The role of IgM in the regulation of skin inflammation

总结 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是重要的。 然而，它们在皮肤免疫应答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细胞才被发现是皮肤免疫系统的组成部分，打开了- 开辟了一个新的领域，发现他们的任务在皮肤内的稳态和疾病。迄今为止，我们的工作发现， 皮肤B谱系细胞的两个主要功能：分泌IgM和IL-10。细胞因子BAFF和 皮肤中的APRIL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，我们最近发现，IL-10+调节性B细胞（BCRs）定位于皮肤本身， 银屑病样炎症和皮肤超敏反应的消退。我们还发现， 在分泌型IgM（sIgM-/-）中， sIgM的作用。然而，IL-10+ BcR急剧增加，这可以替代地解释皮肤减少， sIgM-/-小鼠中的炎症。在B细胞中缺乏sIgM的高亲和力受体FcµR， 相对于来自WT或sIgM-/-小鼠的B细胞，在B细胞中的IL-10+表型为中间，表明sIgM发挥作用， 直接对B细胞的IL-10抑制活性。BCR接合是B中IL-10诱导的关键要求 与FcµR结合后，sIgM是BCR信号强度和B细胞活化的调节剂。因此我们 假设sIgM是B细胞中通过调节BCR信号传导IL-10诱导的主要调节物 强度作为自我约束机制和sIgM水平在组织壁龛，如皮肤（例如，支配 通过局部IgM分泌）可以指导或阻止布雷格在各种类型的皮肤炎症中的诱导 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 然后通过BAFF/APRIL或其它因子的表达局部地影响B细胞的IL-10产生， 从而微调局部免疫反应。拟议工作的目标是定义新的机制， 针对B谱系细胞的皮肤免疫反应。具体而言，目标1是以疾病为导向，并将确定 皮肤炎症的类型和阶段服从于IL-10+皮肤BELT和局部富含IgM的小生境的调节。 我们将采用人类组织以及炎症性皮肤病的小鼠模型。目标二是 机制导向，并将揭示IgM调节B细胞中IL-10编程的机制 关注sIgM调节的BCR信号传导的作用、sIgM的特异性要求和sIgM结合 受体。总之，这一提议将揭示调节皮肤中布雷格反应的机制， 定义新的方法来靶向治疗皮肤BLENZ，与皮肤病理学相关， 炎症和感染到癌症。

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.