The role of IgM in the regulation of skin inflammation

IgM 在皮肤炎症调节中的作用

• 批准号: 10664259
• 负责人: Gudrun Philomena Debes
• 金额: $ 28.47万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10664259
• 关键词: Affect; Affinity; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antigens; Apoptosis; Apoptotic; Atopic Dermatitis; B-Cell Activation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Cell Lineage; Cell secretion; Cells; Competence; Cutaneous; Data; Dinitrofluorobenzene; Disease; Environment; Gene Targeting; Goals; Histologic; Homeostasis; Human; Hypersensitivity; Imiquimod; Immune response; Immune system; Immunity; Immunoglobulin M; Immunoglobulin-Secreting Cells; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Interferon Type II; Interleukin-10; Interleukin-17; Lymphoid Tissue; Malignant Neoplasms; Mus; Pathology; Phase; Phenotype; Phosphorylcholine; Production; Psoriasis; Regulation; Resolution; Role; Signal Transduction; Skin; Specificity; Specimen; Stimulus; T-Lymphocyte; Testing; Therapeutic; Tissues; Translating; Work; antigen binding; base; cytokine; human tissue; in vitro Model; mouse model; novel; prevent; receptor; receptor binding; reconstitution; response; restraint; skin disorder

SUMMARY B lineage cells, B cells and antibody secreting cells, are important in skin-specific immunity and inflammation. However, their roles in skin immune responses were mainly attributed to their functions outside of the skin, e.g. in lymphoid tissues. Only recently, B cells were revealed as components of the skin immune system, opening- up a new field of discovery of their tasks within skin in homeostasis and disease. To date, our work discovered two main functions of skin B lineage cells: secretion of IgM and IL-10. Expression of the cytokines BAFF and APRIL in the skin establish the local niche for B lineage cells and regulate cutaneous secretion of IgM. Importantly, we recently showed that IL-10+ regulatory B cells (Bregs) that localize to the skin itself aid the resolution of psoriasiform inflammation and cutaneous hypersensitivity. We also discovered that mice deficient in secreted IgM (sIgM–/–) have ameliorated psoriasiform skin inflammation, consistent with a pro-inflammatory role for sIgM. However, IL-10+ Bregs are drastically increased, which may alternatively explain the reduced skin inflammation in sIgM–/– mice. Lack of the high affinity receptor for sIgM, FcµR, in B cells, translates into an intermediate IL-10+ phenotype in B cells relative to B cells from WT or sIgM–/– mice, suggesting that sIgM exerts an IL-10 suppressing activity directly on B cells. BCR engagement is a key requirement for IL-10 induction in B cells, and sIgM, upon binding to FcµR, is a modulator of BCR signaling strength and B cell activation. Thus, we hypothesize that sIgM is a major regulator of lL-10 induction in B cells via regulation of BCR signaling strength as a self-restraint mechanism and that sIgM levels in tissue niches like the skin (e.g. governed by local IgM secretion) may instruct or prevent Breg induction across various types of skin inflammation to modulate localized immune responses. Under this concept, the ability of a tissue to regulate IgM levels locally through expression of BAFF/APRIL or other factors would then affect the IL-10 production by B cells, thereby fine-tuning the local immune response. The goal of the proposed work is to define novel mechanisms to target skin immune responses by B lineage cells. Specifically, Aim 1 is disease-oriented and will identify the types and phases of skin inflammation amenable to regulation by IL-10+ skin Bregs and localized IgM-rich niches. We will employ both human tissues as well as mouse models of inflammatory skin diseases. Aim 2 is mechanism-oriented and will reveal the mechanism by which IgM modulates IL-10 programming in B cells focusing on the roles of sIgM-modulated BCR signaling, specificity requirements for sIgM, and sIgM-binding receptors. In summary, this proposal will reveal mechanisms that regulate Breg responses in skin as well as define novel ways to target skin Bregs therapeutically with relevance for cutaneous pathologies ranging from inflammation and infection to cancer.

概括 B 谱系细胞、B 细胞和抗体分泌细胞在皮肤特异性免疫和炎症中发挥重要作用。 然而，它们在皮肤免疫反应中的作用主要归因于它们在皮肤之外的功能，例如， 直到最近，B 细胞才被发现是皮肤免疫系统的组成部分，这开启了—— 迄今为止，我们的工作发现了皮肤在稳态和疾病中的作用的新发现。 皮肤 B 谱系细胞的两个主要功能：分泌 IgM 和 IL-10 表达细胞因子 BAFF 和 APRIL 在皮肤中为 B 谱系细胞建立局部生态位并调节 IgM 的皮肤分泌。 重要的是，我们最近表明，位于皮肤本身的 IL-10+ 调节性 B 细胞 (Bregs) 有助于 我们还发现小鼠缺乏银屑病炎症和皮肤过敏。 分泌型 IgM (sIgM–/–) 可以改善银屑病样皮肤炎症，这与促炎作用一致 然而，IL-10+ Bregs 显着增加，这也可以解释皮肤减少的原因。 B 细胞中 sIgM–/– 小鼠的炎症缺乏 sIgM、FcµR 的高亲和力受体。 相对于 WT 或 sIgM–/– 小鼠的 B 细胞，B 细胞中出现中间 IL-10+ 表型，表明 sIgM 发挥作用 直接作用于 B 细胞的 IL-10 抑制活性是 B 细胞中 IL-10 诱导的关键要求。 细胞，而 sIgM 在与 FcμR 结合后，是 BCR 信号强度和 B 细胞激活的调节剂。 sIgM 是 B 细胞中通过调节 BCR 信号传导诱导 IL-10 的主要调节因子 强度作为一种自我约束机制，并且 sIgM 水平在皮肤等组织生态位中（例如皮肤） 通过局部 IgM 分泌）可以指导或防止 Breg 在各种类型的皮肤炎症中的诱导 在这个概念下，调节局部免疫反应是指组织调节 IgM 水平的能力。 局部通过 BAFF/APRIL 或其他因子的表达会影响 B 细胞产生 IL-10， 微调局部免疫反应所提出的工作的目标是定义新的机制。 具体来说，目标 1 是针对疾病的，并将识别 B 谱系细胞的皮肤免疫反应。 皮肤炎症的类型和阶段受 IL-10+ 皮肤 Bregs 和局部富含 IgM 的微环境的调节。 我们将使用炎症性皮肤病的人体组织和小鼠模型。 机制导向，将揭示 IgM 调节 B 细胞中 IL-10 编程的机制 重点关注 sIgM 调节的 BCR 信号传导的作用、sIgM 的特异性要求以及 sIgM 结合 总之，该提案将揭示调节皮肤和 Breg 反应的机制。 定义了针对皮肤 Breg 进行治疗的新方法，其与皮肤病理相关，包括： 炎症和感染导致癌症。