Browsing by Subject "EAE"

Now showing 1 - 3 of 3
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    An IL-23-STAT4 pathway is required for the proinflammatory function of classical dendritic cells during CNS inflammation
    (National Academy of Sciences, 2024) Alakhras, Nada S.; Zhang, Wenwu; Barros, Nicolas; Sharma, Anchal; Ropa, James; Priya, Raj; Yang, X. Frank; Kaplan, Mark H.; Biochemistry and Molecular Biology, School of Medicine
    Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.
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    New Insights in the Pathogenesis of Multiple Sclerosis—Role of Acrolein in Neuronal and Myelin Damage
    (MDPI, 2013-10-09) Tully, Melissa; Shi, Riyi; Medicine, School of Medicine
    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by an inappropriate inflammatory reaction resulting in widespread myelin injury along white matter tracts. Neurological impairment as a result of the disease can be attributed to immune-mediated injury to myelin, axons and mitochondria, but the molecular mechanisms underlying the neuropathy remain incompletely understood. Incomplete mechanistic knowledge hinders the development of therapies capable of alleviating symptoms and slowing disease progression in the long-term. Recently, oxidative stress has been implicated as a key component of neural tissue damage prompting investigation of reactive oxygen species (ROS) scavengers as a potential therapeutic option. Despite the establishment of oxidative stress as a crucial process in MS development and progression, ROS scavengers have had limited success in animal studies which has prompted pursuit of an alternative target capable of curtailing oxidative stress. Acrolein, a toxic β-unsaturated aldehyde capable of initiating and perpetuating oxidative stress, has been suggested as a viable point of intervention to guide the development of new treatments. Sequestering acrolein using an FDA-approved compound, hydralazine, offers neuroprotection resulting in dampened symptom severity and slowed disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results provide promise for therapeutic development, indicating the possible utility of neutralizing acrolein to preserve and improve neurological function in MS patients.
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    Transcription factor regulation of T helper subset function
    (2015-05-01) Awe, Olufolakemi O.; Kaplan, Mark H.; Blum, Janice S.; Zhou, Baohua; Travers, Jeffery B.
    The immune system protects the body from foreign organisms. T cells and B cells are integral components of the ability of the immune system to generate focused immune responses. The development of specialized subsets of T helper cells is governed by transcription factors. Previous work demonstrated a requirement for the transcription factor PU.1 in the development of IL-9-secreting Th9 cells. Work in this dissertation demonstrates that the Th9 subset is not stable in vitro, and that PU.1 expression decreases during long-term culture. To examine a role for PU.1 in Th9-independent immunity we examined a model of multiple sclerosis termed experimental autoimmune encephalomyelitis (EAE). Mice that lack PU.1 expression in T cells (Sfpi1lck-/- mice) demonstrated more severe disease with attenuated recovery compared to control mice, and this was accompanied by an increase of T cells in the central nervous system. We also observed that following multiple routes of immunization Sfpi1lck-/- mice had increased numbers of T follicular helper (Tfh) cells and increased germinal center responses. This correlated with increased expression of the cytokine IL-21 and the surface protein CD40L in T cells that lacked PU.1 expression and resulted in increased numbers of germinal center B cells and antigen-specific antibody titers compared to control mice. The increased germinal center B cells and antibody titers were attenuated with blocking CD40L antibody but not with neutralizing IL-21 antibody. These results suggest that PU.1 limits the expression of CD40L on Tfh cells to regulate the humoral immune response. Together, the data in this dissertation demonstrate Th9-independent functions of PU.1. Moreover, this work shows that transcription factors promoting the development of one subset of T helper cells can simultaneously have negative effects on distinct T cell lineages.