Migration and function of skin B cells

皮肤 B 细胞的迁移和功能

• 批准号: 9354401
• 负责人: Gudrun Philomena Debes
• 金额: $ 34.64万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354401
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow; Cannulations; Cells; Characteristics; Chimera organism; Chronic; Clinical; Contact Dermatitis; Cutaneous; Cytometry; Data; Development; Disease; Environment; Genetic Models; Homing; Human; Immune; Immune Targeting; Immune system; Impairment; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Integrin alpha4; Integrins; Interleukin-10; Knowledge; Lymph; Mediating; Microscopy; Modeling; Mus; Organ; Pathology; Pathway interactions; Pattern; Peripheral; Phase; Property; Psoriasis; Recruitment Activity; Regulation; Role; Route; Sheep; Skin; Skin Cancer; Specimen; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Translating; Tropism; Work; cellular targeting; experimental study; migration; mouse model; multi-photon; natalizumab; novel; novel strategies; novel therapeutic intervention; novel therapeutics; public health relevance; receptor; response; skin disorder; tool; trafficking; tumor

 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

 描述（由申请人提供）：皮肤是一个重要的屏障器官，也是牛皮癣等免疫介导病理的常见目标，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。我们新发现具有抑制 T 细胞驱动的皮肤炎症潜力的 IL-10+ 调节性 B 细胞 (Bregs) 会优先迁移到小鼠发炎的皮肤中。人类皮肤中的 Breg，验证了我们在小鼠中的研究结果与人类的相关性。我们的研究表明，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，该整合素在 Breg 上以激活状态表达。数据表明，Bregs 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，该途径可能转化为治疗炎症性皮肤病的新方法。我们还认为，皮肤炎症的 Breg 募集受损会加剧皮肤炎症，并且与皮肤 IL-10 的缺乏和临床反应有关。 IL-10 治疗可诱发银屑病，具有保护作用。 因此，银屑病样炎症可能受到皮肤中 IL-10+ Breg 募集减少的影响，在目标 1 下，我们将揭示驱动 Breg 在皮肤中积聚的条件并定义专门的 B 细胞。这些细胞填补了皮肤炎症调节的空白。在目标 2 下，我们将确定人类皮肤 B 细胞亚群（包括 Bregs）的贩运受体特征，并使用绵羊传入淋巴插管模型来揭示皮肤 B 细胞亚群的相对皮肤趋向性使我们能够在治疗上操纵抗炎 B 细胞的定位并识别其迁移失调。最后，在目标 3 下，我们将阻止 IL-10+ Breg 迁移到体内。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 Breg。 Bregs 的定位对于抑制银屑病炎症至关重要。鉴于 B 细胞的广泛关联，该提案将揭示新鉴定的皮肤 IL-10+ B 细胞的迁移途径、所使用的转运受体和抗炎功能。凭借大量的皮肤病理学（从炎症、感染和皮肤癌）以及对皮肤 B 细胞的深入了解，我们的工作将弥合重大知识差距，并具有将所获得的知识用于治疗目的的巨大潜力