95% CI 0.24-0.65 and 95% CI 0.09-0.42, respectively). Patients with at least high school education scored higher on the MoCA (95% CI 2.2-5). When comparing patients dichotomized for CD, patients never on rituximab scored higher than patients only treated with rituximab (p < 0.029). There was no significant association between annualized relapse rate, age, sex, disease duration, AQP4 serostatus or brain lesions, and CD. CD was more pronounced among Black than White patients (95% CI -2.7 to -0.7). Multivariable analysis of serial MoCA did not indicate change (p = 0.715). Descriptive analysis of serial MoCA showed 30% (45/150) of patients with worsening MoCA performance had impaired language and verbal recall.To our knowledge, this is the largest study of diverse cohort to investigate CD in patients with NMOSD. Our findings demonstrate 34% of patients with NMOSD experience mild-to-moderate CD, while 30% of patients demonstrated decline on serial testing. The substantial prevalence of CD in this pilot report highlights the need for improved and validated screening tools and comprehensive measures to investigate CD in NMOSD.

  View details for DOI 10.1212/WNL.0000000000207965

  View details for PubMedID 38165361

• A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis. bioRxiv : the preprint server for biology Hashemi, E., Narain Srivastava, I., Aguirre, A., Tilahan Yoseph, E., Kaushal, E., Awani, A., Kyu Ryu, J., Akassoglou, K., Talebian, S., Chu, P., Pisani, L., Musolino, P., Steinman, L., Doyle, K., Robinson, W. H., Sharpe, O., Cayrol, R., Orchard, P., Lund, T., Vogel, H., Lenail, M., Han, M. H., Bonkowsky, J. L., Van Haren, K. P. 2023

  Abstract

  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.ALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1-null mouse.We generated a cALD phenotype in 8-week-old, male Abcd1-null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue.MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue.This novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination.

  View details for DOI 10.1101/2023.11.07.564025

  View details for PubMedID 37986739

  View details for PubMedCentralID PMC10659266

• Epidemiological and Clinical Outcome Determinants of Post-COVID-19 Myelopathy Sumera, J., Sarkar, T., McDonald, J., Sattarnezhad, N., Nie, E., Kipp, L., Dunn, J., Han, M., Joseph, Y., Tomczak, A., Lock, C. SAGE PUBLICATIONS LTD. 2023: 719

  View details for Web of Science ID 001091311305114

• Blood Biomarkers Elucidate the Mechanism of Cognitive Dysfunction in Neuromyelitis Optica and Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease Han, M., Vlahovic, L., Wilson, E. SAGE PUBLICATIONS LTD. 2023: 827-828

  View details for Web of Science ID 001091311305307

• Impacts of Race and Immunotherapy on Maternal and Fetal Outcomes in Pregnant Patients with NMOSD and MOGAD Hla, A., Sarkar, T., McDonald, J., Han, M. SAGE PUBLICATIONS LTD. 2023: 679

  View details for Web of Science ID 001091311305047

• Longitudinal imaging of microscopic scattering features in the foveal avascular zone of multiple sclerosis using adaptive optics ophthalmoscopy Hargrave, A., Navarro, S., Buickians, D., Kipp, L., Han, M., Kowalski, B., Dubra, A., Moss, H. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2023

  View details for Web of Science ID 001053795604033

• SARS-CoV-2 Vaccine Immune Response on Anti-Complement Therapy, Eculizumab Sattarnezhad, N., Sumera, J., McDonald, J., Nie, E., Tomczak, A., Joseph, Y., Kalle, S., Sarkar, T., Kipp, L., Lock, C., Dunn, J. E., Han, M. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000204308

  View details for Web of Science ID 001053672100108

• Influence of Body Mass Index on B Lymphocyte Repopulation in Multiple Sclerosis Patients Treated with Anti-CD20 Therapy Loeffler, J., Han, M. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000204140

  View details for Web of Science ID 001053672105186

• Risk of acute stroke in young patients with new-onset lupus nephritis: a case series Wu, D., Han, M., Lee, S. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000204219

  View details for Web of Science ID 001053672106241

• Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) in conjunction with Allogeneic Bone Marrow Transplantation and Autoimmune Neutropenia: A study of two companion cases and institutional review of the MOGAD clinical phenotype spectrum Nie, E., McDonald, J., Dunn, J., Han, M. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1212/WNL.0000000000204302

  View details for Web of Science ID 001053672102035

• Clinical and epidemiological correlates of treatment change in patients with NMOSD: insights from the CIRCLES cohort. Journal of neurology Gholizadeh, S., Exuzides, A., Lewis, K. E., Palmer, C., Waltz, M., Rose, J. W., Jolley, A. M., Behne, J. M., Behne, M. K., Blaschke, T. F., Smith, T. J., Sinnott, J., Cook, L. J., Yeaman, M. R., Guthy-Jackson Charitable Foundation CIRCLES Study Group, Aguerre, I., Amezcua, L., Chitnis, T., Lewis, J. C., Engel, C., Han, M. H., Klawiter, E. C., Kocsik, A., Kruse-Hoyer, M., Levine, L., Levy, M., Marcille, M., Mealy, M. A., Moore, S., Mullin, D. S., Nelson, K. E., Onomichi, K. B., Planchon, S. M., Pruitt, A., Repovic, P., Riley, C. S., Rimler, Z., Russo, A. W., Ocampo, C. T., Tomczak, A. J. 2022

  Abstract

  OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) represent rare autoimmune diseases of the central nervous system largely targeting optic nerve(s) and spinal cord. The present analysis used real-world data to identify clinical and epidemiological correlates of treatment change in patients with NMOSD.METHODS: CIRCLES is a longitudinal, observational study of NMOSD conducted at 15 centers across North America. Patients with≥60days of follow-up and receiving on-study maintenance treatment were evaluated. The mean annual relapse rate (ARR) was estimated using negative binomial models; the likelihood of treatment change was estimated using Cox proportional hazards models. Relapses were included as time-varying covariates to estimate the relationship to treatment change.RESULTS: Of 542 patients included, 171 (31.5%) experienced≥1 relapse on the study and 133 patients (24.5%) had≥1 change in the treatment regimen. Two categories of variables significantly correlated with the likelihood of treatment change: (1) relapse: any on-study relapse (hazard ratio [HR]=2.91; p<0.001), relapse phenotypes (HR range=2.15-5.49; p<0.001), and pre-study ARR>0.75 (HR 2.28; p<0.001); 2) disease phenotype: brain syndrome only vs transverse myelitis involvement at onset (HR 2.44; p=0.008), disease duration<1 vs>5years (HR 1.66; p=0.028), or autoimmune comorbidity (HR 1.55; p=0.015). A subset of these factors significantly correlated with shorter time to first rituximab discontinuation.CONCLUSIONS: In CIRCLES, relapse patterns and disease phenotype significantly correlated with changes in the maintenance treatment regimen. Such findings may facilitate the identification of patients with NMOSD who are likely to benefit from treatment change to reduce relapse risk or disease burden and enhance the quality of life.

  View details for DOI 10.1007/s00415-022-11529-6

  View details for PubMedID 36565348

• A Novel Mouse Model of Cerebral Demyelination in X-Linked Adrenoleukodystrophy Highlights NLRP3 Activation in Lesion Pathogenesis Srivastava, I., Van Haren, K., Hashemi, E., Kaushal, E., Han, M., Lund, T., Bonkowsky, J., Yoseph, E. WILEY. 2022: S174

  View details for Web of Science ID 000867884200308

• Visualizing Sphingosine-1-Phosphate Receptor 1(S1P1) Signaling During Central Nervous System De- and Remyelination. Cellular and molecular neurobiology Hashemi, E., Yoseph, E., Tsai, H., Moreno, M., Yeh, L., Mehta, S. B., Kono, M., Proia, R., Han, M. H. 2022

  Abstract

  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 (S1P1-5). S1P receptors are expressed predominantly on immune and CNS cells. Considering the potential neuroprotective properties of S1P signaling, we utilized S1P1-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced demyelination model to investigate in vivo S1P - S1P1 signaling in the CNS. We observed S1P1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. During remyelination, S1P1 signaling is expressed in oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC). In the cuprizone model, we did not observe S1P1 signaling in neurons and astrocytes. We also observed beta-arrestin-dependent S1P1 signaling in lymphocytes during demyelination and CNS inflammation. Our findings reveal beta-arrestin-dependent S1P1 signaling in oligodendrocyte lineage cells implying a role of S1P1 signaling in remyelination.

  View details for DOI 10.1007/s10571-022-01245-0

  View details for PubMedID 35917044

• Immune cell subset profiling in multiple sclerosis after fingolimod initiation and continued treatment: The FLUENT study. Multiple sclerosis journal - experimental, translational and clinical Mao-Draayer, Y., Cohen, J. A., Bar-Or, A., Han, M. H., Singer, B., Williams, I. M., Meng, X., Elam, C., Weiss, J. L., Cox, G. M., Ziehn, M., Cree, B. A., FLUENT study investigators 2022; 8 (3): 20552173221115023

  Abstract

  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.Methods: In FLUENT, a 12-month, prospective, non-randomized, open-label, phase IV study, adult participants received fingolimod 0.5 mg/day. Changes in immune cell subsets, anti-John Cunningham virus (JCV) antibody index, and serum neurofilament levels were assessed.Results: 165 fingolimod-naive and 217 participants treated for 2-12 years in routine clinical practice were enrolled. Levels of all monitored peripheral lymphocyte subsets were reduced from month 3 in fingolimod-naive participants. Greatest reductions occurred in naive and central memory CD4+and CD8+T cells, and in naive and memory B cells. Most lymphocyte subset levels remained stable in the continuous fingolimod group. Components of the innate immune system remained within reference ranges. No increase in JCV seropositivity was observed. No single cellular subset correlated with anti-JCV antibody index at any time point. Neurofilament levels remained within healthy adult reference limits throughout. No opportunistic infections were reported; no new or unexpected safety signals were observed.Conclusion: FLUENT provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk.

  View details for DOI 10.1177/20552173221115023

  View details for PubMedID 35936922

• HLA-DR4-positive Vogt-Koyanagi-Harada (VKH) Syndrome: Review of pathophysiology and clinical correlation (P1-1.Virtual) Loeffler, J., Nie, E., Han, M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500455

• Immune-mediated diseases and thromboembolic events: a modified Delphi panel. Current medical research and opinion Azimi, N., Caldera, F., Cohen, S., Conners, J., Fernandes, T., Han, M., Strand, V., Tapson, V., Weinberg, A., Weinberg, J., Yarur, A. 2021: 1

  Abstract

  INTRODUCTION: A multidisciplinary panel of physicians was convened to gain understanding of the relationship between thromboembolic events (TEs) and immune-mediated diseases (IMDs).The primary objective of the panel was to assess areas of consensus on the IMD most prone to TE as well as modifiable and unmodifiable factors that might exacerbate or mitigate the risk of TEs.METHODS: Thirteen nationally recognized physicians were selected based on their contributions to guidelines, publications, and patient care. The modified Delphi panel consisted of four rounds of engagement: (1) a semi-structured interview, (2) an expert panel questionnaire, (3) an in-person panel discussion, and (4) a consensus statement survey.RESULTS: Ulcerative colitis and Crohn's disease were identified as two of four IMDs with the highest TE risk. Consensus was reached on several non-modifiable and modifiable characteristics of high-risk. Approaches to reduce TE incidence were identified such as altering treatment, requiring the monitoring of patients for TEs, and modifying patient behaviors. Janus kinase inhibitors and corticosteroids were identified as therapies that required further evaluation given their potential TE risk.DISCUSSION: The panel reached a consensus that several IMDs are at an elevated risk of TEs. Physicians are unable to control most patient level risk factors but can control the therapies being used. Consequently, physicians should consider the specific IMD, be aware of TE risk factors, and take into account risk factors in selecting the therapies to optimally manage their conditions and to reduce the risk of TEs in this population.

  View details for DOI 10.1080/03007995.2021.1932450

  View details for PubMedID 34034599

• CD317 puts the brakes on dendritic cell trafficking to the CNS. Proceedings of the National Academy of Sciences of the United States of America Barnes, S. E., Han, M. H. 2021; 118 (18)

  View details for DOI 10.1073/pnas.2104740118

  View details for PubMedID 33850053

• Pericytes regulate vascular immune homeostasis in the CNS. Proceedings of the National Academy of Sciences of the United States of America Torok, O., Schreiner, B., Schaffenrath, J., Tsai, H., Maheshwari, U., Stifter, S. A., Welsh, C., Amorim, A., Sridhar, S., Utz, S. G., Mildenberger, W., Nassiri, S., Delorenzi, M., Aguzzi, A., Han, M. H., Greter, M., Becher, B., Keller, A. 2021; 118 (10)

  Abstract

  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 (Pdgfb ret/ret ), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfb ret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti-ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfb ret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfb ret/ret ;2D2 tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

  View details for DOI 10.1073/pnas.2016587118

  View details for PubMedID 33653955

• New Therapeutic Landscape in Neuromyelitis Optica. Current treatment options in neurology Tugizova, M. n., Vlahovic, L. n., Tomczak, A. n., Wetzel, N. S., Han, M. H. 2021; 23 (4): 13

  Abstract

  This review discusses the current treatment trends and emerging therapeutic landscape for patients with neuromyelitis optica spectrum disorder (NMOSD).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.Recent randomized clinical trials have shown that eculizumab, inebilizumab, and satralizumab are efficacious therapies for AQP4 seropositive NMOSD. These therapies may not have the same benefit in patients with seronegative NMOSD, including MOG-associated disease, and further investigation is required in this population. Reliable biomarkers to guide therapy decisions are urgently needed. There is a plethora of promising investigational therapies currently in the pipeline with exciting and novel mechanisms of action.

  View details for DOI 10.1007/s11940-021-00667-3

  View details for PubMedID 33814893

  View details for PubMedCentralID PMC8008025

• Novel Foveal Features Associated With Vision Impairment in Multiple Sclerosis. Investigative ophthalmology & visual science Hargrave, A., Sredar, N., Khushzad, F., Yarp, J., Tomczak, A., Han, M., Kipp, L., Dubra, A., Moss, H. E. 2021; 62 (12): 27

  Abstract

  To characterize scattering and hyperreflective features in the foveal avascular zone of people with multiple sclerosis (MS) using adaptive optics scanning laser ophthalmoscopy (AOSLO) and to evaluate their relationship with visual function and MS disease characteristics.Twenty subjects with MS underwent confocal reflectance and non-confocal split-detection AOSLO foveal imaging. Peripapillary retinal nerve fiber layer thickness was measured using optic nerve optical coherence tomography. Blood pressure, intraocular pressure (IOP), and best-corrected high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA) were measured. AOSLO images were graded to determine the presence and characteristics of distinct structures.Two distinct structures were seen in the avascular zone of the foveal pit. Hyperreflective puncta, present in 74% of eyes, were associated with IOP and blood pressure. Scattering features, observed in 58% of eyes, were associated with decreased HCVA and LCVA, as well as increased MS duration and disability, but were not associated with retinal nerve fiber layer thickness. Hyperreflective puncta and scattering features were simultaneously present in 53% of eyes.Hyperreflective puncta were associated with parameters affecting ophthalmic perfusion, but they were not associated with MS disease parameters. Scattering features were associated with parameters corresponding to advanced MS, suggesting that they may be related to disease progression. Scattering features were also correlated with reduced visual function independent from ganglion cell injury, suggesting the possibility of a novel ganglion cell-independent mechanism of impaired vision in people with MS.

  View details for DOI 10.1167/iovs.62.12.27

  View details for PubMedID 34581726

• In-depth B cell immunophenotyping to monitor response to anti-CD20 therapy in CNS autoimmunity. Multiple sclerosis and related disorders Su, E., Wetzel, N. S., Oak, J., Kipp, L., Han, M. H. 2020; 46: 102594

  View details for DOI 10.1016/j.msard.2020.102594

  View details for PubMedID 33296989

• Examining the Link Between Autoimmune Disease and Thromboembolic Events: A Modified Delphi Panel Approach Azimi, N., Caldera, F., Cohen, S., Conners, J., Fernandes, T., Han, M., Strand, V., Tapson, V., Weinberg, A. S., Weinberg, J., Yarur, A. LIPPINCOTT WILLIAMS & WILKINS. 2020: S454

  View details for Web of Science ID 000607196702179

• White-matter-nulled MPRAGE at 7T reveals thalamic lesions and atrophy of specific thalamic nuclei in multiple sclerosis MULTIPLE SCLEROSIS JOURNAL Planche, V., Su, J. H., Mournet, S., Saranathan, M., Dousset, V., Han, M., Rutt, B. K., Tourdias, T. 2020; 26 (8): 987–92

  View details for DOI 10.1177/1352458519828297

  View details for Web of Science ID 000547265400014

• Novel microscopic foveal pit pathology in multiple sclerosis revealed with adaptive optics ophthalmoscopy Hargrave, A., Sredar, N., Razeen, M. M., Khushzad, F., Yarp, J., Leishangthem, L., Tomczak, A., Kipp, L., Han, M., Kowalski, B., Dubra, A., Moss, H. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528304317

• Characterization of Retinal vascular changes in Multiple Sclerosis using Adaptive Optics and OCTA Khushzad, F., Yarp, J., Hargrave, A., Sredar, N., Mahesh, V., Tomczak, A., Kipp, L., Han, M., Dubra, A., Moss, H. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528304319

• Comparison of visual function and retinal structure between phases of multiple sclerosis Yarp, J., Khushzad, F., Leishangthem, L., Mahesh, V., Tomczak, A., Han, M., Kipp, L., Moss, H. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528304318

• Changes in immune cell profile, clinical and safety outcomes in fingolimod-treated patients with relapsing multiple sclerosis in the FLUENT study Mao-Draayer, Y., Cohen, J. A., Bar-Or, A., Han, M. H., Singer, B., Jaitly, N., Kolodny, S., Elam, C., Meng, X., Ziehn, M., Cree, B. C. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058006291

• Case series: Hearing loss in neuromyelitis optica spectrum disorders. Multiple sclerosis and related disorders Tugizova, M., Feng, H., Tomczak, A., Steenerson, K., Han, M. 2020; 41: 102032

  Abstract

  BACKGROUND: Aquaporin 4 (AQP4)- and myelin oligodendrocyte glycoprotein (MOG)-associated neuromyelitis optica spectrum disorders (NMOSD) are thought to primarily affect the central nervous system (CNS). However, emerging evidence suggests that there are extra-CNS manifestations of NMOSD, including myopathies, gastrointestinal dysfunction, renal involvement and adverse pregnancy outcomes.1 METHODS: Three patients who reported hearing loss during a NMOSD relapse were identified through a retrospective case review.RESULTS: In this article, we discuss two AQP4-IgG positive NMOSD cases, each presenting with conductive and sensorineural hearing loss, and a case of MOG-IgG-associated NMOSD presenting with sensorineural hearing loss.CONCLUSION: Hearing loss may be present as a relapse in patients with NMOSD. Early recognition and timely treatment are essential to prevent irreversible hearing loss.

  View details for DOI 10.1016/j.msard.2020.102032

  View details for PubMedID 32155460

• Emergence of rheumatoid arthritis following exposure to natalizumab. Multiple sclerosis and related disorders Su Data, E. n., Novic, J. n., Han, M. H. 2020; 40: 101936

  Abstract

  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. BRIEF BACKGROUND: Multiple sclerosis (MS) patients often suffer from concurrent autoimmune conditions, and may be at increased risk for developing rheumatoid arthritis (RA) (Langer-Gould et al., 2010; Tseng et al., 2016). While alemtuzumab and rituximab are known to unmask underlying autoimmune disorders, natalizumab is not commonly associated with autoimmunity. Here, we report a patient with relapsing-remitting MS who developed acute autoimmune arthropathy following exposure to natalizumab. CASE REPORT: A 45-year-old woman with autoimmune thyroiditis presented after episodes of left arm and right leg numbness. MRI showed multiple supratentorial and spinal cord demyelinating lesions. Lumbar puncture yielded CSF with a lymphocytic pleocytosis (11 leukocytes, 97% lymphocytes), normal protein, normal glucose, elevated immunoglobulin G index (2.24), and multiple unmatched oligoclonal bands. Her initial autoimmune workup revealed elevated anti-thyroid peroxidase antibody and rheumatoid factor (22 IU/mL, reference value < 14 IU/mL). The remainder of the patient's rheumatologic evaluation was normal, including aquaporin-4 antibody, anti-nuclear antibody, complements 3 and 4, and Sjogren's antibodies. She fulfilled 2017 McDonald Criteria for multiple sclerosis, and was started on dimethyl fumarate. Three months later, she developed left foot numbness and urinary incontinence. MRI spine showed a new lesion at C7, and her therapy was escalated to natalizumab. Immediately after her initial natalizumab infusion, she experienced transient neck and shoulder pain with decreased range of motion. She had no history of arthropathy. After her second natalizumab infusion, she developed persistent shoulder and hip pain. Her arthralgias resolved after a course of oral steroids. Two weeks after her second natalizumab infusion, she was seen by a rheumatologist who noted mild synovitis of both elbows and wrists on exam, but no significant inflammation involving her shoulders, fingers, knees, ankles, or feet. This time, she had significantly elevated anticyclic citrullinated peptide IgG (> 300 U/mL, reference value < 3 U/mL) and rheumatoid factor (71 IU/mL). Based on the number of small joints involved, and her positive serology, she met 2010 American College of Rheumatology Criteria for rheumatoid arthritis. Natalizumab was discontinued, and the patient was started on methotrexate, with which her rheumatoid arthritis has been controlled for the past two years.

  View details for DOI 10.1016/j.msard.2020.101936

  View details for PubMedID 31982664

• Revealing architectural order with quantitative label-free imaging and deep learning. eLife Guo, S. M., Yeh, L. H., Folkesson, J. n., Ivanov, I. E., Krishnan, A. P., Keefe, M. G., Hashemi, E. n., Shin, D. n., Chhun, B. B., Cho, N. H., Leonetti, M. D., Han, M. H., Nowakowski, T. n., Mehta, S. B. 2020; 9

  Abstract

  We report quantitative label-free imaging with phase and polarization (QLIPP) for simultaneous measurement of density, anisotropy, and orientation 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. We report a variant of UNet architecture, multi-channel 2.5D U-Net, for computationally efficient prediction of fluorescence images in three dimensions and over large fields of view. Further, we develop data normalization methods for accurate prediction of myelin distribution over large brain regions. We show that experimental defects in labeling the human tissue can be rescued with quantitative label-free imaging and neural network model. We anticipate that the proposed method will enable new studies of architectural order at spatial scales ranging from organelles to tissue.

  View details for DOI 10.7554/eLife.55502

  View details for PubMedID 32716843

• The impact of COVID-19 on patients with neuromyelitis optica spectrum disorder; a pilot study. Multiple sclerosis and related disorders Tomczak, A. n., Han, M. H. 2020; 45: 102347

  Abstract

  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. A 15-point questionnaire was administered to 33 participants living in Northern California with NMOSD, MS and other related disorders. Although none of the participants were diagnosed with COVID-19, our results show that 2 participants with NMOSD experienced new onset of neurological symptoms and 2 experienced worsening of previous neurological symptoms - suggesting a possible effect of pandemic-related stress on this CNS autoimmune disorder.

  View details for DOI 10.1016/j.msard.2020.102347

  View details for PubMedID 32645636

• Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Neurology(R) neuroimmunology & neuroinflammation Cook, L. J., Rose, J. W., Alvey, J. S., Jolley, A. M., Kuhn, R., Marron, B., Pederson, M., Enriquez, R., Yearley, J., McKechnie, S., Han, M. H., Tomczak, A. J., Levy, M., Mealy, M. A., Coleman, J., Bennett, J. L., Johnson, R., Barnes-Garcia, M., Traboulsee, A. L., Carruthers, R. L., Lee, L. E., Schubert, J. J., McMullen, K., Kister, I., Rimler, Z., Reid, A., Sicotte, N. L., Planchon, S. M., Cohen, J. A., Ivancic, D., Sedlak, J. L., Sand, I. K., Repovic, P., Amezcua, L., Pruitt, A., Amundson, E., Chitnis, T., Mullin, D. S., Klawiter, E. C., Russo, A. W., Riley, C. S., Onomichi, K. B., Levine, L., Nelson, K. E., Nealon, N. M., Engel, C., Kruse-Hoyer, M., Marcille, M., Tornes, L., Rumpf, A., Greer, A., Kenneally Behne, M., Rodriguez, R. R., Behne, D. W., Blackway, D. W., Coords, B., Blaschke, T. F., Sheard, J., Smith, T. J., Behne, J. M., Yeaman, M. R., Guthy-Jackson Charitable Foundation International Clinical Consortium (GJCF-ICC) 2019; 6 (5): e583

  Abstract

  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 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female.Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

  View details for DOI 10.1212/NXI.0000000000000583

  View details for PubMedID 31355319

• Immunological Aspects of Approved MS Therapeutics FRONTIERS IN IMMUNOLOGY Rommer, P. S., Milo, R., Han, M. H., Satyanarayan, S., Sellner, J., Hauer, L., Illes, Z., Warnke, C., Laurent, S., Weber, M. S., Zhang, Y., Stuve, O. 2019; 10

  View details for DOI 10.3389/fimmu.2019.01564

  View details for Web of Science ID 000475416400001

• Changes in the immune cell profile in fingolimod-treated patients with relapsing multiple sclerosis: primary analysis of the FLUENT study Mao-Draayer, Y., Cohen, J., Bar-Or, A., Cree, B. C., Han, M., Singer, B., Kolodny, S., Meng, X., Schofield, L., Ziehn, M. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965903366

• Immune Cell Subset and Biomarker Changes in Patients with Relapsing Multiple Sclerosis Receiving Fingolimod: Interim Analysis of the FLUENT Study Mao-Draayer, Y., Cohen, J. A., Bar-Or, A., Cree, B. C., Han, M. H., Singer, B. A., Kolodny, S., Meng, X., Schofield, L., Ziehn, M. O. SAGE PUBLICATIONS LTD. 2019: 25

  View details for Web of Science ID 000468918500053

• White-matter-nulled MPRAGE at 7T reveals thalamic lesions and atrophy of specific thalamic nuclei in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) Planche, V., Su, J. H., Mournet, S., Saranathan, M., Dousset, V., Han, M., Rutt, B. K., Tourdias, T. 2019: 1352458519828297

  Abstract

  BACKGROUND:: Investigating the degeneration of specific thalamic nuclei in multiple sclerosis (MS) remains challenging.METHODS:: White-matter-nulled (WMn) MPRAGE, MP-FLAIR, and standard T1-weighted magnetic resonance imaging (MRI) were performed on MS patients ( n=15) and matched controls ( n=12). Thalamic lesions were counted in individual sequences and lesion contrast-to-noise ratio (CNR) was measured. Volumes of 12 thalamic nuclei were measured using an automatic segmentation pipeline specifically developed for WMn-MPRAGE.RESULTS:: WMn-MPRAGE showed more thalamic MS lesions ( n=35 in 9 out of 15 patients) than MP-FLAIR ( n=25) and standard T1 ( n=23), which was associated with significant improvement of CNR ( p<0.0001). MS patients had whole thalamus atrophy ( p=0.003) with lower volumes found for the anteroventral ( p<0.001), the pulvinar ( p<0.0001), and the habenular ( p=0.004) nuclei.CONCLUSION:: WMn-MPRAGE and automatic thalamic segmentation can highlight thalamic MS lesions and measure patterns of focal thalamic atrophy.

  View details for PubMedID 30730233

• MR susceptibility contrast imaging using a 2D simultaneous multi-slice gradient-echo sequence at 7T. PloS one Bian, W., Kerr, A. B., Tranvinh, E., Parivash, S., Zahneisen, B., Han, M. H., Lock, C. B., Goubran, M., Zhu, K., Rutt, B. K., Zeineh, M. M. 2019; 14 (7): e0219705

  Abstract

  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. To compare their image quality with 3D gradient-echo imaging, both 2D and 3D imaging were performed on 11 healthy volunteers and 4 patients with multiple sclerosis (MS). The signal to noise ratio (SNR) in gray and white matter and their contrast to noise ratio (CNR) was simulated for the 2D and 3D magnitude images using parameters from the imaging. The experimental SNRs and CNRs were measured in gray/white matter and deep gray matter structures on magnitude, phase, R2* and QSM images from volunteers and the visibility of MS lesions on these images from patients was visually rated. All SNRs and CNRs were compared between the 2D and 3D imaging using a paired t-test.RESULTS: Although the 3D magnitude images still had significantly higher SNRs (by 13.0~17.6%), the 2D magnitude and QSM images generated significantly higher gray/white matter or globus pallidus/putamen contrast (by 13.3~87.5%) and significantly higher MS lesion contrast (by 5.9~17.3%).CONCLUSION: 2D SMS gradient-echo imaging can serve as an alternative to often used 3D imaging to obtain susceptibility-contrast-weighted images, with an advantage of providing better image contrast and MS lesion sensitivity.

  View details for DOI 10.1371/journal.pone.0219705

  View details for PubMedID 31314813

• Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Neurology(R) neuroimmunology & neuroinflammation Cook, L. J., Rose, J. W., Alvey, J. S., Jolley, A. M., Kuhn, R. n., Marron, B. n., Pederson, M. n., Enriquez, R. n., Yearley, J. n., McKechnie, S. n., Han, M. H., Tomczak, A. J., Levy, M. n., Mealy, M. A., Coleman, J. n., Bennett, J. L., Johnson, R. n., Barnes-Garcia, M. n., Traboulsee, A. L., Carruthers, R. L., Lee, L. E., Schubert, J. J., McMullen, K. n., Kister, I. n., Rimler, Z. n., Reid, A. n., Sicotte, N. L., Planchon, S. M., Cohen, J. A., Ivancic, D. n., Sedlak, J. L., Sand, I. K., Repovic, P. n., Amezcua, L. n., Pruitt, A. n., Amundson, E. n., Chitnis, T. n., Mullin, D. S., Klawiter, E. C., Russo, A. W., Riley, C. S., Onomichi, K. B., Levine, L. n., Nelson, K. E., Nealon, N. M., Engel, C. n., Kruse-Hoyer, M. n., Marcille, M. n., Tornes, L. n., Rumpf, A. n., Greer, A. n., Kenneally Behne, M. n., Rodriguez, R. R., Behne, D. W., Blackway, D. W., Coords, B. n., Blaschke, T. F., Sheard, J. n., Smith, T. J., Behne, J. M., Yeaman, M. R. 2019; 6 (5)

  Abstract

  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.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.As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female.Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

  View details for DOI 10.1212/NXI.0000000000000583

  View details for PubMedID 31454765

• A case of GFAP-astroglial autoimmunity presenting with reversible parkinsonism. Multiple sclerosis and related disorders Tomczak, A. n., Su, E. n., Tugizova, M. n., Carlson, A. M., Kipp, L. B., Feng, H. n., Han, M. H. 2019; 39: 101900

  Abstract

  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. Our patient was a 66-year old male who experienced progressive somnolence, apathy, anxiety, right arm tremor, urinary retention, progressive weakness, and falls over the course of three months, followed by acute delusional psychosis. His neurologic exam on hospital admission was notable for cognitive impairment, myoclonus, rigidity, right hand action tremor, bradykinesia, shuffling gait, and dysmetria. Cerebrospinal fluid examination showed elevated protein, lymphocytic pleocytosis, and one unique oligoclonal band. Magnetic resonance imaging (MRI) revealed non-specific T2/FLAIR hyperintensities in the brain and longitudinally extensive transverse myelitis in the cervical spine. FDG-PET showed a pattern of brain uptake suspicious for limbic encephalitis. Serum and CSF paraneoplastic panel showed presence of GFAP immunoglobulin G (IgG). Treatment with corticosteroids resulted in clinical and radiographic improvement. However, the patient was treated with anti-CD20 immunotherapy due to steroid-dependence. This case exemplifies the recently described neurologic syndrome of autoimmune GFAP astrocytopathy presenting with encephalomyelitis and parkinsonism, reversed by B lymphocyte depletion.

  View details for DOI 10.1016/j.msard.2019.101900

  View details for PubMedID 31881522

• The FLUENT study design: investigating immune cell subset and neurofilament changes in patients with relapsing multiple sclerosis treated with fingolimod. Multiple sclerosis journal - experimental, translational and clinical Cohen, J. A., Bar-Or, A., Cree, B. A., Mao-Draayer, Y., Han, M. H., Singer, B., Jannu, A., Kolodny, S., Meng, X., Winger, R. C. 2019; 5 (1): 2055217318819245

  Abstract

  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.Objective: The FLUENT study will investigate temporal changes in circulating immune cell subsets in patients with RMS treated with fingolimod. Secondary objectives include examining the association between anti-John Cunningham virus (JCV) antibody status/index and phenotypic changes in innate and T and B cell subsets in patients on fingolimod therapy, and the association between serum neurofilament levels and clinical outcomes.Methods: FLUENT is a prospective, multicenter, two-cohort, nonrandomized, open-label Phase IV study. Cohort 1 will include fingolimod-naive patients and Cohort 2 will include patients who have received fingolimod 0.5 mg/day continuously for ≥2 years. Changes in the cellular components of the innate and adaptive immune system will be characterized over 12 months.Results: The study is ongoing.Conclusion: FLUENT may provide evidence for the use of immunologic profiling in predicting efficacy and risk of infection in patients with RMS treated with fingolimod.

  View details for PubMedID 30637116

• Myeloid sphingosine-1-phosphate receptor 1 is important for CNS autoimmunity and neuroinflammation. Journal of autoimmunity Tsai, H. C., Nguyen, K. n., Hashemi, E. n., Engleman, E. n., Hla, T. n., Han, M. H. 2019

  Abstract

  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 (S1P1) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P1(S5A)] developed severe, TH17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P1-mediated TH17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P1 signaling in myeloid cells. First, utilizing the S1P1(S5A) mice in the EAE model, we observed that S1P1 activated and enhanced antigen presentation function in myeloid cells. Second, sequential phosphorylation of STAT3 occurred in dendritic cells, monocytes, and macrophages/microglia during neuroinflammation. Third, we show that pro-inflammatory (CD45hiCD11b+Ly6Chi) monocytes contribute to TH17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P1 overexpression (S1pr1f/stop/f:LysMCre) mice demonstrate that myeloid cell S1P1 directly contributes to severity of neuroinflammation. These findings reveal the critical contribution of myeloid-S1P1 signaling in CNS autoimmunity.

  View details for DOI 10.1016/j.jaut.2019.06.001

  View details for PubMedID 31202617

• Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurology(R) neuroimmunology & neuroinflammation Moreno, M. A., Or-Geva, N., Aftab, B. T., Khanna, R., Croze, E., Steinman, L., Han, M. H. 2018; 5 (4): e466

  Abstract

  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).Results: We report the presence of EBV latent membrane protein 1 (LMP-1) in 93% of MS and 78% of control brains, with a greater percentage of MS brains containing CD138+ plasma cells and LMP-1-rich populations. Notably, 78% of chronic MS lesions and 33.3% of non-MS brains contained parenchymal CD138+ plasma cells. EBV early lytic protein, EBV immediate-early lytic gene (BZLF1), was also observed in 46% of MS, primarily in association with chronic lesions and 44% of non-MS brain tissue. Furthermore, 85% of MS brains revealed frequent EBER-positive cells, whereas non-MS brains seldom contained EBER-positive cells. EBV infection was detectable, by immunohistochemistry and by in situ hybridization, in both MS and non-MS brains, although latent virus was more prevalent in MS brains, while lytic virus was restricted to chronic MS lesions.Conclusions: Together, our observations suggest an uncharacterized link between the EBV virus life cycle and MS pathogenesis.

  View details for PubMedID 29892607

• Molecular signature of Epstein-Barr virus infection in MS brain lesions NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Moreno, M. A., Or-Geva, N., Aftab, B. T., Khanna, R., Croze, E., Steinman, L., Han, M. H. 2018; 5 (4)

  View details for DOI 10.1212/NXI.0000000000000466

  View details for Web of Science ID 000442610100007

• Investigating Immune Phenotype Biomarker Changes in Patients with Relapsing MS Treated with Fingolimod 0.5 mg/day: The FLUENT Study Cohen, J., Bar-Or, A., Cree, B., Mao-Draayer, Y., Han, M., Singer, B., Jannu, A., Kolodny, S., Meng, X., Winger, R. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090800375

• Investigating Immune Phenotype Biomarker Changes in Patients with Relapsing MS Treated with Fingolimod 0.5 Mg/Day: The Fluent Study Cohen, J. A., Bar-Or, A., Cree, B. C., Mao-Draayer, Y., Han, M. H., Singer, B. A., Jannu, A., Kolodny, S., Meng, X., Winger, R. SAGE PUBLICATIONS LTD. 2018: 14

  View details for Web of Science ID 000429034600031

• Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage NEURON Petersen, M. A., Ryu, J., Chang, K., Etxeberria, A., Bardehle, S., Mendiola, A. S., Kamau-Devers, W., Fancy, S. J., Thor, A., Bushong, E. A., Baeza-Raja, B., Syme, C. A., Wu, M. D., Coronado, P., Meyer-Franke, A., Yahn, S., Pous, L., Lee, J. K., Schachtrup, C., Lassmann, H., Huang, E. J., Han, M. H., Absinta, M., Reich, D. S., Ellisman, M. H., Rowitch, D. H., Chan, J. R., Akassoglou, K. 2017; 96 (5): 1003-+

  Abstract

  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. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

  View details for PubMedID 29103804

  View details for PubMedCentralID PMC5851281

• A 3-Dimensional Hydrogel Model of Multiple Sclerosis Brain Lesions Reveals Insights into Re-Myelination JOURNAL OF BIOMATERIALS AND TISSUE ENGINEERING Baisiwala, S., Moreno, M. A., Wang, C., Rogan, H. W., Tsai, H., Yang, F., Han, M. H. 2017; 7 (9): 868–75

  View details for DOI 10.1166/jbt.2017.1644

  View details for Web of Science ID 000410601000015

• Phosphorylation of aB-crystallin supports reactive astrogliosis in demyelination. Proceedings of the National Academy of Sciences of the United States of America Kuipers, H. F., Yoon, J., van Horssen, J., Han, M. H., Bollyky, P. L., Palmer, T. D., Steinman, L. 2017; 114 (9): E1745-E1754

  Abstract

  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. Using the cuprizone model of demyelination, a noninflammatory model that allows the analysis of glial responses in MS, we show that endogenous CRYAB expression is associated with increased severity of demyelination. Moreover, we demonstrate a strong correlation between the expression of CRYAB and the extent of reactive astrogliosis in demyelinating areas and in in vitro assays. In addition, we reveal that CRYAB is differentially phosphorylated in astrocytes in active demyelinating MS lesions, as well as in cuprizone-induced lesions, and that this phosphorylation is required for the reactive astrocyte response associated with demyelination. Furthermore, taking a proteomics approach to identify proteins that are bound by the phosphorylated forms of CRYAB in primary cultured astrocytes, we show that there is clear differential binding of protein targets due to the specific phosphorylation of CRYAB. Subsequent Ingenuity Pathway Analysis of these targets reveals implications for intracellular pathways and biological processes that could be affected by these modifications. Together, these findings demonstrate that astrocytes play a pivotal role in demyelination, making them a potential target for therapeutic intervention, and that phosphorylation of CRYAB is a key factor supporting the pathogenic response of astrocytes to oligodendrocyte injury.

  View details for DOI 10.1073/pnas.1621314114

  View details for PubMedID 28196893

  View details for PubMedCentralID PMC5338510

• Integrative proteomics, genomics, and translational immunology approaches reveal mutated forms of Proteolipid Protein 1 (PLP1) and mutant-specific immune response in multiple sclerosis. Proteomics Qendro, V., Bugos, G. A., Lundgren, D. H., Glynn, J., Han, M. H., Han, D. K. 2017

  Abstract

  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. Quantification of wild type and mutant PLP RNA levels by qPCR further validated the presence of mutant PLP RNA in the MS patients. To seek evidence linking mutations in abundant myelin proteins and immune-mediated destruction of myelin, specific immune response against mutant PLP1 in MS patients was examined. Thus, we have designed paired, wild type and mutant peptide microarrays, and examined antibody response to multiple mutated PLP1 in sera from MS patients. Consistent with the idea of different patients exhibiting unique mutation profiles, we found that 13 out of 20 MS patients showed antibody responses against specific but not against all the mutant-PLP1 peptides. Interestingly, we found mutant PLP-directed antibody response against specific mutant peptides in the sera of pre-MS controls. The results from integrative proteomic, genomic, and immune analyses reveal a possible mechanism of mutation-driven pathogenesis in human MS. The study also highlights the need for integrative genomic and proteomic analyses for uncovering pathogenic mechanisms of human diseases.

  View details for DOI 10.1002/pmic.201600322

  View details for PubMedID 28191734

• Imaging B cells in a mouse model of multiple sclerosis using (64)Cu-Rituximab-PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Hoehne, A. n., Mayer, A. T., Lechtenberg, K. n., Moreno, M. n., Gowrishankar, G. n., Ilovich, O. n., Natarajan, A. n., Johnson, E. M., Nguyen, J. n., Quach, L. n., Han, M. n., Buckwalter, M. n., Chandra, S. n., Gambhir, S. S. 2017

  Abstract

  B lymphocytes are a key pathological feature of multiple sclerosis (MS), and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to non-invasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here we evaluated (64)Cu-Rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using positron emission tomography (PET). Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of Myelin Oligodendrocyte Glycoprotein fragment1-125 (MOG1-125) emulsified in complete Freund's adjuvant. Control mice received complete Freund's adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19h following (64)Cu-Rituximab administration. Mice were perfused and sacrificed after final PET scan, and radioactivity in dissected tissues was measured with a gamma-counter. CNS tissues from these mice were immunostained to quantify B cells or further analyzed via digital autoradiography. Results: Lumbar spinal cord PET signal was significantly higher in EAE mice compared to controls at all evaluated time points (e.g., 1h post-injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 %ID/g, p<0.05). (64)Cu-Rituximab-PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice compared to 1.25±0.08 and 2.24±0.11%ID/g for controls, p<0.05 for all regions except striatum and thalamus at 1h post-injection. Similarly, ex vivo biodistribution results revealed notably higher (64)Cu-Rituximab uptake in brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased (64)Cu-Rituximab uptake in CNS tissues corresponded with elevated B cells. Conclusion: B cells can be detected in the CNS of EAE mice using (64)Cu-Rituximab-PET. Results from these studies warrant further investigation of (64)Cu-Rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the clinic.

  View details for PubMedID 28687602

• Exosomal proteome analysis of cerebrospinal fluid detects biosignatures of neuromyelitis optica and multiple sclerosis. Clinica chimica acta; international journal of clinical chemistry Lee, J., McKinney, K. Q., Pavlopoulos, A. J., Han, M. H., Kim, S., Kim, H. J., Hwang, S. 2016; 462: 118-126

  Abstract

  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. MetaCore pathway analysis of significant proteins supported the involvement of these proteins in disease progression via neurological pathway. Expression levels of target molecules from orthogonal label-free quantification employing quadrupole-Orbitrap hybrid mass spectrometry were in good agreement with those from Western blotting. Additional investigation of GFAP and fibronectin as representative disease molecules revealed their presence in intact exosomes as detected by flow cytometry. This comprehensive study suggests that the exosomal proteomic analysis of CSF can be applied to the identification and characterization of inflammatory disorders of the central nervous system.

  View details for DOI 10.1016/j.cca.2016.09.001

  View details for PubMedID 27609124

• In Vivo 7T MR Quantitative Susceptibility Mapping Reveals Opposite Susceptibility Contrast between Cortical and White Matter Lesions in Multiple Sclerosis AMERICAN JOURNAL OF NEURORADIOLOGY Bian, W., Tranvinh, E., Tourdias, T., Han, M., Liu, T., Wang, Y., Rutt, B., Zeineh, M. M. 2016; 37 (10): 1808-1815

  Abstract

  Magnetic susceptibility measured with quantitative susceptibility mapping has been proposed as a biomarker for demyelination and inflammation in patients with MS, but investigations have mostly been on white matter lesions. A detailed characterization of cortical lesions has not been performed. The purpose of this study was to evaluate magnetic susceptibility in both cortical and WM lesions in MS by using quantitative susceptibility mapping.Fourteen patients with MS were scanned on a 7T MR imaging scanner with T1-, T2-, and T2*-weighted sequences. The T2*-weighted sequence was used to perform quantitative susceptibility mapping and generate tissue susceptibility maps. The susceptibility contrast of a lesion was quantified as the relative susceptibility between the lesion and its adjacent normal-appearing parenchyma. The susceptibility difference between cortical and WM lesions was assessed by using a t test.The mean relative susceptibility was significantly negative for cortical lesions (P < 10(-7)) but positive for WM lesions (P < 10(-22)). A similar pattern was also observed in the cortical (P = .054) and WM portions (P = .043) of mixed lesions.The negative susceptibility in cortical lesions suggests that iron loss dominates the susceptibility contrast in cortical lesions. The opposite susceptibility contrast between cortical and WM lesions may reflect both their structural (degree of myelination) and pathologic (degree of inflammation) differences, in which the latter may lead to a faster release of iron in cortical lesions.

  View details for DOI 10.3174/ajnr.A4830

  View details for Web of Science ID 000383984600014

  View details for PubMedID 27282860

• Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation DRUGS Tsai, H., Han, M. H. 2016; 76 (11): 1067-1079

  Abstract

  Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.

  View details for DOI 10.1007/s40265-016-0603-2

  View details for Web of Science ID 000379497000001

  View details for PubMedID 27318702

• Intravenous Transplantation of Mesenchymal Progenitors Distribute Solely to the Lungs and Improve Outcomes in Cervical Spinal Cord Injury STEM CELLS White, S. V., Czisch, C. E., Han, M. H., Plant, C. D., Harvey, A. R., Plant, G. W. 2016; 34 (7): 1812-1825

  Abstract

  Cellular transplantation strategies utilizing intraspinal injection of mesenchymal progenitor cells have been reported as beneficial for spinal cord injuries. However, intraspinal injection is not only technically challenging, but requires invasive surgical procedures for patients. Therefore, we investigated the feasibility and potential benefits of non-invasive intravenous injection of mesenchymal progenitor cells in two models of cervical spinal cord injury, unilateral C5 contusion and complete unilateral C5 hemisection. Mesenchymal progenitor cells were isolated from GFP-luciferase transgenic mice compact bone (1x10(6) cells) or vehicle (HBSS) were intravenously injected via the tail vein at D1, D3, D7, D10 or D14. Transplanted mesenchymal progenitor cells were tracked via bioluminescence imaging. Live in vivo imaging data showed that intravenously injected mesenchymal progenitor cells accumulate in the lungs, confirmed by post-mortem bioluminescence signal - irrespective of the time of injection or injury model. The results showed a rapid, positive modulation of the inflammatory response providing protection to the injured spinal cord tissue. Histological processing of the lungs showed GFP(+) cells evenly distributed around the alveoli. We propose that injected cells can act as cellular target decoys to an immune system primed by injury, thereby lessening the inflammatory response at the injury site. We also propose that intravenous injected mesenchymal progenitor cells modulate the immune system via the lungs through secreted immune mediators or contact interaction with peripheral organs. In conclusion, the timing of intravenous injection of mesenchymal progenitor cells is key to the success for improving function and tissue preservation following cervical spinal cord injury. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/stem.2364

  View details for Web of Science ID 000379902900009

  View details for PubMedID 26989838

• Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation. JCI insight Tsai, H., Huang, Y., Garris, C. S., Moreno, M. A., Griffin, C. W., Han, M. H. 2016; 1 (9)

  Abstract

  Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models. Long-term treatment with FTY720 induced significant lymphopenia and suppressed Th17 response in the peripheral immune system via downregulating STAT3 phosphorylation in both WT and S1PR1(S5A) mice. However, FTY720 did not effectively prevent neuroinflammation in the S1PR1(S5A) EAE mice as a result of encephalitogenic cells expressing C-C chemokine receptor 6 (CCR6). Combined treatment with FTY720 and anti-CCR6 delayed disease progression in S1PR1(S5A) EAE mice, suggesting that CCR6-mediated cell trafficking can overcome the effects of FTY720. This work may have translational relevance regarding FTY720 efficacy in MS patients and suggests that cell type-specific therapies may enhance therapeutic efficacy in MS.

  View details for PubMedID 27699272

• Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation JCI Insight Tsai, H. 2016; 1 (9): e86462

  Abstract

  Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human S1PR1 variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defective S1pr1 gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models. Long-term treatment with FTY720 induced significant lymphopenia and suppressed Th17 response in the peripheral immune system via downregulating STAT3 phosphorylation in both WT and S1PR1(S5A) mice. However, FTY720 did not effectively prevent neuroinflammation in the S1PR1(S5A) EAE mice as a result of encephalitogenic cells expressing C-C chemokine receptor 6 (CCR6). Combined treatment with FTY720 and anti-CCR6 delayed disease progression in S1PR1(S5A) EAE mice, suggesting that CCR6-mediated cell trafficking can overcome the effects of FTY720. This work may have translational relevance regarding FTY720 efficacy in MS patients and suggests that cell type-specific therapies may enhance therapeutic efficacy in MS.

  View details for DOI 10.1172/jci.insight.86462

  View details for PubMedCentralID PMC5033897

• Acute and Chronic Management of Neuromyelitis Optica Spectrum Disorder CURRENT TREATMENT OPTIONS IN NEUROLOGY Sherman, E., Han, M. H. 2015; 17 (11)

  Abstract

  Neuromyelitis optica and neuromyelitis optica spectrum disorder (NMO/NMOSD) is a rare but clinically aggressive demyelinating disease of the central nervous system (CNS) caused by antibodies against water channel protein aquaporin 4 (AQP4) in the astrocytic foot processes. Patients typically present with optic neuritis (ON) or longitudinally extensive transverse myelitis (LETM). The majority of patients with NMOSD show good response to treatment with steroids and plasmapheresis in the acute setting; however, 90 % of patients will eventually have clinical relapses and accrue permanent disability. Currently, immune modulation is the mainstay of maintenance therapy with anti CD-20 (rituximab, Rituxan™) having collectively the strongest evidence to support its use and mycophenolate mofetil having comparable reductions in absolute relapse rate (ARR) and expanded disability status scale (EDSS) scores. Azathioprine, mitoxantrone, and methotrexate also have retrospective case series data that demonstrate reduction in ARR and stabilization of EDSS but with higher relapse rates and exposure to greater risk of treatment toxicities. Excitingly, multiple novel therapies are under clinical study for patients who are refractory to these first-line therapies including monoclonal antibodies targeting interleukin-6 (IL-6), CD19, CD20, complement, and neutrophil elastase inhibitors which may provide additional options for patients with severe clinical presentations. Importantly, no randomized clinical trials have been published to date comparing clinical outcomes of different maintenance therapies in NMOSD. Several trials are currently underway, and results will help guide future management decisions as current evidence is from many small, retrospective case series and cohort studies with many potential confounds.

  View details for DOI 10.1007/s11940-015-0378-x

  View details for PubMedID 26433388

  View details for PubMedCentralID PMC4592697

• Update on biomarkers in neuromyelitis optica. Neurology® neuroimmunology & neuroinflammation Melamed, E., Levy, M., Waters, P. J., Sato, D. K., Bennett, J. L., John, G. R., Hooper, D. C., Saiz, A., Bar-Or, A., Kim, H. J., Pandit, L., Leite, M. I., Asgari, N., Kissani, N., Hintzen, R., Marignier, R., Jarius, S., Marcelletti, J., Smith, T. J., Yeaman, M. R., Han, M. H., Aktas, O., Apiwattanakul, M., Banwell, B., Bichuetti, D., Broadley, S., Cabre, P., Chitnis, T., de Seze, J., Fujihara, K., Greenberg, B., Hellwig, K., Iorio, R., Jarius, S., Klawiter, E., Kleiter, I., Lana-Peixoto, M., NAKASHIMA, O'Connor, K., Palace, J., Paul, F., Prayoonwiwat, N., Ruprecht, K., Stuve, O., Tedder, T., Tenembaum, S., Garrahan, J. P., Aires, B., Van Herle, K., Van Pelt, D., Villoslada, P., Waubant, E., Weinshenker, B., Wingerchuk, D., Würfel, J., Zamvil, S. 2015; 2 (4)

  Abstract

  Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.

  View details for DOI 10.1212/NXI.0000000000000134

  View details for PubMedID 26236760

• HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature Blaho, V. A., Galvani, S., Engelbrecht, E., Liu, C., Swendeman, S. L., Kono, M., Proia, R. L., Steinman, L., Han, M. H., Hla, T. 2015; 523 (7560): 342-346

  Abstract

  Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P1 signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.

  View details for DOI 10.1038/nature14462

  View details for PubMedID 26053123

  View details for PubMedCentralID PMC4506268

• Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder JAMA NEUROLOGY Kremer, S., Renard, F., Achard, S., Lana-Peixoto, M. A., Palace, J., Asgari, N., Klawiter, E. C., Tenembaum, S. N., Banwell, B., Greenberg, B. M., Bennett, J. L., Levy, M., Villoslada, P., Saiz, A., Fujihara, K., Chan, K., Schippling, S., Paul, F., Kim, H., de Seze, J., Wuerfel, J. T., Guthy-Jackson Charitable Fdn GJCF 2015; 72 (7): 815–22

  Abstract

  Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field. Although quantitative measures such as proton MR spectroscopy or magnetization transfer imaging have not reproducibly revealed diffuse brain injury, preliminary data from diffusion-weighted imaging and brain tissue volumetry indicate greater white matter than gray matter degradation. These findings could be confirmed by ultrahigh-field MRI. The use of nonconventional MRI techniques may further our understanding of the pathogenic processes in NMO spectrum disorders and may help us identify the distinct radiographic features corresponding to specific phenotypic manifestations of this disease.

  View details for PubMedID 26010909

  View details for PubMedCentralID PMC4828237

• Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography MULTIPLE SCLEROSIS JOURNAL Bennett, J. L., de Seze, J., Lana-Peixoto, M., Palace, J., Waldman, A., Schippling, S., Tenembaum, S., Banwell, B., Greenberg, B., Levy, M., Fujihara, K., Chan, K. H., Kim, H. J., Asgari, N., Sato, D. K., Saiz, A., Wuerfel, J., Zimmermann, H., Green, A., Villoslada, P., Paul, F., Iorio, R., Paul, F., Wuerfel, J., Cabre, P., Marignier, R., de Seze, J., Tenembaum, S., Villoslada, P., Levy, M., Chitnis, T., Klawiter, E. C., Wingerchuk, D., Weinshenker, B., Kim, H., Pandit, L., Leite, M., Palace, J., Simon, J., Apiwattanakul, M., Kleiter, I., Broadley, S., Prayoonwiwat, N., Han, M., Hellwig, K., Banwell, B., van Herle, K., John, G., Hooper, D., Fujihara, K., Nakashima, I., Sato, D., Bichuetti, D., Yeaman, M. R., Waubant, E., Zamvil, S., Bennett, J., Smith, T., Lana-Peixoto, M., Stuve, O., Greenberg, B., Aktas, O., Wuerfel, J., Asgari, N., Jacob, A., O'Connor, K., Saiz, A., GJCF-ICC BR 2015; 21 (6): 678–88

  Abstract

  Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel aquaporin-4 present in up to 80% of NMO patients enables distinction from MS. Optic neuritis may occur in either condition resulting in neuro-anatomical retinal changes. Optical coherence tomography (OCT) has become a useful tool for analyzing retinal damage both in MS and NMO. Numerous studies showed that optic neuritis in NMO typically results in more severe retinal nerve fiber layer (RNFL) and ganglion cell layer thinning and more frequent development of microcystic macular edema than in MS. Furthermore, while patients' RNFL thinning also occurs in the absence of optic neuritis in MS, subclinical damage seems to be rare in NMO. Thus, OCT might be useful in differentiating NMO from MS and serve as an outcome parameter in clinical studies.

  View details for DOI 10.1177/1352458514567216

  View details for Web of Science ID 000354258600002

  View details for PubMedID 25662342

  View details for PubMedCentralID PMC4425816

• Patient experience and practice trends in multiple sclerosis - clinical utility of fingolimod PATIENT PREFERENCE AND ADHERENCE Lee, J., Han, M. H. 2015; 9

  Abstract

  Targeting sphingosine-1-phosphate pathway with orally available immune-modulatory fingolimod (Gilenya™) therapy ameliorates relapsing-remitting multiple sclerosis (RRMS) by decreasing relapse rate as shown in FREEDOMS and TRANSFORMS. Fingolimod has also been shown to be superior to interferon-beta therapy as evidenced by TRANSFORMS. Albeit multiple benefits in treatment of multiple sclerosis including high efficacy and ease of administration, potential untoward effects such as cardiotoxicity, risk of infection, and cancer exist, thus mandating careful screening and frequent monitoring of patients undergoing treatment with fingolimod. This review outlines mechanism of action, observations, side effects, and practice guidelines on use of fingolimod in treatment of RRMS.

  View details for DOI 10.2147/PPA.S57354

  View details for Web of Science ID 000354946400001

  View details for PubMedID 26056436

  View details for PubMedCentralID PMC4446999

• Differential phosphorylation of alpha B-crystallin in astrocytes and oligodendrocytes suggests a diversity in its biological function Kuipers, H. F., Yoon, J., Winderl, J., Van Horssen, J., Han, M. H., Palmer, T. D., Steinman, L. ELSEVIER SCIENCE BV. 2014: 157–58

  View details for DOI 10.1016/j.jneuroim.2014.08.423

  View details for Web of Science ID 000345192100412

• Genome-wide RNA expression profiling in human grey and white matter tissue reveals a role for PSA-NCAM dysregulation in MS pathogenesis Bruinsma, I., Eijsink, V., Kooi, E., Baranzini, S., Ji, X., Axtell, R., Han, M., Kuipers, H., Sobel, R., Polman, C., Geurts, J., Martens, G., Poelmans, G., Steinman, L., De Jong, B. ELSEVIER SCIENCE BV. 2014: 180–81

  View details for DOI 10.1016/j.jneuroim.2014.08.485

  View details for Web of Science ID 000345192100474

• Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond IMMUNOLOGY Garris, C. S., Blaho, V. A., Hla, T., Han, M. H. 2014; 142 (3): 347-353

  Abstract

  Sphingosine-1-phosphate (S1P) is a lipid second messenger that signals via five G protein-coupled receptors (S1P1-5 ). S1P receptor (S1PR) signalling is associated with a wide variety of physiological processes including lymphocyte biology, their recirculation and determination of T-cell phenotypes. The effect of FTY720 (Fingolimod, Gilenya™) to regulate lymphocyte egress and to ameliorate paralysis in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis led to the use of FTY720 as a first-line oral agent for treatment of relapsing-remitting multiple sclerosis. However, a significant body of research suggests that S1P signalling may participate in diverse immune regulatory functions other than lymphocyte trafficking. This review article discusses the current knowledge of S1P signalling in the fate and function of T regulatory, T helper type 17 and memory T cells in health and disease.

  View details for DOI 10.1111/imm.12272

  View details for Web of Science ID 000337600500003

  View details for PubMedCentralID PMC4080950

• Sphingosine-1-Phosphate Receptor Phosphorylation and its Effects on Autoimmune Neuroinflammation Garris, C. S., Wu, L., Sobel, R. A., Snyder, M., Hla, T. T., Dorfman, L. J., Han, M. H. SAGE PUBLICATIONS LTD. 2014: 958

  View details for Web of Science ID 000337854400196

• Optimization of magnetization-prepared 3-dimensional fluid attenuated inversion recovery imaging for lesion detection at 7 T. Investigative radiology Saranathan, M., Tourdias, T., Kerr, A. B., Bernstein, J. D., Kerchner, G. A., Han, M. H., Rutt, B. K. 2014; 49 (5): 290-298

  Abstract

  The aim of this study was to optimize the 3-dimensional (3D) fluid attenuated inversion recovery (FLAIR) pulse sequence for isotropic high-spatial-resolution imaging of white matter (WM) and cortical lesions at 7 T.We added a magnetization-prepared (MP) FLAIR module to a Cube 3D fast spin echo sequence and optimized the refocusing flip angle train using extended phase graph simulations, taking into account image contrast, specific absorption rate (SAR), and signal-to-noise ratio (SNR) as well as T1/T2 values of the different species of interest (WM, grey matter, lesions) at 7 T. We also effected improved preparation homogeneity at 7 T by redesigning the refocusing pulse used in the MP segments. Two sets of refocusing flip angle trains-(a) an SNR-optimal and (b) a contrast-optimal set-were derived and used to scan 7 patients with Alzheimer disease/cognitive impairment and 7 patients with multiple sclerosis. Conventional constant refocusing flip MP-FLAIR images were also acquired for comparison. Lesion SNR, contrast, and lesion count were compared between the 2 optimized and the standard FLAIR sequences.Whole brain coverage with 0.8 mm isotropic spatial resolution in ∼5-minute scan times was achieved using the optimized 3D FLAIR sequences at clinically acceptable SAR levels. The SNR efficiency of the SNR-optimal sequence was significantly better than that of conventional constant refocusing flip MP-FLAIR sequence, whereas the scan time was reduced more than 2-fold (∼5 vs >10 minutes). The contrast efficiency of the contrast-optimal sequence was comparable with that of the constant refocusing flip sequence. Lesion load ascertained by lesion counting was not significantly different among the sequences.Magnetization-prepared FLAIR-Cube with refocusing flip angle trains optimized for SNR and contrast can be used to characterize WM and cortical lesions at 7 T with 0.8 mm isotropic resolution in short scan times and without SAR penalty.

  View details for DOI 10.1097/RLI.0000000000000041

  View details for PubMedID 24566291

• Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nature immunology Garris, C. S., Wu, L., Acharya, S., Arac, A., Blaho, V. A., Huang, Y., Moon, B. S., Axtell, R. C., Ho, P. P., Steinberg, G. K., Lewis, D. B., Sobel, R. A., Han, D. K., Steinman, L., Snyder, M. P., Hla, T., Han, M. H. 2013; 14 (11): 1166-1172

  Abstract

  Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.

  View details for DOI 10.1038/ni.2730

  View details for PubMedID 24076635

• Piet Mondrian's trees and the evolution in understanding multiple sclerosis, Charcot Prize Lecture 2011 MULTIPLE SCLEROSIS JOURNAL Steinman, L., Axtell, R. C., Barbieri, D., Bhat, R., Brownell, S. E., de Jong, B. A., Dunn, S. E., Grant, J. L., Han, M. H., Ho, P. P., Kuipers, H. F., Kurnellas, M. P., Ousman, S. S., Rothbard, J. B. 2013; 19 (1): 5-14

  Abstract

  Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian's progressive interpretations of trees serve as a heuristic.

  View details for DOI 10.1177/1352458512470730

  View details for Web of Science ID 000313272100003

  View details for PubMedID 23303879

• Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice JOURNAL OF EXPERIMENTAL MEDICINE Han, M. H., Lundgren, D. H., Jaiswal, S., Chao, M., Graham, K. L., Garris, C. S., Axtell, R. C., Ho, P. P., Lock, C. B., Woodard, J. I., Brownell, S. E., Zoudilova, M., Hunt, J. F., Baranzini, S. E., Butcher, E. C., Raine, C. S., Sobel, R. A., Han, D. K., Weissman, I., Steinman, L. 2012; 209 (7): 1325-1334

  Abstract

  Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47(-/-) mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.

  View details for DOI 10.1084/jem.20101974

  View details for Web of Science ID 000306174300008

  View details for PubMedID 22734047

  View details for PubMedCentralID PMC3405500

• Identification of Naturally Occurring Fatty Acids of the Myelin Sheath That Resolve Neuroinflammation SCIENCE TRANSLATIONAL MEDICINE Ho, P. P., Kanter, J. L., Johnson, A. M., Srinagesh, H. K., Chang, E., Purdy, T. M., Van Haren, K., Wikoff, W. R., Kind, T., Khademi, M., Matloff, L. Y., Narayana, S., Hur, E. M., Lindstrom, T. M., He, Z., Fiehn, O., Olsson, T., Han, X., Han, M. H., Steinman, L., Robinson, W. H. 2012; 4 (137)

  Abstract

  Lipids constitute 70% of the myelin sheath, and autoantibodies against lipids may contribute to the demyelination that characterizes multiple sclerosis (MS). We used lipid antigen microarrays and lipid mass spectrometry to identify bona fide lipid targets of the autoimmune response in MS brain, and an animal model of MS to explore the role of the identified lipids in autoimmune demyelination. We found that autoantibodies in MS target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. Administration of these lipids ameliorated experimental autoimmune encephalomyelitis by suppressing activation and inducing apoptosis of autoreactive T cells, effects mediated by the lipids' saturated fatty acid side chains. Thus, phospholipids represent a natural anti-inflammatory class of compounds that have potential as therapeutics for MS.

  View details for DOI 10.1126/scitranslmed.3003831

  View details for PubMedID 22674551

• Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein MULTIPLE SCLEROSIS JOURNAL Herges, K., de Jong, B. A., Kolkowitz, I., Dunn, C., Mandelbaum, G., Ko, R. M., Maini, A., Han, M. H., Killestein, J., Polman, C., Goodyear, A. L., Dunn, J., Steinman, L., Axtell, R. C. 2012; 18 (4): 398-408

  Abstract

  The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-β treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-β, in contrast to disease induced with Th1 where treatment attenuated symptoms.This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease.Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-β on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 or Th17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor.We show Th17 cytokines, granulocyte chemokines, type 1 interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-β stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE.The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.

  View details for DOI 10.1177/1352458512440060

  View details for Web of Science ID 000302289900006

  View details for PubMedID 22343184

  View details for PubMedCentralID PMC3319834

• Impaired neurosteroid synthesis in multiple sclerosis BRAIN Noorbakhsh, F., Ellestad, K. K., Maingat, F., Warren, K. G., Han, M. H., Steinman, L., Baker, G. B., Power, C. 2011; 134: 2703-2721

  Abstract

  High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription-polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis.

  View details for DOI 10.1093/brain/awr200

  View details for Web of Science ID 000294959800025

  View details for PubMedID 21908875

• T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis NATURE MEDICINE Axtell, R. C., de Jong, B. A., Boniface, K., Van der Voort, L. F., Bhat, R., De Sarno, P., Naves, R., Han, M., Zhong, F., Castellanos, J. G., Mair, R., Christakos, A., Kolkowitz, I., Katz, L., Killestein, J., Polman, C. H., Malefyt, R. d., Steinman, L., Raman, C. 2010; 16 (4): 406-U21

  Abstract

  Interferon-beta (IFN-beta) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-beta in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-beta was effective in reducing EAE symptoms induced by T helper type 1 (T(H)1) cells but exacerbated disease induced by T(H)17 cells. Effective treatment in T(H)1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In T(H)17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-beta treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-gamma. In the absence of IFN-gamma signaling, IFN-beta therapy was ineffective in EAE. In RRMS patients, IFN-beta nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-beta is proinflammatory in T(H)17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-beta.

  View details for DOI 10.1038/nm.2110

  View details for Web of Science ID 000276446800044

  View details for PubMedID 20348925

  View details for PubMedCentralID PMC3042885

• Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1-and TH17-mediated autoimmunity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Platten, M., Youssef, S., Hur, E. M., Ho, P. P., Han, M. H., Lanz, T. V., Phillips, L. K., Goldstein, M. J., Bhat, R., Raine, C. S., Sobel, R. A., Steinman, L. 2009; 106 (35): 14948-14953

  Abstract

  The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.

  View details for DOI 10.1073/pnas.0903958106

  View details for Web of Science ID 000269481000040

  View details for PubMedID 19706421

  View details for PubMedCentralID PMC2736463

• Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system NATURE MEDICINE Schulze-Topphoff, U., Prat, A., Prozorovski, T., Siffrin, V., Paterka, M., Herz, J., Bendix, I., Ifergan, I., Schadock, I., Mori, M. A., van Horssen, J., Schroetter, F., Smorodchenko, A., Han, M. H., Bader, M., Steinman, L., Aktas, O., Zipp, F. 2009; 15 (7): 788-793

  Abstract

  Previous proteomic and transcriptional analyses of multiple sclerosis lesions revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg(9)-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-betaNal(7), Ile(8)]des-Arg(9)-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1(-/-)) C57BL/6 mice immunized with a myelin oligodendrocyte glycoprotein fragment, MOG(35-55), showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow-chimeric mice reconstituted with Bdkrb1(-/-) T lymphocytes, which showed enhanced T helper type 17 (T(H)17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human T(H)17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.

  View details for DOI 10.1038/nm.1980

  View details for Web of Science ID 000267806900032

  View details for PubMedID 19561616

• Systems biology for identification of molecular networks in multiple sclerosis MULTIPLE SCLEROSIS Han, M. H., Steinman, L. 2009; 15 (5): 529-530

  View details for DOI 10.1177/1352458509103318

  View details for Web of Science ID 000265513400001

  View details for PubMedID 19389747

• Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets Han, M. H., Steinman, L. SPRINGER WIEN. 2008: 1717

  View details for Web of Science ID 000261180300027

• Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets NATURE Han, M. H., Hwang, S., Roy, D. B., Lundgren, D. H., Price, J. V., Ousman, S. S., Fernald, G. H., Gerlitz, B., Robinson, W. H., Baranzini, S. E., Grinnell, B. W., Raine, C. S., Sobel, R. A., Han, D. K., Steinman, L. 2008; 451 (7182): 1076-U2

  Abstract

  Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.

  View details for DOI 10.1038/nature06559

  View details for PubMedID 18278032

• Proteomic profiling of multiple sclerosis lesions identify potential targets for therapy 7th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Han, M. H., Hwang, S., Roy, D., Raine, C., Robinson, W. H., Sobel, R. A., Han, D., Steinman, L. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S153–S153

  View details for DOI 10.1016/j.clim.2007.03.075

  View details for Web of Science ID 000247137200398

• Proteomic profiling of multiple sclerosis plaques 8th International Conference of Neuroimmunology Han, M. H., Hwang, S., Robinson, W. H., Raine, C. S., Sobel, R., Han, D. K., Steinman, L. ELSEVIER SCIENCE BV. 2006: 23–23

  View details for Web of Science ID 000241633100043

• Monoclonal antibodies to myelin proteolipid protein (PLP) epitopes inhibit neurite outgrowth: Implications for MS Hinojoza, J. R., Han, M. H., Eaton, M., Sharpe, O., Steinman, L., Robinson, W. H., Sobel, R. A. BLACKWELL PUBLISHING. 2006: S13

  View details for Web of Science ID 000239938600027

• Neurologic aspects of infections in international travelers NEUROLOGIST Han, M. H., Zunt, J. R. 2005; 11 (1): 30-44

  Abstract

  As international travel for business and pleasure becomes part of contemporary lifestyle, the clinician today is confronted with an increasing number of travelers returning ill with unfamiliar syndromes. The physician will encounter a myriad of patients with exotic infections, emerging infectious diseases, or resurgent Old-World infections.This review article will discuss salient points of important infectious diseases associated with overseas travel, provide a syndromic approach to the traveler who returns with neurologic manifestations, and list resources for additional diagnostic, therapeutic, and preventive information.As many of infections acquired in other countries can directly or indirectly affect the nervous system, the care of the ill traveler often falls into the hands of neurologists. The contemporary neurologist should therefore be knowledgeable of the clinical manifestations, potential complications, and appropriate management of region-specific infections.

  View details for DOI 10.1097/01.nrl.0000149972.87731.0f

  View details for Web of Science ID 000226265500004

  View details for PubMedID 15631642

• Effects of protein kinase CK2, extracellular signal-regulated kinase 2, and protein phosphatase 2A on a phosphatidic acid-preferring phospholipase A1 JOURNAL OF BIOLOGICAL CHEMISTRY Han, M. H., Han, D. K., Aebersold, R. H., Glomset, J. A. 2001; 276 (29): 27698-27708

  Abstract

  A soluble, phosphatidic acid-preferring phospholipase A1, expressed in mature bovine testes but not in newborn calf testes, may contribute to the formation or function of sperm. Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo. Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730; 5) CK2alpha formed a stable, MgATP/MgGTP-dependent complex with the phospholipase by a novel mechanism; and 6) the complex showed reduced phospholipase activity and resembled a complex identified in homogenates of macaque testis. These results provide the first available information about the effects of reactions of phosphorylation and dephosphorylation on the behavior of the phospholipase, shed light on properties of CK2alpha that may be required for the formation of complexes with its substrates, and raise the possibility that a complex containing CK2alpha and the phospholipase may play a special biological role in the testis.

  View details for Web of Science ID 000169966900127

  View details for PubMedID 11328814

• Cloning of a phosphatidic acid-preferring phospholipase A(1) from bovine testis JOURNAL OF BIOLOGICAL CHEMISTRY Higgs, H. N., Han, M. H., Johnson, G. E., Glomset, J. A. 1998; 273 (10): 5468-5477

  Abstract

  We report the molecular cloning and expression of a phosphatidic acid-preferring phospholipase A1 from bovine testis. The open reading frame encoded an 875-amino acid protein with a calculated molecular mass of 97,576 daltons and a pI of 5.61. The sequence included a region similar to a lipase consensus sequence containing the putative active site serine and also included a potential, coiled-coil-forming region. Expression of the open reading frame in COS1 cells resulted in a 20-44-fold increase in phosphatidic acid phospholipase A1 activity over that of control cells. Mutation of the putative active site serine (amino acid 540) demonstrated that it was essential for this increase in enzyme activity. Northern blot analysis revealed at least five different messages with the highest overall message levels in mature testis, but detectable message in all tissues examined. Two possible alternately spliced regions in the open reading frame also were identified. Finally, a search of the data base identified six related proteins: a potential counterpart of the phospholipase A1 in Caenorhabditis elegans, two putative lipases in yeast, and three proteins separately encoded by the Drosophila retinal degeneration B gene and its mouse and human homologues.

  View details for Web of Science ID 000072345000012

  View details for PubMedID 9488669