PDF(Pubmed)
Abstract：
Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
摘要：
抗IgLON5疾病是自身免疫性脑炎的一种罕见且可能未被诊断的亚型。该疾病表现出包括睡眠在内的异质性表型，运动,和球相关的功能障碍。CSF/血清中存在IgLON5抗体，与HLA-DRB1*10:01~DQB1*05:01强相关，支持自身免疫基础。在这项研究中,一项针对87名抗IgLON5患者的多中心HLA研究显示，与HLA-DQ的相关性强于HLA-DR。具体来说,我们在85%的患者中发现了与HLA-DQA1*01:05~DQB1*05:01,HLA-DQA1*01:01~DQB1*05:01和HLA-DQA1*01:04~DQB1*05:03的易感等级相关.这三个DQ异源二聚体的HLA序列和结合核心相似，与相关的DRB1等位基因不同，支持与HLA-DQ的因果关系。这种关联进一步反映在每个基因型组的发病年龄越来越晚，延迟长达11年，而在非易感DQ1等位基因存在的情况下，风险降低也提示了HLA-DQ剂量依赖性效应。用竞争结合测定法研究观察到的HLA-DQ分子的功能相关性。这些概念验证实验揭示了IgLON5在翻译后修饰中的优先结合，但不是本地人，状态为所有三种风险相关的HLA-DQ受体。Further,来自IgLON5激活的T细胞的Ig2结构域的脱酰胺肽在两名患者中，与一个携带HLA-DQA1*01:05~DQB1*05:01的对照相比。一起来看,这些数据支持HLA-DQ介导的T细胞对IgLON5的应答是启动该疾病自身免疫的潜在关键步骤.
