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很重要。 但是，它们在皮肤免疫反应中的作用主要归因于它们在皮肤外的功能，例如 在淋巴组织中。直到最近，B细胞才显示为皮肤免疫系统的成分，开放 - 在稳态和疾病中，在皮肤中发现其任务的新领域。迄今为止，我们发现的工作 皮肤B谱系细胞的两个主要功能：IgM和IL-10的分泌。细胞因子Baff的表达和 四月在皮肤中建立了B谱系细胞的局部利基，并调节IgM的皮肤分泌。 重要的是，我们最近表明，将其本地定位于皮肤本身的IL-10+调节B细胞（Bregs）有助于 牛皮癣状注射和皮肤超敏反应的分辨率。我们还发现小鼠不足 在分泌的IgM（SIGM - / - ）中，具有牛皮癣状皮肤感染，与促炎性一致 SIGM的角色。但是，IL-10+ Bregs大幅增加，这可以解释皮肤还原 SIGM - / - 小鼠的炎症。 B细胞中缺乏SIGM，FCµR的高亲和力受体，可以转化为 B细胞中的中间IL-10+表型相对于WT或SIGM –/ - 小鼠的B细胞，表明SIGM执行 IL-10直接在B细胞上抑制活性。 BCR参与是B中IL-10归纳的关键要求 细胞和SIGM与FCµR结合后，是BCR信号强度和B细胞激活的调节剂。那，我们 假设SIGM是通过调节BCR信号传导的B细胞LL-10诱导的主要调节剂 力量作为一种自由度的机制，以及像皮肤这样的组织壁ni的SIGM水平（例如 通过局部IGM分泌）可以指导或防止各种皮肤炎症的Breg诱导 调节局部免疫反应。在这个概念下，组织调节IgM水平的能力 然后，通过BAFF/APRR的表达或其他因素在局部影响B细胞的IL-10产生， 从而微调局部免疫反应。拟议工作的目的是将新型机制定义为 B谱系细胞靶向皮肤免疫反应。具体而言，目标1是面向疾病的，将确定 皮肤炎症的类型和阶段可容纳IL-10+皮肤BREG和局部IgM富含IGM的壁ni。 我们将同时采用人体组织以及炎症性皮肤疾病的小鼠模型。 AIM 2是 面向机理，将揭示IgM调节B细胞中IL-10编程的机制 专注于SIGM调节的BCR信号，SIGM的特异性要求和SIGM结合的作用 接收者。总而言之，该提案将揭示调节皮肤中布雷格反应的机制以及 定义新颖的方法来靶向皮肤，并与皮肤病理相关 炎症和癌症感染。