Dose and Hg species determine the T-helper cell activation in murine autoimmunity.
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.
Havarinasab
Said
S
Molecular and Immunological Pathology (AIR), Department of Molecular and Clinical Medicine, Linköping University, SE-581 85 Linköping, Sweden. saiha@imk.liu.se
Björn
Erik
E
Ekstrand
Jimmy
J
Hultman
Per
P
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002868:Chromosomal Proteins, Non-Histone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000145:classification / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008627:Mercuric Chloride / Q000737:chemistry / Q000276:immunology / Q000633:toxicity*; D051379:Mice; D009687:Nuclear Proteins / Q000097:blood; D009915:Orbit / Q000098:blood supply; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013849:Thimerosal / Q000737:chemistry / Q000276:immunology / Q000633:toxicity; D013997:Time Factors
D000974:Antibodies, Antinuclear; D002868:Chromosomal Proteins, Non-Histone; D007074:Immunoglobulin G; D009687:Nuclear Proteins; C047458:fibrillarin; D013849:Thimerosal; D008627:Mercuric Chloride