Migration and function of cutaneous B cells

总结 皮肤是一个关键的屏障器官和免疫介导的病理学，如牛皮癣的常见目标。 尽管最近发现B细胞在促炎和抗炎皮肤反应中的关键作用，但知之甚少 关于皮肤相关的B细胞。我们最近发现，IL-10+调节性B细胞（BCRs）具有已知的潜力， 抑制T细胞驱动的皮肤炎症优先迁移到小鼠的发炎皮肤。我们也 在人类皮肤中鉴定了IL-10+ Bcl 3，验证了我们在小鼠中的发现与人类的相关性。我们的研究表明 布雷格进入皮肤的运输不依赖于典型的皮肤归巢受体，而是需要α4β1- 整合素，其以活化状态组成性地表达于Bceptin上。数据显示， 有效的皮肤靶向细胞，并指出一个迄今为止尚未探索的抗炎途径， 炎性皮肤病的新治疗方法。我们假设皮肤细菌填充了 在调节皮肤炎症的专门利基，他们可以通过他们的目标， 迁移我们还提出，受损的布雷格招募到皮肤加剧皮肤炎症。 人银屑病与皮肤IL-10缺乏相关，并且临床上对IL-10治疗有反应。B 细胞耗竭在某些个体中诱导银屑病，支持B细胞在这种疾病中的保护作用。 因此，银屑病样炎症可能受到IL-10+ Bcl 3向皮肤中募集减少的影响， 我们研究的重点。在目标1下，我们将揭示促使布雷格在皮肤中积累的条件， 定义了炎症过程中皮肤炎症的IL-10依赖性和非依赖性调节特性。下 目的2：我们将确定人皮肤B细胞亚群的运输受体特征，包括BCR 4， 并利用绵羊传入淋巴管模型揭示皮肤B细胞的相对趋皮性 子集这些结果将使我们能够在治疗上操纵抗炎B细胞的定位， to recognize承认dysregulation失调of their其migration迁移.最后，在目标3下，我们将阻断IL-10+布雷格迁移到皮肤中 在银屑病样炎症模型中，从而阐明布雷格运输到皮肤中是否是银屑病样炎症所必需的。 限制炎症。我们还将评估受银屑病影响的人类皮肤是否可能缺乏招募 很好这将确定皮肤募集和定位的Bcirrhosis是否是必要的抑制 银屑病样炎症最后，这项建议将揭示移徙路线、受雇贩运人口、 受体和新鉴定的皮肤IL-10+ B细胞的抗炎功能。鉴于广泛的 B细胞与大量皮肤病理学的关联，包括炎症、感染和皮肤 癌症和缺乏有关皮肤B细胞的知识，我们的工作将填补一个重大的知识差距， 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