Migration and function of cutaneous B cells

皮肤 B 细胞的迁移和功能

• 批准号: 9213284
• 负责人: Gudrun Philomena Debes
• 金额: $ 31.2万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-05 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213284
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; 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; Recruitment Activity; 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; response; skin disorder; tool; trafficking; tumor

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 皮肤是重要的屏障器官，也是免疫介导疾病（例如牛皮癣）的常见目标。 尽管新发现了 B 细胞在促炎和抗炎皮肤反应中的关键作用，但人们知之甚少 关于皮肤相关 B 细胞，我们新发现了具有已知潜力的 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中。 我们的研究表明，在人类皮肤中发现了 IL-10+ Bregs，验证了我们的研究结果与人类的相关性。 Breg 转运到皮肤中不依赖于典型的皮肤归巢受体，而是需要 α4β1- 整合素，其在Bregs上以激活状态组成型表达。数据表明Bregs是。 有效的皮肤靶向细胞，并指出迄今为止尚未探索的抗炎途径，该途径可能转化为 我们努力让皮肤布雷格斯填补炎症性皮肤病的新疗法。 调节皮肤炎症的专门利基，并且可以通过它们的作用来靶向它们 我们还认为，皮肤中的 Breg 募集受损会加剧皮肤炎症。 人类牛皮癣与皮肤 IL-10 缺乏有关，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发牛皮癣，这支持了 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皮肤中 IL-10+ Bregs 募集减少和 我们研究的主要重点是在目标 1 下，我们将揭示导致皮肤和皮肤中 Breg 积累的条件。 定义了炎症期间皮肤 Bregs 的 IL-10 依赖和独立调节特性。 目标 2 我们将确定人类皮肤 B 细胞亚群的运输受体特征，包括 Bregs、 以及利用绵羊传入淋巴插管模型揭示皮肤 B 细胞的相对皮肤趋向性 这些结果将使我们能够在治疗上操纵抗炎 B 细胞的定位。 最后，在目标 3 下，我们将阻止 IL-10+ Breg 迁移到皮肤中。 在银屑病炎症模型中，从而阐明 Breg 转运到皮肤中是否对于 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药物。 这将确定 Bregs 的皮肤募集和定位是否对于抑制至关重要。 总之，该提案将揭示银屑病炎症的迁徙路线和贩运方式。 鉴于广泛的研究，新发现的皮肤 IL-10+ B 细胞的受体和抗炎功能。 B 细胞与大量皮肤病理学的关联，包括炎症、感染和皮肤病 由于癌症和皮肤 B 细胞知识的缺乏，我们的工作将弥合与皮肤 B 细胞之间的重大知识差距 将所获得的知识用于治疗目的的巨大潜力