Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica (UGC) Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain.
Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
Front Immunol. 2021 Dec 16;12:778204. doi: 10.3389/fimmu.2021.778204. eCollection 2021.
Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients.
Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation .
Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β induction of PBMC, 6/7 patients increased the sIFNAR2 expression.
IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.
干扰素β受体 2 亚基（IFNAR2）可以作为跨膜蛋白产生，也可以通过选择性剪接或蛋白水解切割产生可溶性形式（sIFNAR2），其对 IFN-β具有激动剂和拮抗剂活性。然而，其对于复发缓解型多发性硬化症（RRMS）患者对 IFN-β的临床反应的作用尚不清楚。我们旨在评估 IFN-β治疗 RRMS 患者的短期效应以及治疗开始后 6 个月和 12 个月时 sIFNAR2 的产生及其与临床反应的关系。
纳入 94 例 RRMS 患者，在治疗开始时、治疗后 6 个月和 12 个月进行评估。将 41 例患者分为 IFN-β治疗的应答者和无应答者。采用 ELISA 法测定 sIFNAR2 血清水平。采用 RT-PCR 法测定 IFNAR1、IFNAR2 剪接变体、MxA 和蛋白酶的 mRNA 表达。通过 IFN-β刺激 RRMS 患者的 PBMC 评估短期效应。
IFN-β 治疗后 sIFNAR2 的蛋白和 mRNA 水平增加。根据临床反应，仅无应答者在蛋白和 mRNA 水平上均显著增加 sIFNAR2。sIFNAR2 基因表达与跨膜同工型表达相关，表达水平高 2.3 倍。治疗后 MxA 基因表达显著增加，而 IFNAR1 和 IFNAR2 仅略有增加。在 PBMC 短期 IFN-β诱导后，6/7 例患者增加了 sIFNAR2 的表达。
IFN-β 给药诱导 RRMS 中 sIFNAR2 的产生，较高水平可能与治疗反应降低有关。因此，可监测 sIFNAR2 的水平，以优化 IFN-β 治疗的有效反应。
