B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita
B Cells, Dendritic Cells, and Macrophages Are Required To Induce an Autoreactive CD4 Helper T Cell Response in Experimental Epidermolysis Bullosa Acquisita
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DOI：
10.4049/jimmunol.1300310
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发表时间：
2013-09-15
影响因子：
4.4
通讯作者：
Ludwig, Ralf J.
中科院分区：
文献类型：
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作者：
Iwata, Hiroaki;Bieber, Katja;Ludwig, Ralf J.
在自身免疫性大疱性皮肤病（AIBD）中，自身抗体诱导皮肤或粘膜上的水疱，或两者。使用AIBD动物模型已经很好地表征了持续自身抗体产生和起泡的机制。然而，导致初始自身抗体产生的机制尚未详细研究。获得性大疱性表皮病（EBA）是一种与VII型胶原（COL 7）自身抗体相关的AIBD。大多数EBA患者的血清识别非胶原结构域1，包括血管性血友病因子A样结构域2（vWFA 2）。在GST-COL 7免疫诱导的实验EBA中，疾病表现取决于遗传背景、Th 1极化和GST标签。在该模型中，裸鼠既不产生自身抗体也不产生水泡。目前还不确定EBA诱导需要哪些APC和T细胞亚群。我们建立了一个新的EBA模型免疫vWFA 2融合内含肽（缺乏GST标签）。所有测试的小鼠品系均产生自身抗体，但仅在携带H2的小鼠中观察到水疱。在免疫小鼠中，检测到vWFA 2特异性CD 4 T细胞，其诱导需要B细胞、树突状细胞和巨噬细胞的存在。当转移到健康小鼠中时，位于致密层的抗vWFA 2自身抗体结合到盐裂皮肤的真皮侧并诱导水疱。在免疫时缺乏CD 8 T细胞没有影响，而在同一时间段内耗尽CD 4 T细胞延迟了自身抗体的产生和水疱。总的来说，我们证明了靶向COL 7的vWFA 2结构域的Ab的致病相关性，并显示了APC诱导的CD 4 T细胞诱导实验EBA的要求。
In autoimmune bullous dermatoses (AIBD), autoantibodies induce blisters on skin or mucous membranes, or both. Mechanisms of continued autoantibody production and blistering have been well characterized using AIBD animal models. Mechanisms leading to the initial autoantibody production, however, have not been investigated in detail. Epidermolysis bullosa acquisita (EBA) is an AIBD associated with autoantibodies to type VII collagen (COL7). The majority of EBA patients' sera recognize the noncollagenous domain 1, including the von Willebrand factor A-like domain 2 (vWFA2). In experimental EBA induced by immunization with GST-COL7, disease manifestation depended on the genetic background, a Th1 polarization, and the GST-tag. In this model, nude mice neither produced autoantibodies nor blisters. It has remained uncertain which APC and T cell subsets are required for EBA induction. We established a novel EBA model by immunization with vWFA2 fused to intein (lacking the GST-tag). All tested mouse strains developed autoantibodies, but blisters were exclusively observed in mice carrying H2s. In immunized mice, CD4 T cells specific for vWFA2 were detected, and their induction required presence of B cells, dendritic cells, and macrophages. Anti-vWFA2 autoantibodies located at the lamina densa bound to the dermal side of salt-split skin and induced blisters when transferred into healthy mice. Absence of CD8 T cells at time of immunization had no effect, whereas depletion of CD4 T cells during the same time period delayed autoantibody production and blisters. Collectively, we demonstrate the pathogenic relevance of Abs targeting the vWFA2 domain of COL7 and show the requirement of APC-induced CD4 T cells to induce experimental EBA.