Repetitive Immunization Breaks Tolerance to Type XVII Collagen and Leads to Bullous Pemphigoid in Mice
Repetitive Immunization Breaks Tolerance to Type XVII Collagen and Leads to Bullous Pemphigoid in Mice
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DOI：
10.4049/jimmunol.1100596
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发表时间：
2011-08-01
影响因子：
4.4
通讯作者：
Ludwig, Ralf J.
中科院分区：
文献类型：
--
作者：
Hirose, Misa;Recke, Andreas;Ludwig, Ralf J.
大疱性类天疱疮（BP）是一种发生于老年人的表皮下自身免疫性水疱性疾病，具有相当高的发病率和死亡率。由于非特异性免疫抑制剂仍然是BP治疗的支柱，已经开发了几种基于自身抗体或免疫细胞被动转移的动物模型，以更好地了解BP的发病机制并评估新的治疗干预措施。在这项研究中，我们描述了一个实验模型诱导BP免疫小鼠的免疫功能与重组形式的免疫显性第15次非胶原结构域的小鼠BP 180（XVII型胶原）。人BP 180的同源非胶原16 A结构域先前已被鉴定为人BP中的免疫显性区域。用鼠肽免疫雌性SJL/J小鼠在14周内导致56%的小鼠临床疾病。相比之下，尽管存在自身抗体，但其他菌株均未发生水泡。临床疾病表现为至少8周，无需进一步操作。这种新的免疫诱导模型反映了人BP的关键免疫病理学特征，包括补体固定自身抗体沿着真皮-表皮交界处的结合、血清总IgE水平升高以及嗜酸性粒细胞浸润皮肤病变。使用免疫活性小鼠和诱导持续的临床疾病，不需要额外的干预，使这种免疫诱导的小鼠模型最适合进一步探索BP的发病机制和新的治疗干预，这种和其他自身抗体介导的疾病。免疫学杂志，2011，187：1176 - 1183。
Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease of the elderly associated with considerable morbidity and mortality. As unspecific immunosuppressants are still the mainstay of BP therapy, several animal models, based on the passive transfer of autoantibodies or immune cells, have been developed to obtain a better understanding of the pathogenesis of BP and evaluate novel therapeutic interventions. We describe in this study an experimental model inducing BP by immunization of immunocompetent mice with a recombinant form of the immunodominant 15th noncollagenous domain of murine BP180 (type XVII collagen). The homologous noncollagenous 16A domain of human BP180 has previously been identified as an immunodominant region in human BP. Immunization of female SJL/J mice with the murine peptide led to clinical disease within 14 wk in 56% of mice. In contrast, none of the other strains developed blisters despite the presence of autoantibodies. The clinical disease manifested for at least 8 wk without further manipulation. This novel immunization-induced model reflects key immunopathological characteristics of human BP, including binding of complement-fixing autoantibodies along the dermal-epidermal junction, elevated total IgE serum levels, and infiltration of skin lesions with eosinophilic granulocytes. The use of immunocompetent mice and the induction of sustained clinical disease not requiring additional interventions make this immunization-induced mouse model most suitable to further explore the pathogenesis of BP and novel therapeutic interventions for this and other autoantibody-mediated diseases. The Journal of Immunology, 2011, 187: 1176-1183.