Clinical Focus

  • Neurology

Academic Appointments

Professional Education

  • Fellowship:Stanford University (2009) CA
  • Medical Education:Institute of Medicine 1 Yangon (1996) Myanmar
  • Residency:University of Washington (2005) WA
  • Board Certification: Neurology, American Board of Psychiatry and Neurology (2011)
  • Internship:University of Washington (2002) WA

Research & Scholarship

Current Research and Scholarly Interests

Multiple sclerosis
Neuromyelitis optica
Autoimmune CNS disorders


2014-15 Courses

Graduate and Fellowship Programs


All Publications

  • 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

    View details for DOI 10.1111/imm.12272

    View details for Web of Science ID 000337600500003

  • Defective sphingosine 1-phosphate receptor 1 (S1P(1)) phosphorylation exacerbates T(H)17-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-U128

    View details for DOI 10.1038/ni.2730

    View details for Web of Science ID 000326023400013

  • 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


    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


    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


    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 ? (SIRP-?). 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

  • 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)


    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 Web of Science ID 000305075700005

    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


    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-? treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-?, 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-? 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-? 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

  • 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


    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


    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

  • 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


    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

  • 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


    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 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


    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 Web of Science ID 000253453600035

    View details for PubMedID 18278032

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


    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


    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


    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

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