法国巴黎 Imagine 研究所Sylvain Latour团队近期取得重要工作进展，他们研究提出，IL-27RA缺乏揭示了IL-27在Epstein-Barr病毒感染中的作用。相关研究成果2024年3月20日在线发表于《自然》杂志上。

据介绍，Epstein-Barr病毒（EBV）感染可引起严重的B细胞淋巴增生性疾病。原发性感染通常无症状或引起传染性单核细胞增多症（IM），这是一种自限性淋巴增生性疾病。有报道指出，EBV的选择易感性与遗传突变损害T细胞对EBV的免疫有关。

研究人员报道了IL27RA中的双等位基因功能丧失变异，它是急性和严重原发性EBV感染的基础，尽管如此，仍有良好的结果，需要最低限度的治疗。一个突变等位基因（rs201107107）在芬兰人群中富集（次要等位基因频率=0.0068），当发生纯合突变时具有严重感染性单核细胞增多症的高风险。IL27RA编码IL-27受体α亚基。在缺乏IL-27RA的情况下，IL-27对STAT1和STAT3的磷酸化在T细胞中被消除。

在体外研究中，IL-27对患者细胞缺乏的T细胞受体依赖性T细胞增殖发挥协同作用，导致强效抗EBV效应细胞毒性CD8⁺ T细胞的扩增受损。IL-27由EBV感染的B淋巴细胞产生，维持EBV转化的B细胞需要IL-27RA–IL-27自分泌回路。这可能解释了EBV诱导的病毒性疾病在IL-27RA缺乏症患者中的最终有利结果。

此外，研究人员在大多数出现散发性感染性单核细胞增多症和慢性EBV感染的个体中发现了中和性抗IL-27自身抗体。

总之，这些结果证明了IL-27RA–IL-27在EBV免疫中的关键作用，以及EBV劫持这种防御以促进受感染转化B细胞的扩增。

附： 英文原文

Title: Role of IL-27 in Epstein–Barr virus infection revealed by IL-27RA deficiency

Author: Martin, Emmanuel, Winter, Sarah, Garcin, Ccile, Tanita, Kay, Hoshino, Akihiro, Lenoir, Christelle, Fournier, Benjamin, Migaud, Mlanie, Boutboul, David, Simonin, Mathieu, Fernandes, Alicia, Bastard, Paul, Le Voyer, Tom, Roupie, Anne-Laure, Ben Ahmed, Yassine, Leruez-Ville, Marianne, Burgard, Marianne, Rao, Geetha, Ma, Cindy S., Masson, Ccile, Soudais, Claire, Picard, Capucine, Bustamante, Jacinta, Tangye, Stuart G., Cheikh, Nathalie, Seppnen, Mikko, Puel, Anne, Daly, Mark, Casanova, Jean-Laurent, Neven, Bndicte, Fischer, Alain, Latour, Sylvain

Issue&Volume: 2024-03-20

Abstract: Epstein–Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency=0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA–IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA–IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

DOI: 10.1038/s41586-024-07213-6

Source: https://www.nature.com/articles/s41586-024-07213-6