Antigen-specific immune mechanisms of neuronal hyperexcitability and chronic pain

描述(申请人提供)：将探索一种新的慢性疼痛机制：免疫球蛋白G(Ig G)免疫复合体通过神经元Fcγ受体I(Fc3RI)对初级感觉传入的兴奋作用。慢性疼痛通常伴随自身免疫性、过敏性或感染性疾病，涉及外周组织、神经或感觉神经节的抗原特异性免疫反应，尽管其潜在机制很大程度上尚不清楚。这些疾病的一个共同特征是血清中抗原特异性免疫球蛋白水平升高，并在受影响的组织中存在免疫球蛋白免疫复合体。最近发现，具有伤害性的背根神经节神经元亚群表达高亲和力的Ig G受体Fc3RI，并可被Ig G免疫复合物直接激活。初步数据表明，在先前免疫的大鼠中，用抗原挑战皮肤的皮肤痛敏反应持续时间长于急性炎症的迹象。我建议在免疫和未免疫的大鼠的皮肤或脊神经节上应用特定的外来抗原，以探讨与Fc3RI和疼痛相关行为有关的功能识别的伤害性初级感觉神经元的兴奋性和神经化学性质的影响。本研究将通过免疫复合物对初级感觉神经元表达的Fc受体的影响，揭示抗原特异性免疫反应驱动慢性疼痛的新机制。它将为慢性疼痛的治疗提供潜在的新的治疗策略。公共卫生相关性：这项研究将通过免疫复合物对初级感觉神经元表达的Fc受体的影响，揭示抗原特异性免疫反应驱动慢性疼痛的一种新机制。它将为慢性疼痛的治疗提供潜在的新的治疗策略。

Description (provided by applicant): A novel mechanism of chronic pain will be explored: the excitatory effects of the immunoglobulin G (IgG) immune complex on primary sensory afferents via neuronal Fc gamma receptor I (Fc3RI). Chronic pain often accompanies autoimmune, allergic or infectious diseases involving antigen-specific immune responses in the peripheral tissue, nerve or sensory ganglia though the underlying mechanisms are largely unknown. A common feature among these disorders is the elevated level of antigen-specific IgG in the serum and the presence of IgG immune complex in the affected tissue. Recently it was discovered that a subpopulation of dorsal root ganglion neurons with nociceptive properties expressed the high-affinity IgG receptor, Fc3RI and could be directly activated by IgG immune complex. Preliminary data indicate that cutaneous hyperalgesia in skin challenged with antigen in previously immunized rats long outlasts signs of acute inflammation. I propose to explore the effects of a specific foreign antigen, applied to the skin or to the spinal ganglia, in immunized vs. unimmunized rats, on the excitability and neurochemical properties of functionally identified nociceptive primary sensory neurons in relation to Fc3RI and pain-related behaviors. This study will reveal a novel mechanism of chronic pain driven by the antigen-specific immune response via the effects of IgG immune complex on the Fc receptors expressed in primary sensory neurons. It will provide potentially new therapeutic strategies in the treatment of chronic pain. PUBLIC HEALTH RELEVANCE: This study will reveal a novel mechanism of chronic pain driven by the antigen-specific immune response via the effects of IgG immune complex on the Fc receptors expressed in primary sensory neurons. It will provide potentially new therapeutic strategies in the treatment of chronic pain.