Migration and function of skin B cells

 描述(申请人提供)：皮肤是一个重要的屏障器官，经常成为免疫介导性疾病的目标，如牛皮癣。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，但人们对皮肤相关的B细胞知之甚少。我们最近发现，IL-10调节B细胞(Bregs)具有抑制T细胞驱动的皮肤炎症的已知潜力，优先迁移到小鼠发炎的皮肤。我们还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的皮肤转运不依赖于典型的皮肤归巢受体，而是需要41-整合素，它在Bregs上以激活的状态结构性表达。这些数据表明，Bregs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，可能会转化为治疗炎症性皮肤病的新方法。我们假设，皮肤粘连细胞在调节皮肤炎症的时间和空间上填补了一个特殊的位置，并且它们可以通过它们的迁移而成为靶点。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细胞耗尽可诱发银屑病，起到保护作用 B细胞在这种疾病中的作用。因此，银屑病样炎症可能受到IL-10Bregs在皮肤中募集减少的影响，这也是我们研究的一个主要重点。在目标1下，我们将揭示促使Breg在皮肤中积累的条件，并定义这些细胞参与皮肤炎症调节的专门利基。在目标2中，我们将确定包括Bregs在内的人类皮肤B细胞亚群的转运受体特征，并使用绵羊的传入淋巴管模型来揭示皮肤B细胞亚群的相对皮肤趋向性。这一结果将使我们能够在治疗上操纵抗炎B细胞的定位，并认识到它们迁移的失调。最后，在目标3下，我们将在牛皮癣样炎症模型中阻止IL-10 Breg迁移到皮肤，从而阐明Breg迁移到皮肤是否对限制炎症至关重要。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Bregs。这将决定Bregs的皮肤募集和定位是否对于抑制银屑病样炎症是必不可少的。总之，这项建议将揭示新发现的皮肤IL-10B细胞的迁移途径、利用的运输受体和抗炎功能。鉴于B细胞与从炎症、感染到皮肤癌等大量皮肤疾病的广泛关联，以及对皮肤B细胞知识的匮乏，我们的工作将填补一个重大的知识鸿沟，具有利用所获得的知识用于治疗目的的巨大潜力

 DESCRIPTION (provided by applicant): 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 41- 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 temporally and spatially 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 can induce psoriasis, 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 specialized niche these cells fill in the regulation of skin inflammation.. Under Aim 2 we will both determine the traffickng 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