Inflammatory mechanisms in the context of gene x environment interactions in affective disorders

免疫失调是情感性精神障碍(ADS)病理生理学中的一个长期谜团。然而，GxE在AD中相互作用的潜在机制以及相关的免疫变化在很大程度上尚不清楚。因此，需要在动物模型和暴露于GxE相互作用的人类中进行纵向研究，以获得对免疫信号及其在AD中的预后和功能意义的新见解。我们在第一个资助期进行的动物研究揭示了CACNA1C+/-对照WT大鼠对社会隔离和环境/社会丰富的免疫反应和表观遗传调节的变化。此外，在CACNA1C+/-条件下，小胶质细胞的激活和对免疫刺激的生物能量能力被取消，这表明与该危险基因相关的整体免疫能力降低。与大鼠模型类似，我们的人类研究指出，与健康人相比，MDD患者外周血中刺激的免疫细胞产生细胞因子和生物能量的能力降低。在此基础上，建立了单细胞水平的细胞大规模多参数流式细胞仪筛选系统。细胞类型的特异性特征非常重要，因为免疫细胞的重叠细胞因子谱可能调节AD炎症反应的总体结果，更重要的是，特定细胞亚群的免疫特征可能具有预测预后的潜力。我们目前的发现形成了工作假说的基础，探索了暴露于AD风险的GxE风险下的人类和啮齿动物的免疫特征改变。我们假设，特定的免疫信号表征了AD的特定疾病阶段，并可能作为人类预后的标志。我们在第二个资助期对MDD患者和MACS队列的健康参与者，包括那些有家族遗传风险和暴露于早期生活压力(童年虐待)的人进行了一项纵向研究，解决了这个假设。此外，我们将在CACNA1C+/-鼠模型中调查在患者中发现的改变的免疫信号是否也与GxE风险交互作用有关，在社交隔离、丰富的环境和额外的免疫刺激的条件下。我们假设，CACNA1C风险基因杂合表达可能会影响与AD相关行为改变相关的外周免疫特征和神经炎性反应，这些大鼠受到环境风险和/或外部炎性刺激。WP4的这种翻译方法将为暴露于AD风险因素GxE的动物和人类的外周免疫细胞亚群中改变的签名提供新的见解。识别的免疫特征可以作为AD不同阶段和处于危险状态的人类的生物标记物。同时，大鼠模型和衍生的小胶质细胞培养将允许在确定的GxE风险环境中对改变的外周免疫能力和神经炎性反应之间的相互作用进行机械分析。

Immune dysregulations represent a longstanding enigma in the pathophysiology of affective disorders (ADs). However, the underlying mechanisms of GxE interactions in AD and associated immune alterations are largely unknown. Therefore, longitudinal studies are needed in animal models and in humans exposed to GxE interactions to gain novel insights into immune signatures and their prognostic and functional significance in AD. Our animal studies in the 1st funding period revealed altered immune responses and epigenetic regulations in Cacna1c+/- versus WT rats in response to social isolation and environmental/social enrichment. Further, microglial activation and bioenergetic capacities to an immune stimulus were abrogated under Cacna1c+/- conditions, suggesting an overall reduced immune capacity associated with this risk gene. In analogy to the rat model, our human studies point toward reduced cytokine-producing and bioenergetic capacities of stimulated immune cells from the peripheral blood of MDD patients compared to healthy individuals. Further, we established a cellular large-scale multi-parameter flow cytometry screen at the single cell level. Cell-type specific characterisations are of major importance, since overlapping cytokine profiles of immune cells may modulate the overall outcome of inflammatory responses in AD and, importantly, immune signatures of specific cell subsets may harbour prognostic potential. Our current findings formed the basis for the working hypotheses, probing altered immune signatures in humans and rodents exposed to GxE risks for AD. We hypothesise that specific immune signatures characterise particular disease phases in AD and may serve as prognostic markers in humans. We address this hypothesis in the 2nd funding period in a longitudinal study in MDD patients and in healthy participants of the MACS cohort, including those with familial genetic risk and exposure to early life stress (childhood maltreatment). Further, we will investigate whether the altered immune signatures identified in patients are also associated with GxE risk interaction in the Cacna1c+/- rat model in conditions of social isolation, enriched environment, and an additional immune stimulus. We hypothesise that heterozygous Cacna1c risk gene expression may affect peripheral immune signatures and neuroinflammatory responses associated with AD-related behavioural changes in rats subjected to environmental risk and/or an external inflammatory stimulus. This translational approach of WP4 will provide new insights into altered signatures in subsets of peripheral immune cells in animals and humans exposed to GxE risk factors for AD. The identified immune signatures may serve as biomarkers in different phases of AD and in humans at risk. In parallel, the rat model and derived microglial cultures will allow for mechanistic analyses of interactions between the altered peripheral immune capacity and neuro-inflammatory responses in defined GxE risk settings.