Department of Medical Education, Tokyo Medical University, Tokyo, Japan.
Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000, Charleroi, Belgium.
J Neurol. 2024 Oct;271(10):7046-7053. doi: 10.1007/s00415-024-12596-7. Epub 2024 Jul 25.
Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor.
免疫介导的小脑共济失调（IMCAs）是一组以免疫系统主要靶向小脑和相关结构为特征的疾病。我们探讨了近期该领域进展所阐明的 IMCAs 的诊断和免疫学发病机制的基本问题。已经确定了多种类型的 IMCAs，包括感染后小脑炎、米勒费舍尔综合征、麸质共济失调、副肿瘤性小脑变性（PCD）、眼阵挛-肌阵挛综合征和抗 GAD 共济失调。在某些情况下，几种特征明确的自身抗体的鉴定指出了 IMCAs 的特定病因，并导致了明确的诊断。在其他情况下，已经报道了各种自身抗体，但它们的解释需要仔细考虑。事实上，一些自身抗体仅在有限数量的病例中得到记录，其因果关系尚未建立。为了便于早期治疗和预防不可逆损伤，近年来定义了新的实体，如原发性自身免疫性小脑共济失调（PACA）和潜伏性自身免疫性小脑共济失调（LACA）。PACA 的特征是具有自身免疫特征，但与传统病因不符，而 LACA 则对应于前驱期。LACA 并不意味着开始免疫治疗，但需要密切随访。同时，临床数据的积累导致了关于自身免疫机制的有趣假设，例如针对突触的自身免疫发病机制（突触病），以及当免疫靶向离子通道和星形胶质细胞时整个神经系统的易感性。免疫检查点抑制剂治疗的患者中 PCD 的发展表明，分子模拟特异性决定了自身免疫的方向，而这种反应的强度由共信号分子调节，这些分子增强或抑制抗原特异性 T 细胞受体的信号。
