Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus.
Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an antihypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naïve syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B lymphocyte tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the pathogenesis of hydralazine-induced lupus and idiopathic human lupus.
Mazari
Lynda
L
Institut National de la Santé et de la Recherche Médicale, U430, University of Paris 6, F-75674 Paris, France.
Ouarzane
Meryem
M
Zouali
Moncef
M
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006830:Hydralazine / Q000633:toxicity*; D007126:Immunoglobulin Allotypes / Q000187:drug effects / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000276:immunology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D008822:Mice, Transgenic; D017634:Self Tolerance / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
D001323:Autoantibodies; D004268:DNA-Binding Proteins; D005419:Flavonoids; D007126:Immunoglobulin Allotypes; C499308:Rag2 protein, mouse; D006830:Hydralazine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one