Bonanno Silvia, Cavalcante Paola, Salvi Erika, Giagnorio Eleonora, Malacarne Claudia, Cattaneo Marco, Andreetta Francesca, Venerando Anna, Pensato Viviana, Gellera Cinzia, Zanin Riccardo, Arnoldi Maria Teresa, Dosi Claudia, Mantegazza Renato, Masson Riccardo, Maggi Lorenzo, Marcuzzo Stefania
Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Front Cell Neurosci. 2022 Aug 11;16:982760. doi: 10.3389/fncel.2022.982760. eCollection 2022.
Multisystem involvement in spinal muscular atrophy (SMA) is gaining prominence since different therapeutic options are emerging, making the way for new SMA phenotypes and consequent challenges in clinical care. Defective immune organs have been found in preclinical models of SMA, suggesting an involvement of the immune system in the disease. However, the immune state in SMA patients has not been investigated so far. Here, we aimed to evaluate the innate and adaptive immunity pattern in SMA type 1 to type 3 patients, before and after nusinersen treatment.
Twenty one pediatric SMA type 1, 2, and 3 patients and 12 adult SMA type 2 and 3 patients were included in this single-center retrospective study. A Bio-Plex Pro-Human Cytokine 13-plex Immunoassay was used to measure cytokines in serum and cerebrospinal fluid (CSF) of the study cohort before and after 6 months of therapy with nusinersen.
We detected a significant increase in IL-1β, IL-4, IL-6, IL-10, IFN-γ, IL-17A, IL-22, IL-23, IL-31, and IL-33, in serum of pediatric and adult SMA patients at baseline, compared to pediatric reference ranges and to adult healthy controls. Pediatric patients showed also a significant increase in TNF-α and IL-17F levels at baseline. IL-4, IFN-γ, Il-22, IL-23, and IL-33 decreased in serum of pediatric SMA patients after 6 months of therapy when compared to baseline. A significant decrease in IL-4, IL-6, INF-γ, and IL-17A was detected in serum of adult SMA patients after treatment. CSF of both pediatric and adult SMA patients displayed detectable levels of all cytokines with no significant differences after 6 months of treatment with nusinersen. Notably, a higher baseline expression of IL-23 in serum correlated with a worse motor function outcome after treatment in pediatric patients. Moreover, after 6 months of treatment, patients presenting a higher IL-10 concentration in serum showed a better Hammersmith Functional Motor Scale Expanded (HFMSE) score.
Pediatric and adult SMA patients show an inflammatory signature in serum that is reduced upon modulating treatment, and the presence of inflammatory mediators in CSF. Our findings enhance SMA knowledge with potential clinical and therapeutic implications.
随着多种治疗方案的出现，脊髓性肌萎缩症（SMA）的多系统受累日益显著，这为新的SMA表型开辟了道路，也给临床护理带来了新的挑战。在SMA的临床前模型中发现了免疫器官缺陷，提示免疫系统参与了该疾病。然而，迄今为止尚未对SMA患者的免疫状态进行研究。在此，我们旨在评估1型至3型SMA患者在接受诺西那生治疗前后的先天性和适应性免疫模式。
本单中心回顾性研究纳入了21例1型、2型和3型小儿SMA患者以及12例2型和3型成人SMA患者。使用Bio-Plex Pro-人类细胞因子13联免疫测定法，测量研究队列在接受诺西那生治疗6个月前后血清和脑脊液（CSF）中的细胞因子。
与小儿参考范围和成人健康对照相比，我们在基线时检测到小儿和成人SMA患者血清中的白细胞介素-1β（IL-1β）、白细胞介素-4（IL-4）、白细胞介素-6（IL-6）、白细胞介素-10（IL-10）、干扰素-γ（IFN-γ）、白细胞介素-17A（IL-17A）、白细胞介素-22（IL-22）、白细胞介素-23（IL-23）、白细胞介素-31（IL-31）和白细胞介素-33（IL-33）显著增加。小儿患者在基线时肿瘤坏死因子-α（TNF-α）和白细胞介素-17F水平也显著增加。与基线相比，小儿SMA患者在治疗6个月后血清中的IL-4、IFN-γ、IL-22、IL-23和IL-33下降。治疗后成人SMA患者血清中的IL-4、IL-6、INF-γ和IL-17A显著下降。小儿和成人SMA患者的脑脊液中所有细胞因子均有可检测水平，在接受诺西那生治疗6个月后无显著差异。值得注意的是，小儿患者血清中IL-23的较高基线表达与治疗后较差的运动功能结局相关。此外，治疗6个月后，血清中IL-10浓度较高的患者哈默史密斯功能运动量表扩展版（HFMSE）评分较好。
小儿和成人SMA患者血清中表现出炎症特征，经调节治疗后炎症特征减轻，且脑脊液中存在炎症介质。我们的研究结果增进了对SMA的认识，具有潜在的临床和治疗意义。
