Migration and function of skin B cells

 描述（由申请人提供）：皮肤是关键的屏障器官，也是免疫介导的病理学（如银屑病）的常见靶点。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，但对皮肤相关B细胞知之甚少。我们新发现，IL-10+调节性B细胞（BCRs）具有抑制T细胞驱动的皮肤炎症的已知潜力，优先迁移到小鼠的发炎皮肤中。我们还在人类皮肤中鉴定了IL-10+ Bcl 2，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，布雷格运输到皮肤是独立的典型的皮肤归巢受体，而是需要β 4 β 1-整联蛋白，这是组成性表达的活化状态下的布雷格上。这些数据表明，BERGO是有效的皮肤靶向细胞，并指出了迄今为止尚未探索的抗炎途径，可能转化为炎症性皮肤病的新治疗方法。我们假设，皮肤细菌填补了一个时间和空间专门的生态位在皮肤炎症的调节，他们可以通过他们的迁移为目标。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细胞耗竭可诱导银屑病，支持银屑病的保护作用。 B细胞在这种疾病中。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，这是我们研究的主要焦点。在目标1下，我们将揭示驱动布雷格在皮肤中积累的条件，并定义这些细胞在皮肤炎症调节中填充的专门龛位。在目标2下，我们将确定人皮肤B细胞亚群（包括BCRs）的转运受体特征，以及使用绵羊传入淋巴管模型来揭示皮肤B细胞亚群的相对皮肤嗜性。这些结果将使我们能够在治疗上操纵抗炎B细胞的定位，并识别它们迁移的失调。最后，在目标3下，我们将在银屑病样炎症模型中阻断IL-10+布雷格迁移到皮肤中，从而阐明布雷格运输到皮肤中是否对限制炎症是必需的。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的生物素。这将确定皮肤募集和局部化是否是必不可少的抑制银屑病样炎症。总之，这一建议将揭示新鉴定的皮肤IL-10+ B细胞的迁移途径、所使用的运输受体和抗炎功能。鉴于B细胞与炎症、感染和皮肤癌等大量皮肤病理学的广泛关联，以及对皮肤B细胞知识的缺乏，我们的工作将填补一个重大的知识空白，具有将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