Contribution of T cells to immune complex-induced tissue damage

自身免疫性大疱性皮肤病（AIBD）的特征在于针对皮肤结构蛋白的自身抗体和粘膜皮肤组织损伤。尽管治疗选择有所改善，但AIBD患者的死亡率仍显着增加，这可能部分归因于免疫抑制治疗的程度。因此，由于发病率的上升，对于为这些患者开发有效和安全的治疗策略存在明确且迄今未满足的医疗需求。此外，对AIBD发病机制的理解还远未完成。虽然T细胞对自身免疫应答的耐受性丧失和维持的贡献已被清楚地证明，但仍不清楚T细胞是否有助于AIBD中免疫复合物诱导的嗜中性粒细胞依赖性组织损伤。有趣的是，对大疱性类天疱疮（一种具有针对XVII型胶原蛋白的自身抗体的AIBD）患者的真皮白细胞浸润的详细研究清楚地证明，绝大多数（60%）炎性细胞是CD 3+细胞。我们最近证实了实验性获得性大疱性表皮病（EBA）小鼠皮肤中CD 3表达增加，EBA是一种具有针对VII型胶原（COL 7）的自身抗体的AIBD。基于这一观察结果，我们解决了T细胞在实验EBA中的功能贡献，该实验EBA通过将抗COL 7抗体转移到T细胞缺陷小鼠和对照小鼠中诱导。在该模型中，我们观察到T细胞缺陷小鼠中EBA严重程度的显著降低。对照实验表明，这种作用不依赖于针对转移抗体的免疫应答、中性粒细胞计数的差异或所用小鼠品系。基于这些数据，我们现在旨在测试以下假设：（i）T细胞调节嗜中性粒细胞依赖的免疫复合物诱导的组织损伤，（ii）不同的T细胞亚群差异性地调节嗜中性粒细胞依赖的免疫复合物诱导的组织损伤;即活化的和/或Th 17 T细胞增强，而Treg抑制组织损伤，以及（iii）靶向不同的T细胞亚群可以在AIBD中治疗性地使用。 鉴于这些假设可以通过实验验证，AIBD中T细胞亚群的调节可以提供新的治疗选择，其靶向耐受性丧失的产生/维持以及自身抗体诱导的嗜中性粒细胞依赖性组织损伤。

Autoimmune bullous dermatoses (AIBD) are characterized by autoantibodies against cutaneous structural proteins and mucocutaneous tissue injury. Despite improved therapeutic options, mortality of patients with AIBD is still significantly increased, which can be partially attributed to the extent of immunosuppressive therapy. Therefore and due to the rising incidence there is a clear and so far unmet medical need for the development of effective and save therapeutic strategies for these patients. In addition, the understanding of AIBD pathogenesis is far from complete. While the contribution of T cells to the loss of tolerance and maintenance of the autoimmune response has clearly been demonstrated, it remains unclear, if T cells contribute to the immune complex-induced, neutrophil-dependent tissue injury in AIBD. Interestingly, detailed investigation of the dermal leukocyte infiltration in patients with bullous pemphigoid, an AIBD with autoantibodies directed against type XVII collagen, clearly documented, that the vast majority (60%) of the inflammatory cells are CD3+ cells. We recently demonstrated an increased expression of CD3 in the skin of mice with experimental epidermolysis bullosa acquisita (EBA), an AIBD with autoantibodies directed against type VII collagen (COL7). Based on this observation, we addressed the functional contribution of T cells in experimental EBA induced by transfer of anti-COL7 antibodies into T cell-deficient and control mice. In this model, we observed a significant reduction of EBA severity in T cell deficient mice. Control experiments showed, that this effect was independent on an immune response against the transferred antibody, differences in neutrophil counts, or the mouse strain used. Based on these data, we here now aim to test the following hypothesis: (i) T cells modulate neutrophil-depended, immune complex-induced tissue damage, (ii) Different T cell subsets differentially modulate neutrophil-depended, immune complex-induced tissue damage; i.e. activated and/or Th17 T cells enhance, while Treg inhibit tissue injury, and (iii) Targeting different T cell subsets can be used therapeutically in AIBD. Given, that these assumptions can be experimentally validated, modulation of T cell subsets in AIBD may offer novel therapeutic options that target both the generation/maintenance of the loss of tolerance, as well as the autoantibody-induced, neutrophil-dependent tissue injury.