Current advisor: Robyn S. Klein, MD, PhD
Undergraduate university: Washington University
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that leads to demyelination, axonal damage, and neuronal loss. Patients are typically diagnosed early in adulthood and due to the chronic nature of the disease, will continue to develop symptoms over their lifetime. Currently available therapeutics for MS focus on symptomatic relief and reduce severity of relapses; however, they are unable to prevent disease progression or promote recovery. Therefore, there is a critical need to understand the biological mechanisms driving neuroinflammatory and neurodegenerative processes in MS and to translate these findings into novel therapeutic strategies.
We employ a commonly used murine model, experimental autoimmune encephalomyelitis (EAE), that replicates the neuroinflammatory phenotypes observed in MS. We first examine the role of astrocyte – T cell crosstalk in determining the location of lesions within the CNS. Using in vitro cultures, we show that Th17 associated cytokines upregulate VCAM-1 expression preferentially on brainstem astrocytes, while Th1 associated cytokines upregulate CXCR7 expression preferentially on spinal cord astrocytes. We then take advantage of different EAE models, which promote either spinal cord or hindbrain inflammation, to show that these regional differences in astrocyte gene expression are maintained in vivo and that astrocyte specific targeting of these localization cues diminishes lymphocyte entry into the corresponding CNS region. We next examine a novel role for type III interferons (interferon lambda or IFNL) in maintaining chronic neuroinflammation. Using genetic knockdown and antibody mediated neutralization approaches, we show that ablation of IFNL signaling during EAE prevents chronic inflammation, decreases Th1 effector cell function within the CNS, and reduces axonal injury. Conditional deletion of the IFNL receptor on CD11c+ cells also results in improved recovery during EAE, suggesting that CD11c+ cells are critical targets of IFNL signaling. IFNL ligand and receptor levels are increased in lesions of MS patients compared with their normal appearing white matter, highlighting the relevance of our murine studies to human disease. Lastly, we use a model of relapsing remitting EAE to show that targeting sphingosine-1-phosphate-receptor-2 (S1PR2) with a selective antagonist following disease onset diminishes severity of subsequent relapses and reduces immune cell infiltration into the CNS meninges. In vitro studies reveal that the S1P-S1PR2 signaling axis promotes CXCR4 – mediated transmigration of MS patient CD4+ T cells, highlighting a mechanism by which S1PR2 may promote disease. Overall, our data explore the roles of key molecules driving different stages of CNS autoimmune disease and highlight their therapeutic potentials.
Manivasagam S, Williams JL, Vollmer LL, Bollman B, Bartleson JM, Ai S, Wu GF, Klein RS. 2022 Targeting IFN-λ Signaling Promotes Recovery from Central Nervous System Autoimmunity. J Immunol, 208(6):1341-51.
Manivasagam S, Klein RS. 2021 Type III Interferons: Emerging Roles in Autoimmunity. Front Immunol, 12():764062.
Williams JL, Manivasagam S, Smith BC, Sim J, Vollmer LL, Daniels BP, Russell JH, Klein RS. 2020 Astrocyte-T cell crosstalk regulates region-specific neuroinflammation. Glia, 68(7):1361-1374.
Klein RS, Garber C, Funk KE, Salimi H, Soung A, Kanmogne M, Manivasagam S, Agner S, Cain M. 2019 Neuroinflammation During RNA Viral Infections. Annu Rev Immunol, 37():73-95.