Migration and function of cutaneous B cells

摘要 皮肤是一个重要的屏障器官，经常成为免疫介导的病理疾病，如牛皮癣的靶子。 尽管最近发现了B细胞在促炎和抗炎皮肤反应中的关键作用，但人们对此知之甚少 关于皮肤相关的B细胞。我们新发现具有已知潜能的IL-10调节性B细胞(Bregs) 为了抑制T细胞驱动的皮肤炎症，优先迁移到小鼠发炎的皮肤。我们也 在人类皮肤中发现了IL-10 Bregs，验证了我们在小鼠身上的发现与人类的相关性。我们的研究表明 BREG转运到皮肤不依赖于典型的皮肤归巢受体，而是需要α4β1- 整合素，在Bregs上以激活状态组成性表达。数据表明，布雷格人是 有效的皮肤靶向细胞，并指出了一种迄今未被探索的抗炎途径，该途径可能转化为 炎症性皮肤病的新治疗方法。我们假设皮肤凹陷填补了一个 在调节皮肤炎症方面的专门利基，他们可以通过他们的 迁移。我们还提出，受损的Breg重新进入皮肤会加剧皮肤炎症。 人类银屑病与皮肤IL-10缺乏有关，临床上对IL-10治疗有反应。B类 细胞耗尽会导致一些人患上牛皮癣，支持B细胞在这种疾病中的保护作用。 因此，银屑病样炎症可能是由于IL-10Bregs在皮肤中的募集减少和 我们研究的主要重点。在目标1下，我们将揭示促使Breg在皮肤和皮肤中积累的条件 明确IL-10依赖和非依赖的皮肤Bregs在炎症过程中的调节特性。在……下面 目的2我们将确定人皮肤B细胞亚群的贩运受体特征，包括Bregs， 以及使用绵羊传入淋巴管的模型来揭示皮肤B细胞的相对皮肤趋向性 子集。这一结果将使我们能够在治疗和治疗方面操纵抗炎B细胞的定位 认识到它们迁徙过程中的失调。最后，在目标3下，我们将阻止IL-10 Breg迁移到皮肤 在牛皮癣样炎症模型中，从而阐明Breg转运到皮肤是否对 限制炎症。我们还将评估受牛皮癣影响的人类皮肤是否可能缺乏招募的 布雷格斯。这将决定Bregs的皮肤招募和本地化是否对抑制至关重要 牛皮癣样炎症。总而言之，这项建议将揭示移民路线，就业人口贩运 新发现的皮肤IL-10B细胞的受体和抗炎功能。考虑到广度 B细胞与包括炎症、感染和皮肤在内的大量皮肤病变的相关性 癌症和皮肤B细胞知识的匮乏，我们的工作将缩小与 将所获得的知识用于治疗目的的巨大潜力

SUMMARY The skin is a critical barrier organ and the frequent target of immune-mediated pathologies, such as psoriasis. Despite a newly identified key role of B cells in pro-and anti-inflammatory cutaneous responses, little is known about skin-associated B cells. We newly discovered that IL-10+ regulatory B cells (Bregs) with known potential to suppress T cell-driven skin inflammation preferentially migrate into the inflamed skin of mice. We also identified IL-10+ Bregs in human skin, validating human relevance of our findings in mice. Our studies show that Breg trafficking into skin is independent of canonical skin-homing receptors and instead requires α4β1- integrin, which was constitutively expressed in an activated state on Bregs. The data suggest that Bregs are efficient skin-targeting cells and point to a so far unexplored anti-inflammatory pathway that may translate into novel therapeutic approaches for inflammatory skin diseases. We hypothesize that skin Bregs fill a specialized niche in the regulation of skin inflammation and that they can be targeted through their migration. We also propose that impaired Breg recruitment into skin exacerbates skin inflammation. Human psoriasis is associated with a dearth of cutaneous IL-10 and clinically responsive to IL-10 therapy. B cell depletion induces psoriasis in some individuals, supporting a protective role of B cells in this disease. Therefore, psoriasiform inflammation is likely affected by reduced recruitment of IL-10+ Bregs into skin and a main focus of our studies. Under Aim 1 we will reveal the conditions that drive Breg accumulation in skin and define the IL-10-dependent and -independent regulatory properties of skin Bregs during inflammation. Under Aim 2 we will both determine the trafficking receptor signatures of human skin B cell subsets, including Bregs, as well as use a model of afferent lymph cannulation in sheep to reveal the relative skin tropism of skin B cell subsets. The results will allow us to manipulate the localization of anti-inflammatory B cells therapeutically and to recognize dysregulation of their migration. Finally, under Aim 3, we will block IL-10+ Breg migration into skin in a model of psoriasiform inflammation, thereby elucidating whether Breg trafficking into skin is essential to limiting inflammation. We will also evaluate human skin affected by psoriasis for a potential lack of recruited Bregs. This will determine whether skin recruitment and localization of Bregs are essential for the suppression of psoriasiform inflammation. In conclusion, this proposal will reveal the migratory routes, employed trafficking receptors, and anti-inflammatory functions of newly identified cutaneous IL-10+ B cells. Given the wide association of B cells with a large number of skin pathologies, ranging from inflammation, infection and skin cancers and the dearth of knowledge about skin B cells, our work will close a significant knowledge gap with great potential to exploit the gained knowledge for therapeutic purposes