Major depressive disorder (MDD) is a common, severe and disabling neuropsychiatric disorder with a heterogenous etiology. Among the most widely recognized etiological models, immunopathogenesis is a predominant one. Numerous studies have demonstrated aberrant levels of inflammatory markers in the peripheral blood, cerebrospinal fluid (CSF) and brain of patients with MDD. Multiple studies including meta-analyses have reported increased peripheral levels of acute phase proteins, and pro-inflammatory cytokines, particularly IL-1β, TNF-α, and IL-6 in MDD. Postmortem brain studies similarly demonstrated upregulated expressions of these pro-inflammatory cytokines. This along with evidence of monocytic, lymphocytic and microglial activation, suggest an activated inflammatory response system (IRS) in MDD.

A few studies show increased levels of anti-inflammatory cytokines or defective inflammatory pathways and a deficit in T cell maturation and responses in MDD patients. This suggests the presence of a Compensatory Immune Response System (CIRS), which can counterbalance the effects of IRS in major depression. More recently, simultaneously increased levels of both the pro-and anti-inflammatory cytokines are reported in the brain of MDD patients; this indicates activity of both the IRS and CIRS in MDD. The IRS and CIRS are the evolutionarily conserved and integral elements of an overarching system. The relevance of a dysregulated IRS-CIRS system in the neurobiological construct of MDD is just beginning to be understood. Speculation is rife that the disrupted IRS-CIRS elements might determine the onset, episodes, neuroprogressive processes, treatment response as well as recovery of patients with MDD. Notably, the signatures of an activated IRS-CIRS might emerge as potential biomarkers of MDD. Herein, an attempt has been made to highlight the biology and pathobiological relevance of IRS-CIRS activation in MDD and provide an insight into the role of these components in pharmacological therapy.

重度抑郁症 (MDD) 是一种常见的、严重的、致残的神经精神疾病，病因各异。在最广泛认可的病因学模型中，免疫发病机制是主要的一种。大量研究表明，MDD 患者的外周血、脑脊液 (CSF) 和大脑中的炎症标志物水平异常。包括荟萃分析在内的多项研究报告了 MDD 中急性期蛋白和促炎细胞因子，特别是 IL-1β、TNF-α 和 IL-6 的外周水平升高。死后大脑研究同样证明了这些促炎细胞因子的表达上调。这与单核细胞、淋巴细胞和小胶质细胞激活的证据一起表明 MDD 中存在激活的炎症反应系统 (IRS)。

一些研究表明，MDD 患者的抗炎细胞因子水平升高或炎症通路缺陷以及 T 细胞成熟和反应不足。这表明存在补偿性免疫反应系统 (CIRS)，它可以抵消 IRS 在重度抑郁症中的影响。最近，据报道，MDD 患者的大脑中促炎细胞因子和抗炎细胞因子的水平同时增加。这表明 IRS 和 CIRS 在 MDD 中的活动。IRS 和 CIRS 是总体系统的进化上保守和不可或缺的元素。失调的 IRS-CIRS 系统在 MDD 的神经生物学结构中的相关性才刚刚开始被理解。人们普遍猜测，被破坏的 IRS-CIRS 元素可能决定发病、发作、神经进展过程、治疗反应以及 MDD 患者的康复。值得注意的是，激活的 IRS-CIRS 的特征可能会成为 MDD 的潜在生物标志物。本文试图强调 IRS-CIRS 激活在 MDD 中的生物学和病理生物学相关性，并提供对这些成分在药物治疗中的作用的洞察。