Langerhans Cells and Nerves: Bidirectional Signaling

描述（由申请人提供）：有大量证据表明，压力，情绪状态和神经活动调节免疫反应。然而，除了内分泌效应外，这种调节的机制在细胞和分子水平上仍然不清楚。皮肤免疫系统是一个能够建立机械联系的系统。在皮肤中，表皮中的抗原呈递细胞朗格汉斯细胞（LC）受神经支配。此外，本实验室先前已证实去甲肾上腺素（NE）、肾上腺素（EPI）和三种神经肽[降钙素基因相关肽（CGRP）、垂体腺苷酸激活肽（PACAP）和血管活性肠肽（VIP）]均能在体内和体外调节皮肤免疫反应。这种神经-免疫相互作用可能在（a）某些病理状况（特应性皮炎、银屑病、自身免疫性疾病）、（B）对入侵病原体的正常应答和（c）疫苗接种期间对抗原的应答中是重要的。然而，在理解这些途径方面存在很大差距。目前尚不清楚哪种细胞内信号通路负责介导神经递质的作用，或者不同的神经递质是否影响不同的通路。虽然神经影响Th 1反应，但不清楚它们是否影响Th 2反应或Th 1与Th 2反应的平衡。我们在此提出的假设，即神经递质调节Th 1和Th 2依赖性免疫反应，通过调节细胞内信号通路，特别是cAMP依赖性抑制NF κ B的激活。与此假设相关的是，神经系统可能在选择发生的免疫反应类型方面发挥作用。 这将在3个具体目标：目标1 -确定和研究介导NE/EPI，PACAP，VIP和CGRP对LC成熟的影响的细胞内信号传导事件。 目的2 -确定神经肽或神经递质是否调节Th 2应答、Th 1/Th 2细胞因子平衡和/或抗体产生。 目的3 -确定去神经支配是否影响LC的数量，其成熟状态或其诱导接触过敏的能力。通过进一步探索由神经系统调节的皮肤免疫应答的类型，并通过确定这种调节的分子机制，我们将创建合理设计药物以修改病理和正常皮肤免疫应答所需的知识。皮肤的免疫反应。

DESCRIPTION (provided by applicant): There is substantial evidence that stress, emotional status and neural activity modulate immunological responsiveness. However, except for endocrine effects, the mechanism(s) of this regulation remain obscure at the cellular and molecular levels. One system that is amenable to establishing mechanistic links is the cutaneous immune system. In the skin, Langerhans cells (LCs), antigen presenting cells in the epidermis, are innervated. Furthermore, our laboratory has previously established that norepinephrine (NE), epinephrine (EPI) and three neuropeptides [calcitonin gene-related peptide (CGRP), pituitary adenylate activating polypeptide (PACAP), and vasoactive intestinal peptide (VIP)] are all able to modulate cutaneous immune responses in vivo and in vitro. This neuro-immunological interaction is probably important in (a) some pathological conditions (atopic dermatitis, psoriasis, autoimmune disorders), (b) the normal responses to invading pathogens and (c) the response to antigens during vaccination. Nevertheless, there are substantial gaps in understanding these pathways. It is not known which intracellular signaling pathway(s) are responsible for mediating the effects of neurotransmitters or if different neurotransmitters influence different pathways. Although nerves influence Th1 responses, it is not clear if they influence Th2 responses or the balance of Th1 to Th2 responses. We propose herein to test the hypothesis that neurotransmitters modulate both Th1- and Th2-dependent immune responses by modulating intracellular signaling pathways, especially the cAMP-dependent inhibition of NFkappaB activation. A correlate of this hypothesis is that the nervous system may have a role in selecting the type of immune response that occurs. This will be done in 3 specific aims: Aim 1 - To identify and study the intracellular signaling events that mediate the effects of NE/EPI, PACAP, VIP, and CGRP on the maturation of LCs. Aim 2 - To determine if neuro-peptides or neurotransmitters modulate the Th2 response, the Th1/Th2 cytokine balance and/or antibody production. Aim 3 - To determine if denervation influences the number of LCs, their maturation state or their capacity to induce contact hypersen-sitivity. By further exploring the types of cutaneous immune responses that are regulated by the nervous system and by determining the molecular mechanisms of this regulation, we will create the knowledge needed for rational design of drugs to modify cutaneous immune responses in pathological and normal. Immune responses in the skin.