Identification of Quantitative Trait Loci in Experimental Epidermolysis Bullosa Acquisita
Identification of Quantitative Trait Loci in Experimental Epidermolysis Bullosa Acquisita
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DOI：
10.1038/jid.2011.466
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发表时间：
2012-05-01
影响因子：
6.5
通讯作者：
Ibrahim, Saleh M.
中科院分区：
文献类型：
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作者：
Ludwig, Ralf J.;Mueller, Susen;Ibrahim, Saleh M.
获得性大疱性表皮松解症(EBA)是一种慢性大疱性黏膜自身免疫性皮肤水疱病。有几条证据强调了抗II型胶原(COL7)自身抗体在EBA发病机制中的作用。此外，EBA的易感性与患者的MHC单倍型(HL A-DR2)和免疫诱导的小鼠EBA(H 2S)相关。后一项研究表明，非MHC基因对疾病易感性有额外的贡献。为了确定控制EBA易感性的非MHC基因，我们将易感EBA的MRL/MPJ与耐EBA的NZM2410/J、Bxd2/TyJ以及CAST小鼠杂交。用小鼠COL7基因片段免疫第四代易发生自身免疫的高级异交系小鼠，诱导EBA。84%的小鼠检测到抗COL7自身抗体，50%的小鼠真皮-表皮交界处有补体沉积，33%的小鼠出现明显的临床EBA。临床疾病的发病与9、12、14和19号染色体上的多个数量性状基因座(QTL)有关，而疾病的最严重程度与1、15和19号染色体上的QTL有关。对EBA发病机制的更详细了解可能最终导致EBA和其他自身抗体介导的疾病的新的治疗策略。
Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease. Several lines of evidence underscore the contribution of autoantibodies against type VII collagen (COL7) to the pathogenesis of EBA. Furthermore, EBA susceptibility is associated with the MHC haplotype in patients (HLA-DR2) and in immunization-induced EBA in mice (H2s). The latter study indicated an additional contribution of non-MHC genes to disease susceptibility. To identify non-MHC genes controlling EBA susceptibility, we intercrossed EBA-susceptible MRL/MpJ with EBA-resistant NZM2410/J and BXD2/TyJ as well as Cast mice. Mice of the fourth generation of this four-way autoimmune-prone advanced intercross line were immunized with a fragment of murine COL7 to induce EBA. Anti-COL7 autoantibodies were detected in 84% of mice, whereas deposition of complement at the dermal-epidermal junction (DEJ) was observed in 50% of the animals; 33% of immunized mice presented with overt clinical EBA. Onset of clinical disease was associated with several quantitative trait loci (QTLs) located on chromosomes 9, 12, 14, and 19, whereas maximum disease severity was linked to QTLs on chromosomes 1, 15, and 19. This more detailed insight into the pathogenesis of EBA may eventually lead to new treatment strategies for EBA and other autoantibody-mediated diseases.