Therapeutic Targeting of STAT pathways in CNS autoimmune diseases

Molecular Immunology Section
JAK-STAT 09/2013; 2(1):e24134. DOI: 10.4161/jkst.24134
Source: PubMed


Signal transducers and activators of transcription (STATs) transduce extracellular signals that regulate the initiation, duration and intensity of immune responses. However, unbridled activation of STATs by pro-inflammatory cytokines or growth factors contributes to pathogenic autoimmunity. In this review, we briefly discuss STAT pathways that promote the development and expansion of T cells that mediate two CNS inflammatory diseases, multiple sclerosis (MS) and uveitis. Particular focus is on animal models of MS and uveitis and new approaches to the treatment of CNS autoimmune diseases based on therapeutic targeting of Th17 cells and STAT pathways.

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Available from: Joseph Larkin, Jul 30, 2014
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    • "As mentioned previously, Th17 cells were found to be the central effector lineage involved in the pathogenicity of murine EAE, an important model of multiple sclerosis (MS) [11]. MS is a neurodegenerative autoimmune disorder in which axon demyelination lesions develop in the central nervous system (CNS) [90]. Prior to the discovery of Th17 cells, researchers had already begun to publish on the positive correlations found between levels of IL-17, IL-6, and G-CSF and the progression of active multiple sclerosis [152]. "
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    ABSTRACT: Th17 and IL-17 play important roles in the clearance of extracellular bacterial and fungal infections. However, strong evidence also implicates the Th17 lineage in several autoimmune disorders including multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. The Th17 subset has also been connected with type I diabetes, although whether it plays a role in the pathogenicity of or protection from the disease remains a controversial issue. In this review we have provided a comprehensive overview of Th17 pathogenicity and function, including novel evidence for a protective role of Th17 cells in conjunction with the microbiota gut flora in T1D onset and progression.
    Clinical and Developmental Immunology 12/2013; 2013(7):986789. DOI:10.1155/2013/986789 · 2.93 Impact Factor
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    • "Treatment of SJL/J mice with SOCS1-KIR beginning 12 days post-immunization with myelin basic protein (MBP) resulted in minimal symptoms of EAE, while most control treated mice developed paraplegia (90). Th1 and Th17 cells via IFNγ and IL-17, respectively, are thought to play critical roles in the pathogenesis of EAE and multiple sclerosis (91). SOCS1-KIR treatment suppressed interleukin-17A (IL-17A) production by MBP-specific lymphocytes, as well as MBP-induced lymphocyte proliferation. "
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    ABSTRACT: Regulatory T cells (Tregs) play an indispensable role in the prevention of autoimmune disease, as interferon gamma (IFNγ) mediated, lethal auto-immunity occurs (in both mice and humans) in their absence. In addition, Tregs have been implicated in preventing the onset of autoimmune and auto-inflammatory conditions associated with aberrant IFNγ signaling such as type 1 diabetes, lupus, and lipopolysaccharide (LPS) mediated endotoxemia. Notably, suppressor of cytokine signaling-1 deficient (SOCS1(-/-)) mice also succumb to a lethal auto-inflammatory disease, dominated by excessive IFNγ signaling and bearing similar disease course kinetics to Treg deficient mice. Moreover SOCS1 deficiency has been implicated in lupus progression, and increased susceptibility to LPS mediated endotoxemia. Although it has been established that Tregs and SOCS1 play a critical role in the regulation of IFNγ signaling, and the prevention of lethal auto-inflammatory disease, the role of Treg/SOCS1 cross-talk in the regulation of IFNγ signaling has been essentially unexplored. This is especially pertinent as recent publications have implicated a role of SOCS1 in the stability of peripheral Tregs. This review will examine the emerging research findings implicating a critical role of the intersection of the SOCS1 and Treg regulatory pathways in the control of IFN gamma signaling and immune system function.
    Frontiers in Immunology 12/2013; 4:469. DOI:10.3389/fimmu.2013.00469
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    09/2013; 2(1):e24198. DOI:10.4161/jkst.24198
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