Rosenkranz Sina C, Häußler Vivien, Kolster Manuela, Willing Anne, Matschke Jakob, Röcken Christoph, Stürner Klarissa, Leypoldt Frank, Tolosa Eva, Friese Manuel A
Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Germany.
Department of Neurology, University Medical Center Hamburg-Eppendorf, Germany.
Brain Commun. 2021 Dec 16;4(1):fcab292. doi: 10.1093/braincomms/fcab292. eCollection 2022 Feb.
Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4 T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.
虽然结节病患者中大多数进行性多灶性白质脑病病例是由免疫抑制药物治疗所致，但在未经治疗的结节病患者中也有报道，这意味着结节病患者普遍易患进行性多灶性白质脑病。事实上，有研究表明活动性结节病患者的调节性T细胞频率增加，这可能导致随后的全身免疫抑制。然而，尚不清楚T细胞亚群频率发生系统性改变的结节病是否构成进行性多灶性白质脑病发生的危险因素，而结节病治疗是否可以抵消这一危险因素。在这项队列研究中，我们纳入、表征并随访了6例经活检确诊为明确的进行性多灶性白质脑病且患有明确或可能结节病的患者，这些患者于2013年4月至2019年1月期间就诊，其中4例在首次出现进行性多灶性白质脑病症状时未接受免疫抑制治疗。对这些患者免疫细胞亚群的分析显示，CD4 T细胞和调节性T细胞频率存在显著失衡。由于4例患者的进行性多灶性白质脑病病情进展，我们决定治疗结节病，期望免疫细胞亚群频率恢复正常，从而改善进行性多灶性白质脑病。值得注意的是，通过使用英夫利昔单抗（一种抗肿瘤坏死因子-α抗体）进行治疗，3例患者临床症状持续改善，脑脊液中不再检测到JC病毒，调节性T细胞频率降低。1例患者最初被误诊为神经结节病，在开始治疗9周后因吸入性肺炎死亡。我们的研究表明，结节病可导致T细胞亚群频率改变，从而易患进行性多灶性白质脑病。虽然在进行性多灶性白质脑病中应避免使用免疫抑制药物，但矛盾的是，对于结节病患者，使用免疫抑制性药物英夫利昔单抗治疗可能会恢复正常的T细胞分布，从而阻止进行性多灶性白质脑病的进展。
