A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice
A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice
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DOI：
10.1111/j.1365-2133.2004.06056.x
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发表时间：
2004-08-01
影响因子：
10.3
通讯作者：
Nishikawa, T
中科院分区：
文献类型：
--
作者：
Aoki-Ota, M;Tsunoda, K;Nishikawa, T
寻常天疱疮（PV）是由抗桥粒芯糖蛋白3（anti-Dsg 3）IgG自身抗体引起的自身免疫性水疱性疾病。最近，本研究通过将重组Dsg 3免疫的Dsg 3（-/-）小鼠脾细胞过继转移至表达Dsg 3的Rag 2（-/-）免疫缺陷小鼠，建立了PV小鼠模型。将免疫的Dsg 3（-/-）脾细胞接种到Rag 2（-/-）小鼠中，并将它们的PV表型与接受免疫的Dsg 3（-/-）脾细胞的那些小鼠进行比较。结果小鼠接受了幼稚Dsg 3（-/-）脾细胞产生的抗Dsg 3 IgG，在体内与角质形成细胞表面结合，并形成PV表型，包括口腔糜烂伴基底上棘层松解。与接受免疫脾细胞的小鼠相比，接受幼稚脾细胞的小鼠中抗体产生和PV表型的出现延迟约2周。然而，一旦PV表型形成，两种模型之间的疾病严重程度没有明显差异。有趣的是，接受幼稚脾细胞的小鼠中的抗Dsg 3 IgG滴度显著低于接受免疫脾细胞的小鼠，表明前者抗体比后者更有效。抗Dsg 3 IgG产生的频率取决于转移的幼稚脾细胞的数量。结论Dsg 3（-/-）小鼠的Dsg 3特异性幼稚淋巴细胞可以被受体小鼠的内源性Dsg 3启动和激活，在无需主动免疫的情况下产生致病性抗Dsg 3 IgG。来自幼稚Dsg 3（-/-）小鼠的CD 4 + T细胞和B220+ B细胞对于产生抗Dsg 3 IgG抗体至关重要。这种使用幼稚淋巴细胞的方法提供了一种独特的模型来剖析针对外周自身免疫靶点的耐受性的免疫机制。
Background Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by antidesmoglein3 (anti-Dsg3) IgG autoantibodies. Recently, we developed a PV mouse model by adoptive transfer of splenocytes from recombinant Dsg3-immunized Dsg3(-/-) mice to Rag2(-/-) immunodeficient mice that expressed Dsg3.Objectives We determined whether the adoptive transfer of naive splenocytes from nonimmunized Dsg3(-/-) mice induces the anti-Dsg3 IgG production and the PV phenoytpe in recipient mice.Methods We adoptively transferred naive Dsg3(-/-) splenocytes into Rag2(-/-) mice and compared their PV phenoytpe with those mice receiving immunized Dsg3(-/-) splenocytes. The numbers of splenocytes and their subpopulations required for anti-Dsg3 IgG production were examined.Results Mice that received naive Dsg3(-/-) splenocytes produced anti-Dsg3 IgG, which bound to keratinocyte cell surfaces in vivo, and developed the PV phenotype, including oral erosions with suprabasilar acantholysis. Antibody production and the appearance of the PV phenotype were delayed by approximately 2 weeks in mice that received naive splenocytes compared with mice that received immunized splenocytes. However, once the PV phenotypes developed, there were no apparent differences in disease severity between the two models. Interestingly, the anti-Dsg3 IgG titres were significantly lower in mice that received naive splenocytes than in mice that received immunized splenocytes, suggesting that the former antibodies were more potent than the latter. The frequency of anti-Dsg3 IgG production depended on the number of transferred naive splenocytes. Both CD4+ T cells and B220+ B cells from naive Dsg3(-/-) mice were essential for the production of anti-Dsg3 IgG antibodies.Conclusions Dsg3-specific naive lymphocytes in Dsg3(-/-) mice can be primed and activated by the endogenous Dsg3 in recipient mice to produce pathogenic anti-Dsg3 IgG without active immunization. This approach using naive lymphocytes provides a unique model to dissect immunological mechanisms of tolerance against peripheral autoimmune targets.