Background

Immunity decreases with age, which leads to reactivation of varicella zoster virus (VZV). In human subjects age-associated immune changes are usually measured in blood leukocytes; however, this might not reflect alterations in tissue-specific immunity.

Objectives

We used a VZV antigen challenge system in the skin to investigate changes in tissue-specific mechanisms involved in the decreased response to this virus during aging.

Methods

We assessed cutaneous immunity based on the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsy specimens taken from the challenge site in young (<40 years) and old (>65 years) subjects.

Results

Old human subjects exhibited decreased erythema and induration, CD4⁺ and CD8⁺ T-cell infiltration, and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared with young subjects. This was associated with increased sterile inflammation in the skin in the same subjects related to p38 mitogen-activated protein kinase–related proinflammatory cytokine production (P < .0007). We inhibited systemic inflammation in old subjects by means of pretreatment with an oral small-molecule p38 mitogen-activated protein kinase inhibitor (Losmapimod; GlaxoSmithKline, Brentford, United Kingdom), which reduced both serum C-reactive protein levels and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge were increased significantly in the same subjects (P < .0003).

Conclusion

Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However, this can be reversed by inhibition of inflammatory cytokine production that can be used to promote vaccine efficacy and the treatment of infections and malignancy during aging.

中文翻译：

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通过阻断 p38 丝裂原活化蛋白 (MAP) 激酶诱导的炎症增强衰老过程中的皮肤免疫

背景

免疫力会随着年龄的增长而降低，这会导致水痘带状疱疹病毒 (VZV) 的重新激活。在人类受试者中，与年龄相关的免疫变化通常在血液白细胞中测量；然而，这可能并不反映组织特异性免疫的改变。

目标

我们在皮肤中使用 VZV 抗原攻击系统来研究与衰老过程中对这种病毒的反应降低有关的组织特异性机制的变化。

方法

我们根据皮内 VZV 抗原注射后红斑和硬结的程度评估皮肤免疫。我们还对取自年轻（<40 岁）和老年（>65 岁）受试者的攻击部位的皮肤活检标本进行了免疫组织学和转录组学分析。

结果

与年轻受试者相比，老年人受试者表现出减少的红斑和硬结、CD4 ⁺和 CD8 ⁺ T 细胞浸润，以及在皮肤 VZV 抗原攻击部位的整体基因激活减弱。这与与 p38 丝裂原活化蛋白激酶相关促炎细胞因子产生相关的相同受试者的皮肤无菌炎症增加有关（P < .0007)。我们通过口服小分子 p38 丝裂原活化蛋白激酶抑制剂（Losmapimod；葛兰素史克公司，布伦特福德，英国）预处理来抑制老年受试者的全身炎症，该抑制剂可降低血清 C 反应蛋白水平和外周血单核细胞分泌IL-6 和 TNF-α。相反，在相同受试者中，对 VZV 抗原攻击的皮肤反应显着增加 ( P  < .0003)。

结论

抗原攻击后早期皮肤的过度炎症会延缓抗原特异性免疫。然而，这可以通过抑制炎症细胞因子的产生来逆转，炎症细胞因子的产生可用于促进疫苗效力以及治疗衰老过程中的感染和恶性肿瘤。