Hideaki Nishihara1, Fumitaka Shimizu2, Takao Kitagawa3, Nanami Yamanaka1, Junko Akada4, Yasuhiro Kuramitsu3, Yasuteru Sano1, Yukio Takeshita1, Toshihiko Maeda1, Masaaki Abe1, Michiaki Koga1, Kazuyuki Nakamura5, Takashi Kanda1. 1. Department of Neurology and Clinical Neuroscience, Graduate School of Medicine, Yamaguchi University, Ube, Japan. 2. Department of Neurology and Clinical Neuroscience, Graduate School of Medicine, Yamaguchi University, Ube, Japan/Biogen, Cambridge, MA, USA. 3. Department of Biochemistry and Functional Proteomics, Graduate School of Medicine, Yamaguchi University, Ube, Japan. 4. Department of Biochemistry and Functional Proteomics, Graduate School of Medicine, Yamaguchi University, Ube, Japan/Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Japan. 5. Department of Biochemistry and Functional Proteomics, Graduate School of Medicine, Yamaguchi University, Ube, Japan; Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan, Japan.
Abstract
BACKGROUND: Recent studies have revealed that the disruption of the blood-brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS). OBJECTIVE: We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS). METHODS: We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity. RESULTS: We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3. CONCLUSION: Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.
BACKGROUND: Recent studies have revealed that the disruption of the blood-brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS). OBJECTIVE: We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS). METHODS: We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity. RESULTS: We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3. CONCLUSION:Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.
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