Han Lab Publications

Associate Professor of Neurology

Publications

  • 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

  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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

  • Immunological Aspects of Approved MS Therapeutics. Frontiers in immunology Rommer, P. S., Milo, R. n., Han, M. H., Satyanarayan, S. n., Sellner, J. n., Hauer, L. n., Illes, Z. n., Warnke, C. n., Laurent, S. n., Weber, M. S., Zhang, Y. n., Stuve, O. n. 2019; 10: 1564

    Abstract

    Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.

    View details for DOI 10.3389/fimmu.2019.01564

    View details for PubMedID 31354720

    View details for PubMedCentralID PMC6637731

  • 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)
  • 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
  • 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