Abstract：
OBJECTIVE: This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)-associated neurological immune-related adverse events (nirAE).
METHODS: A systematic literature review was made, with case observations of a melanoma and a non-small cell lung cancer (NSCLC) patient who developed ICI-associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement.
RESULTS: Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c-LETM), respectively. Intrathecal inflammation with chemokine C-X-C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death-1 (PD-1) expression on CSF T cells; the c-LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first-line treatment. The NSCLC case improved upon administration of B cell-depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI-associated LETM case with intrathecal CXCL13 elevation, three cases with ICI-associated aquaporin-4 antibody neuromyelitis spectrum disorder, and evidence of B cell-mediated toxicity based on antibody-mediated immune pathologies in ICI-associated immune-related adverse events.
CONCLUSIONS: The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI-associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.
METHODS: A systematic literature review was made, with case observations of a melanoma and a non-small cell lung cancer (NSCLC) patient who developed ICI-associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement.
RESULTS: Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c-LETM), respectively. Intrathecal inflammation with chemokine C-X-C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death-1 (PD-1) expression on CSF T cells; the c-LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first-line treatment. The NSCLC case improved upon administration of B cell-depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI-associated LETM case with intrathecal CXCL13 elevation, three cases with ICI-associated aquaporin-4 antibody neuromyelitis spectrum disorder, and evidence of B cell-mediated toxicity based on antibody-mediated immune pathologies in ICI-associated immune-related adverse events.
CONCLUSIONS: The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI-associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.
摘要：
目的：本研究旨在提高人们对B细胞在免疫检查点抑制剂（ICI）相关的神经免疫相关不良事件（nirAE）中的作用的认识。
方法：进行了系统的文献综述，1例黑色素瘤和1例非小细胞肺癌（NSCLC）患者发生ICI相关nirAE，脑脊液（CSF）发现提示B细胞受累。
结果：两名接受ipilimumab/nivolumab治疗黑色素瘤和化疗/pembrolizumab治疗非小细胞肺癌的患者发展为心肌炎/肌炎/重症肌无力重叠综合征（三M）和小脑炎加纵向横行性脊髓炎（c-LETM），分别。两名患者均出现鞘内炎症伴趋化因子C-X-C基序配体（CXCL13）升高；三重M病例具有乙酰胆碱受体抗体，抗菌素反应性，血液中CD4/CD8T细胞比例改变，CSFT细胞上的程序性死亡-1（PD-1）表达降低；c-LETM病例显示鞘内抗体产生和浆细胞。两名患者对一线治疗反应不足。NSCLC病例在给予利妥昔单抗B细胞耗竭治疗后有所改善，而黑色素瘤患者在开始升级治疗前死亡.文献研究显示，另一例ICI相关的LETM病例鞘内CXCL13升高，三例ICI相关水通道蛋白4抗体神经脊髓炎谱系障碍，以及在ICI相关免疫相关不良事件中基于抗体介导的免疫病理学的B细胞介导毒性的证据。
结论：病例观察强调了ICI相关nirAE的诊断和治疗中存在过多的不确定性，举例说明所涉及的免疫机制的异质性，并暗示了B细胞的作用，这可能是诊断不足。鞘内注射CXCL13可以作为B细胞参与nirAE的生物标志物，鞘内免疫球蛋白合成支持，浆细胞的存在，和/或募集同源免疫细胞。
方法：进行了系统的文献综述，1例黑色素瘤和1例非小细胞肺癌（NSCLC）患者发生ICI相关nirAE，脑脊液（CSF）发现提示B细胞受累。
结果：两名接受ipilimumab/nivolumab治疗黑色素瘤和化疗/pembrolizumab治疗非小细胞肺癌的患者发展为心肌炎/肌炎/重症肌无力重叠综合征（三M）和小脑炎加纵向横行性脊髓炎（c-LETM），分别。两名患者均出现鞘内炎症伴趋化因子C-X-C基序配体（CXCL13）升高；三重M病例具有乙酰胆碱受体抗体，抗菌素反应性，血液中CD4/CD8T细胞比例改变，CSFT细胞上的程序性死亡-1（PD-1）表达降低；c-LETM病例显示鞘内抗体产生和浆细胞。两名患者对一线治疗反应不足。NSCLC病例在给予利妥昔单抗B细胞耗竭治疗后有所改善，而黑色素瘤患者在开始升级治疗前死亡.文献研究显示，另一例ICI相关的LETM病例鞘内CXCL13升高，三例ICI相关水通道蛋白4抗体神经脊髓炎谱系障碍，以及在ICI相关免疫相关不良事件中基于抗体介导的免疫病理学的B细胞介导毒性的证据。
结论：病例观察强调了ICI相关nirAE的诊断和治疗中存在过多的不确定性，举例说明所涉及的免疫机制的异质性，并暗示了B细胞的作用，这可能是诊断不足。鞘内注射CXCL13可以作为B细胞参与nirAE的生物标志物，鞘内免疫球蛋白合成支持，浆细胞的存在，和/或募集同源免疫细胞。
