Investigating links between regulatory T-cell depletion and psychosis

精神病-心境障碍严重影响个人的生活质量，并给社会带来巨大负担。这类疾病的遗传风险变异集中在神经元、组蛋白和免疫途径上[1]。在精神病-情绪谱系障碍中，最一致的免疫发现之一是循环调节性T细胞比例的降低[2-4]，这可能会被药物逆转[5]。我们认为Treg缺失对脑髓鞘形成过程的影响可能会增加女性产后精神病的风险[6]。我们的目标是首次系统地研究急性Treg耗竭的后果，以期了解Treg水平降低如何影响相关的情感(恐惧/焦虑)、认知(感觉加工和注意力)和免疫表型；然后我们将尝试挽救任何与免疫调节或抗精神病药物有关的异常。我们将使用两种小鼠模型，其中Treg补体可以部分(注射抗CD25抗体)或完全耗尽(给表达Tregs上DT受体的转基因小鼠白喉毒素(DT))，以总结临床情况，或诱导最大的表型效应。急性实验操作对总体健康/幸福感没有影响。在最近的一项初步研究中，我们发现成年雌性小鼠急性、完全的Treg枯竭与几个与精神病有关的基因如GBP4、Lcn2、SGK1和IFITM3的脑表达显著改变有关。与来自布里斯托尔的具有遗传流行病学专业知识的共同申请者一起，我们将测试对Treg枯竭敏感的基因/路径是否丰富了与精神病情绪障碍相关的遗传风险变量，将我们的动物工作与人类遗传风险变量联系起来。老鼠的实验操作将在雄性和雌性野生型动物身上进行，在关键的发育时间点，在雌性动物中，在产后时期。行为遗传学小组在开发和运行复杂的行为/认知分析方面拥有丰富的经验，通过神经科学和心理健康研究所，我们可以获得神经科学多个方面的专业知识。

Psychotic-mood spectrum disorders significantly affect an individual's quality of life and place a large burden upon society. Genetic risk variants for such disorders converge upon neuronal, histone and immune pathways [1]. One of the most consistent immune findings across psychotic-mood spectrum disorders is a reduction in the proportion of circulating regulatory T-cells [2-4] which may be reversed with medication [5]. We have argued that the effects of Treg depletion on brain myelination processes may confer postpartum psychosis risk in women [6]. We aim to systematically investigate, for the first time, the consequences of acute Treg depletion, with a view to understanding how reduced Treg levels might influence relevant affective (fear/anxiety), cognitive (sensory processing and attention) and immune phenotypes; we will then attempt to rescue any abnormalities identified with immunomodulatory or antipsychotic drugs. We will use two mouse models in which Treg complement can either be partially (anti-CD25 antibody administration) or fully (diphtheria-toxin (DT) administration to transgenic mice expressing DT receptor on Tregs) depleted, to recapitulate the clinical situation, or to elicit maximal phenotypic effects, respectively. The acute experimental manipulations have no effect on gross health/wellbeing. In a recent pilot study, we have shown that acute, complete Treg depletion in adult female mice is associated with significantly altered brain expression of several genes implicated in psychosis e.g. Gbp4, Lcn2, Sgk1 and Ifitm3. With co-applicants from Bristol with expertise in genetic epidemiology, we will test whether genes/pathways sensitive to Treg depletion are enriched for genetic risk variants associated with psychotic mood disorder, linking our animal work to human genetic risk variants. The mouse experimental manipulations will be performed in male and female wildtype animals, at key developmental timepoints, and, in females, in the postpartum period. The Behavioural Genetics Group have considerable experience in developing and running sophisticated behavioural/cognitive assays, and via the Neuroscience and Mental Health Research Institute, we have access to expertise in numerous aspects of neuroscience.