The role of IgM in the regulation of skin inflammation

摘要 B细胞是B细胞和抗体分泌细胞，在皮肤特异性免疫和炎症中起重要作用。 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外的功能。 在淋巴组织中。直到最近，B细胞才被发现是皮肤免疫系统的组成部分，打开- 打开了一个新的领域，发现了他们在皮肤内的任务，在动态平衡和疾病方面。迄今为止，我们的工作发现 皮肤B系细胞的两个主要功能：分泌IgM和IL-10。细胞因子BAFF和BAFF的表达 四月在皮肤上为B系细胞建立局部利基，调节皮肤免疫球蛋白M的分泌。 重要的是，我们最近表明，定位于皮肤本身的IL-10调节性B细胞(Bregs)有助于 银屑病样炎症和皮肤过敏的消退。我们还发现，有缺陷的老鼠 在分泌型IgM(SIGM-/-)中有改善银屑病样皮肤炎症的作用，与促炎作用一致 Sigm的角色。然而，IL-10Bregs急剧增加，这可能也解释了皮肤减少的原因 SIGM-/-小鼠的炎症。在B细胞中，缺乏SIgM的高亲和力受体FcµR，会转化为 WT或SIGM-/-小鼠B细胞的中间IL-10表型，提示SIGM发挥作用 IL-10直接抑制B细胞的活性。BCR参与是诱导B细胞产生IL-10的关键条件 SIGM与FcµR结合后，是BCR信号强度和B细胞激活的调节器。因此，我们 假设SIgM是通过调节BCR信号诱导B细胞中IL-10的主要调节因子 力量作为一种自我约束机制，而SIGM水平在皮肤等组织利基中(例如， 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诱导 来调节局部免疫反应。在这个概念下，组织调节IgM水平的能力 局部通过表达BAFF/APRIL或其他因素会影响B细胞产生IL-10， 从而微调局部免疫反应。拟议工作的目标是定义新的机制，以 以B细胞为靶点的皮肤免疫反应。具体地说，目标1是以疾病为导向的，将确定 皮肤炎症的类型和阶段服从于IL-10皮肤炎症的调节和局部的富含IgM的利基。 我们将使用人类组织以及炎症性皮肤病的小鼠模型。目标2是 以机制为导向，将揭示IgM调节B细胞IL-10编程的机制 重点介绍SIGM调节的BCR信号的作用、SIGM的特异性要求和SIGM结合 感受器。总之，这项提议将揭示调节皮肤和皮肤中Breg反应的机制 定义以皮肤疱疹为靶点的新方法，与皮肤病理相关，范围包括 发炎和感染致癌。

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.