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

情感障碍中基因与环境相互作用背景下的炎症机制

• 批准号: 250991473
• 负责人: Professorin Dr. Judith Alferink
• 金额: --
• 依托单位: Klinik für Psychische Gesundheit
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250991473?language=en
• 关键词: Inflammatory; mechanisms; context; gene; environment

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.

免疫失调是情感性精神障碍（AD）病理生理学中一个长期存在的谜团。然而，在AD和相关的免疫改变中GxE相互作用的潜在机制在很大程度上是未知的。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，以获得对免疫特征及其在AD中的预后和功能意义的新见解。我们在第一个资助期的动物研究显示，Cacna 1c +/-与WT大鼠相比，在社会隔离和环境/社会丰富的反应中，免疫反应和表观遗传调节发生了变化。此外，在Cacna 1c +/-条件下，小胶质细胞活化和对免疫刺激的生物能量能力被废除，表明与该风险基因相关的免疫能力总体降低。与大鼠模型类似，我们的人体研究指出，与健康个体相比，来自MDD患者外周血的刺激免疫细胞的细胞因子产生和生物能量能力降低。此外，我们在单细胞水平上建立了细胞大规模多参数流式细胞术筛选。细胞类型特异性表征是非常重要的，因为免疫细胞的重叠细胞因子谱可以调节AD中炎症反应的总体结果，并且重要的是，特定细胞亚群的免疫特征可以具有预后潜力。我们目前的研究结果形成了工作假设的基础，探索了暴露于GxE风险的人类和啮齿动物中改变的免疫特征。我们假设特定的免疫信号与AD的特定疾病阶段相关，并可能作为人类的预后标志物。我们在第二个资助期对MDD患者和MACS队列的健康参与者进行了一项纵向研究，包括那些具有家族遗传风险和暴露于早期生活压力（儿童期虐待）的参与者。此外，我们将研究在患者中发现的改变的免疫特征是否也与Cacna 1c +/-大鼠模型在社会隔离，丰富的环境和额外的免疫刺激条件下的GxE风险相互作用相关。我们假设，杂合子Cacna 1c风险基因表达可能会影响周围免疫特征和神经炎症反应与AD相关的行为变化在大鼠受到环境风险和/或外部炎症刺激。WP 4的这种翻译方法将为暴露于AD GxE风险因素的动物和人类外周免疫细胞亚群中的改变特征提供新的见解。所鉴定的免疫特征可以作为AD的不同阶段和处于风险中的人类的生物标志物。同时，大鼠模型和衍生的小胶质细胞培养物将允许在定义的GxE风险设置中对改变的外周免疫能力和神经炎症反应之间的相互作用进行机制分析。