Immune modulating therapies to treat complex regional pain syndrome

摘要 复杂性区域疼痛综合征(CRPS)是一种病因不明的慢性疼痛障碍，可影响一个或多个 更多的四肢。治疗慢性阻塞性肺疾病的困难源于对潜在的 机械装置。尽管临床表现不同，但有明显证据表明感官刺激的处理方式发生了变化 在CRPS中已证实会导致痛觉过敏、痛觉过敏和感觉过敏。异常免疫 据报道，功能参与了CRPS的病理过程。皮肤中的自体炎症和自身免疫机制 据报道，患肢的疼痛和全身循环中的疼痛会增加疼痛的敏感度。 系统性CRPS患者前炎性单核细胞增多，循环记忆T细胞改变 (TCircm)。长寿命中央记忆CD8+和CD4+T细胞的扩增与促炎作用的增加 据报道，CRPS患者存在信号转导。然而，目前对TCircm的研究没有考虑到局部组织驻留 记忆T细胞(Trm)与多种自身免疫性疾病有关。差异化集群69 (CD69)是一种II型C-凝集素膜受体，在T细胞激活时迅速诱导，使其能够 蓄积在皮肤等非淋巴组织中。CD69拮抗细胞表面G蛋白的表达 偶联鞘氨醇-1-磷酸受体-1和5(S1PR1/5)。通过抑制S1PR1/5、CD69的表达 损害外流并促进T细胞驻留。我们已经发现了循环中miRNA信号的失调 对于CRPS患者和小鼠胫骨骨折模型(TFM)的CRPS都有共同的作用，可以调节TCircm。 有趣的是，几种miRNA，包括一种与CRPS患者的阳性结果直接相关的miRNA， 可以靶向对Trm发育至关重要的基因。这导致我们评估了TfM小鼠的TCircm和Trm功能障碍，其中 初步数据表明，TFM小鼠形成了病理性Trm。我们假设T的调节失调 CRPS中的细胞聚集在对TCircm动态平衡和Trm形成都至关重要的靶点上。我们将测试一下 病理TCircm和Trm在CRPS病理中起作用，如果合作针对两者的治疗 种群可以作为一种新的治疗策略。通过遵循TCircm和Trm，我们将阐明机制 治疗T细胞功能障碍，并研究治疗CRPS的新型免疫调节疗法。

Abstract Complex regional pain syndrome (CRPS) is a chronic pain disorder of unknown etiology that can affect one or more extremities. Difficulty in treating CRPS stems from incomplete understanding of the underlying mechanisms. Despite different clinical presentations, clear evidence for altered processing of sensory stimuli leading to allodynia, hyperalgesia, and hyperaesthesia has been demonstrated in CRPS. Aberrant immune function is reported to contribute to CRPS pathology. Autoinflammatory and autoimmune mechanisms in the skin of the affected limb, and systemically in circulation, reportedly contribute to increased pain hypersensitivity. Systemically, CRPS patients have increased proinflammatory monocytes, and altered circulating memory T cells (Tcircm). An expansion of long-lived central memory CD8+ and CD4+ T cells with increased proinflammatory signaling is reported in CRPS patients. However, current studies on Tcircm do not account for local tissue-resident memory T cells (Trm) which have been implicated in several autoimmune disorders. Cluster of differentiation 69 (CD69) is a type II C-lectin membrane receptor that is rapidly induced upon T cell activation, enabling their accumulation in nonlymphoid tissues like skin. CD69 antagonizes the cell-surface expression of G-protein– coupled sphingosine-1-phosphate receptor-1 and 5 (S1PR1/5). By inhibiting the expression of S1PR1/5, CD69 impairs egress and promotes T cell residency. We have identified dysregulation of circulating miRNA signatures common to both CRPS patients and mouse tibia fracture model (TFM) of CRPS that can regulate Tcircm. Interestingly several miRNAs, including a miRNA directly associated with positive outcomes for CRPS patients, can target genes critical to Trm development. This led us to evaluate Tcircm and Trm dysfunction in TFM mice, where preliminary data demonstrate formation of pathological Trm in TFM mice. We hypothesize that dysregulation of T cells in CRPS converges on targets crucial for both Tcircm homeostasis and Trm formation. We will test whether pathological Tcircm and Trm contribute to CRPS pathology, and if therapies that cooperatively target both populations can serve as a novel therapeutic strategy. By following Tcircm and Trm, we will elucidate mechanisms of T cell dysfunction and investigate novel immune modulating therapies for treating CRPS.