Dose and Hg species determine the T-helper cell activation in murine autoimmunity |
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| Authors: | Havarinasab Said Björn Erik Ekstrand Jimmy Hultman Per |
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| Institution: | 1. Molecular and Immunological Pathology (AIR), Department of Molecular and Clinical Medicine, Linköping University, SE-581 85 Linköping, Sweden;2. Department of Chemistry, Analytical Chemistry, Umeå University, SE-901 87 Umeå, Sweden;1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China;2. State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing 100142, China;4. The Department of Vascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China;5. The Department of Clinical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China;1. Key Laboratory for Basic Pharmacology of Ministry of Education, Zunyi Medical College, Zunyi, China;2. Northwest Plateau Institute of biology of Chinese Academy of Sciences, Xining, China;1. Institute for Genome Research and Systems Biology, Center for Biotechnology (CeBiTec), Bielefeld University, D-33615 Bielefeld, Germany;2. Faculty of Technology, Center for Biotechnology (CeBiTec), Bielefeld University, D-33615 Bielefeld, Germany;3. Pacific Biosciences Germany GmbH, Germany;4. Departamento de Bioquímica y Biología Molecular, Universidad de Córdoba, Córdoba, Spain;5. Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Veterinaria, Universidad de Extremadura, Avenida de la Universidad SN, E-10071Cáceres, Spain;1. Department of Chemistry and Materials Science, Faculty of Experimental Sciences, University of Huelva, Campus de El Carmen, Av. Fuerzas Armadas s/n, 21007 Huelva, Spain;2. Research Center on Health and Environment (CYSMA), University of Huelva, Huelva, Spain;3. International Campus of Excellence on Agrofood (ceiA3), University of Huelva, Huelva, Spain;4. Department of Environmental Biology and Public Health, Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, 21007 Huelva, Spain;5. Department of Biochemistry and Molecular Biology, S. Ochoa Building, University of Córdoba, Rabanales Campus, 14071 Córdoba, Spain |
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| Abstract: | Inorganic mercury (mercuric chloride--HgCl(2)) induces in mice an autoimmune syndrome (HgIA) with T cell-dependent polyclonal B cell activation and hypergammaglobulinemia, dose- and H-2-dependent production of autoantibodies targeting the 34 kDa nucleolar protein fibrillarin (AFA), and systemic immune-complex deposits. The organic mercury species methylmercury (MeHg) and ethylmercury (EtHg--in the form of thimerosal) induce AFA, while the other manifestations of HgIA seen after treatment with HgCl(2) are present to varying extent. Since these organic Hg species are converted to the autoimmunogen Hg(2+) in the body, their primary autoimmunogen potential is uncertain and the subject of this study. A moderate dose of HgCl(2) (8 mg/L drinking water--internal dose 148 micro gHg/kg body weight bw]/day) caused the fastest AFA response, while the induction was delayed after higher (25 mg/L) and lower (1.5 and 3 mg/L) doses. The lowest dose of HgCl(2) inducing AFA was 1.5 mg/L drinking water which corresponded to a renal Hg(2+) concentration of 0.53 micro g/g. Using a dose of 8 mg HgCl(2)/L this threshold concentration was reached within 24 h, and a consistent AFA response developed after 8-10 days. The time lag for the immunological part of the reaction leading to a consistent AFA response was therefore 7-9 days. A dose of thimerosal close to the threshold dose for induction of AFA (2 mg/L drinking water--internal dose 118 micro gHg/kg bw per day), caused a renal Hg(2+) concentration of 1.8 micro g/g. The autoimmunogen effect of EtHg might therefore be entirely due to Hg(2+) formed from EtHg in the body. The effect of organic and inorganic Hg species on T-helper type 1 and type 2 cells during induction of AFA was assessed as the presence and titre of AFA of the IgG1 and IgG2a isotype, respectively. EtHg induced a persistent Th1-skewed response irrespectively of the dose and time used. A low daily dose of HgCl(2) (1.5-3 mg/L) caused a Th1-skewed AFA response, while a moderate dose (8 mg/L) after 2 weeks resulted in a balanced or even Th2-skewed response. Higher daily doses of HgCl(2) (25 mg/L) caused a balanced Th2-Th1 response already from onset. In conclusion, while metabolically formed Hg(2+) might be the main AFA-inducing factor also after treatment with EtHg, the quality of the Hg-induced AFA response is modified by the species of Hg as well as the dose. |
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