Migration and function of cutaneous B cells

皮肤 B 细胞的迁移和功能

基本信息

批准号：
10078848
负责人：
Gudrun Philomena Debes
金额：
$ 30.41万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-05 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078848
关键词：
Affect Anti-Inflammatory Agents B-Lymphocyte Subsets B-Lymphocytes Blood Cannulations Cells Characteristics Chronic Clinical Contact Dermatitis Cutaneous Cytometry Data Defect Development Disease Environment Genetic Models Homing Human Immune Immune Targeting Immune system Impairment Individual Infection Infectious Skin Diseases Inflammation Inflammatory Integrin alpha4 Integrin alpha4beta1 Integrins Interleukin-10 Knowledge Lymph Mediating Modeling Mus Organ Pathology Pathway interactions Patients Pattern Peripheral Phase Property Psoriasis Regulation Role Route Sheep Skin Skin Cancer Specimen T-Lymphocyte Testing Therapeutic Therapeutic immunosuppression Translating Tropism Work experimental study migration mouse model natalizumab novel novel strategies novel therapeutic intervention novel therapeutics receptor recruit response skin disorder tool trafficking tumor

项目摘要

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

概括皮肤是一个关键的屏障器官，也是免疫介导的病理（例如牛皮癣）的经常靶标。尽管B细胞在促炎和抗炎皮肤反应中的新鉴定出的关键作用却鲜为人知关于皮肤相关的B细胞。我们新发现的IL-10+调节B细胞（Bregs）具有已知潜力为了抑制T细胞驱动的皮肤感染优先迁移到小鼠的发炎皮肤中。我们也是鉴定出人类皮肤中的IL-10+ Bregs，证实了我们在小鼠中发现的人类相关性。我们的研究表明 Breg运输到皮肤上是独立于典型的皮肤归纳受体，而是需要α4β1- 整联蛋白，在布雷格的激活状态下始终表达。数据表明布雷格是有效的皮肤靶向细胞，并指向迄今为止意外的抗炎途径，可能会转化为炎性皮肤疾病的新型治疗方法。我们假设皮肤bre填充了专门针对皮肤感染调节的细分市场，可以通过其目标迁移。我们还建议招募Breg招募皮肤会加剧皮肤炎症。人牛皮癣与皮肤IL-10的死亡有关，并且对IL-10治疗有临床反应。 b 细胞耗竭会在某些个体中诱导牛皮癣，从而支持B细胞在该疾病中的受保护作用。因此，牛皮癣的注射可能会受到IL-10+ Bregs募集到皮肤和A的影响我们研究的主要重点。在AIM 1下，我们将揭示促使布雷格在皮肤中积累的条件定义炎症期间皮肤的IL-10依赖性和非依赖性调节特性。在下面 AIM 2我们都将确定包括Bregs，包括Bregs的人类皮肤B细胞子集的运输受体特征以及在绵羊中使用传入的淋巴管插管模型来揭示皮肤B细胞的相对皮肤偏见子集。结果将使我们能够操纵抗炎B细胞的定位，并认识到其迁移的失调。最后，在AIM 3下，我们将阻止IL-10+ Breg迁移到皮肤在牛皮癣样注射的模型中，从而阐明了布雷格贩运是否对皮肤是必不可少的限制炎症。我们还将评估受牛皮癣影响的人类皮肤，以免招募布雷格斯。这将确定招募皮肤和布雷格的定位对于抑制至关重要牛皮癣的注射。总之，该提案将揭示迁徙路线，进行贩运新鉴定的皮肤IL-10+ B细胞的受体和抗炎功能。给定宽 B细胞与大量皮肤病理的关联，从感染，感染和皮肤范围癌症和有关皮肤B细胞知识的死亡，我们的工作将弥合重要的知识差距探索出于治疗目的而获得的知识的巨大潜力