Text Image: UM Medical School: Graduate Program in Immunology
Text Image: Faculty

Benjamin Segal, M.D.
Holtom-Garrett Professor of Neurology
Director, U-M Multiple Sclerosis Center

Our research investigates how chemokine and cytokine networks and leukocyte subsets act together, both in peripheral lymphoid tissues and the central nervous system (CNS), to mediate autoimmune diseases that target neuronal or glial antigens normally sequestered behind the blood-brain-barrier . We are particularly interested in the inflammatory demyelinating disease, multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). One part of the laboratory is devoted to human immunological studies (involving the analysis of peripheral blood and cerebrospinal fluid mononuclear cells that are collected from patients with MS or other neurological diseases and healthy controls). Currently we are investigating the relationship between the expression of selected cytokines (such as IL-23 and IL-17) and disease activity, as detected by advanced MRI techniques, in individuals with progressive multiple sclerosis. A complementary division of our lab is dedicated to animal studies, primarily using the EAE model.

Some of our on-going projects are to investigate the following: (i) the expression pattern and role of the interleukin (IL)-12 p40 family of monokines in secondary progressive MS; (ii) the role of IL-12 and IL-23 in T cell homing to the CNS and epitope spreading during the course of EAE; (iii) CNS expression and functional significance of “lymphoid” chemokines, such as CXCL13 and CCL21, in driving the formation of organized inflammatory infiltrates during relapsing EAE and MS; (iv) the origin and biological activities of dendritic cells that accumulate in demyelinating lesions during EAE; (v) the importance of regulatory T cells for remission during relapsing autoimmune demyelination; (vi) the role of neutrophils and the chemokines that attract them in blood-brain-barrier breakdown during EAE; and (vii) the impact of b -IFN therapy on the immune system of patients with MS.

Representative Publications

Segal, B.M. , Dwyer, B., Shevach, E.M. An IL-12/IL-10 Immunoregulatory Circuit Controls Susceptibility to Autoimmune Disease. Journal of Experimental Medicine 187: 537-546, 1998.

Chang, J.T., Shevach, E.M., Segal, B.M. Regulation of IL-12 Receptor ß2 Subunit Expression by Endogenous IL-12: A Critical Step in the Differentiation of Pathogenic Autoreactive T cells. Journal of Experimental Medicine 189: 969-978, 1999.

Segal, B.M., Chang, J.T., Shevach, E.M. CpG Oligonucleotides are Potent Adjuvants for the Activation of Autoreactive Encephalitogenic T Cells in Vivo. Journal of Immunology 164: 5683-5688, 2000.

Segal, B.M. , Glass, D. and Shevach, E.M. IL-10 Producing Tr1 Cells Mediate Tumor Rejection, Journal of Immunology (Cutting Edge) 168: 1-4, 2002.

Ichikawa , H., Williams, L.P. and Segal, B.M. Activation of Antigen Presenting Cells through CD40 or Toll-9 Receptors Overcomes Tolerance and Precipitates Autoimmune Disease. Journal of Immunology , 169:2781-2787 2002.

Segal, B.M. Experimental Autoimmune Encephalomyelitis: Cytokines, Antigen Presenting Cells and Immunoregulation. Current Allergy and Asthma Reports 3(1): 86-93, 2003.

Bagaeva, L., Williams, L.P. and Segal, B.M. IL-12 Dependent/ IFNg Independent Expression of CCR5 by Myelin Reactive T Cells Correlates with Encephalitogenicity. Journal of Neuroimmunology 137(1-2): 109-116, 2003.

Segal, B.M. CNS Chemokines, Cytokines, and Dendritic Cells in Autoimmune Demyelination. J Neurol Sci. 228(2):210-4, 2005.

King, I. and Segal, B.M. Cutting Edge: IL-12 induces CD4 + CD25 - T Cell Activation in the Presence of Regulatory T Cells. Journal of Immunology (Cutting Edge section) 175(2): 641-5, 2005.

Deshpande, P. and Segal, B.M. IL-12 Driven Upregulation of P-selectin Ligand on Myelin-Specific T Cells is a Critical Step in an Animal Model of Autoimmune Demyelination. Journal of Neuroimmunology 173(1-2):35-44, 2006.

Bagaeva, L.V., Rao, P., Powers, J.M. and Segal, B.M. CXCL13 Plays a Role in Experimental Autoimmune Encephalomyelitis. Journal of Immunology 176(12):7676-85, 2006.

Deshpande, P., King, I.L. and Segal, B.M. Cutting Edge: CNS CD11c + Cells from Mice with Encephalomyelitis Polarize Th17 Cells and Support CD25 + CD4 + Mediated Immunosuppression, Suggesting Dual Roles in the Disease Process. Journal of Immunology 178(11): 6695-99, 2007.

Carlson, T., Kroenke, M., Rao, P., Lane, T.E., Segal, B.M. The Th17-ELR+ CXC Chemokine Pathway is Essential for the Development of CNS Autoimmune Disease. Journal of Experimental Medicine,208; 205(4): 811-823, 2008.
PMID: PMC2292221

Kroenke MA, Carlson TJ, Andjelkovic A, Segal BM. IL-12 and IL-23 modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 2008;205(7): 1535-1541. PMCID: PMC2442630

Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH on behalf of the Ustekinumab MS Investigators. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008;7(9): 796-804.

King IL, Dickendesher TL, Segal BM. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 2009;113(14): 3190-3197. PMCID: PMC2665891.

Segal BM. Getting to the crux of the matter: IL-23 and Th17 cell accumulation in the CNS. Eur J Immunol 2009; 39(7):1713-1715. PMCID: PMC2760599.

Segal BM. Th17 cells in autoimmune demyelinating disease. Semin Immunopathol, 2010; 32(1):71-77. PMCID: PMC2874248.

King IL, Kroenke MA, Segal BM. GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J Exp Med 2010;207(5): 953-61. PMCID: PMC2867280.

Lalor SJ, Segal BM.  Lymphoid chemokines in the CNS.  J Neuroimmunol 2010; 224(1-2):56-  PMCID:  PMC2910210

Kroenke MA, Chensue SW, Segal BM.  EAE mediated by a non-IFN-γ/non-IL-17 pathway.   Eur  J Immunol, 2010; 40(8):2340-8. PMCID:  PMC2942985
(Note: This article was selected to be highlighted in the In This Issue section)

Kroenke MA, Segal BM. IL-23 modulated myelin-specific T cells induce EAE via an IFNy driven, IL-17 independent pathway. Brain Behav Immun 2010; 25(5):932-7.  PMCID: PMC3064959

Tian W, Zhu T, Zhong J, Liu X, Rao P, Segal BM, Ekholm S. Progressive Decline in Fractional Anisotropy on Serial DTI Examinations of the Corpus Callosum: A Putative Marker of Disease Activity and Progression in SPMS. Neuroradiology 2012; 54(4):287-97

Becher B and Segal BM. Th17 cells in CNS Autoimmunity. Current Opinions in Immunology. 2011; 23(6):707-12. PMCID:  PMC3535446

Braley TJ, Segal BM and Chervin RD. Sleep-disordered breathing in multiple sclerosis. Neurology 2012; 79(9):929-36.  PMCID:  PMC3425840

Braley TJ, Young HL, Mohan S, Segal BM, Berini S and Srinivasan A. Differences in diffusion tensor imaging derived metrics in the corpus callosum of multiple sclerosis patients without and  with gadolinium enhancing cerebral lesions. Journal of Computer Assisted Tomography 2012; 36: 410-415.

Segal BM. The unwavering commitment of regulatory T cells in the suppression of autoimmune encephalomyelitis: Another aspect of immune privilege in the CNS. Eur J Immunol 2012; 42(5):1102-5.

Rao, P and Segal BM. Experimental autoimmune encephalomyelitis. Methods Mol Biol. 2012; 900:363-80.

Braley TJ, Chervin RD and Segal BM. Fatigue, tiredness, lack of energy, and sleepiness in multiple sclerosis patients referred for clinical polysomnography. Multiple Sclerosis International 2012; 2012:673936.  PMCID:  PMC3539354

Segal BM. Neurosarcoidosis-- Diagnostic Approaches and Therapeutic Strategies. Curr Opin Neurol. 2013; E pub ahead of print.  PMC Journal – In Process

Braley T and Segal BM. B cell-targeting agents in the treatment of multiple sclerosis. Curr Treatment Options in Neurology. 2013; PMCID: PMC3677195

Beran RG, Braley TJ, Segal BM and Chervin RD. Sleep-disordered breathing in multiple sclerosis. Neurology 2013; 80: 1354-5. PMCID: PMC3425840

Lalor S and Segal BM. TH1 mediated experimental autoimmune encephalomyelitis in CXCR3-independent.  Eur. J. Immunol.; In Press

Rainey-Barger EK, Blakely PK, Huber AK, Segal BM and Irani DN. Virus-induced CD8+ T cells accelerate the onset of experimental autoimmune encephalomyelitis: implications for how viral infections might trigger multiple sclerosis exacerbations. J Neuroimmunol. 2013; In Press. PMCID: PMC3654028

Sandy AR, Stoolman J, Mallot K, Pangtornpipat P, Segal BM and Maillard I.  Notch regulates accumulation and function of myelin-reactive T cells in the central nervous system during experimental autoimmune encephalomyelitis.  J Immunol. 2013; In Press


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