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. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric 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 to 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.

中文翻译：

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HLA-DQB1*05 亚型而非 DRB1*10:01 介导抗 IgLON5 疾病的风险

抗 IgLON5 疾病是一种罕见且可能未被充分诊断的自身免疫性脑炎亚型。该疾病表现出异质性表型，包括睡眠、运动和延髓相关功能障碍。CSF/血清中存在 IgLON5 抗体，以及与 HLA-DRB1*10:01∼DQB1*05:01 的强烈关联，支持自身免疫基础。在这项研究中，对 87 名抗 IgLON5 患者进行的多中心 HLA 研究显示，与 HLA-DQ 的关联性强于 HLA-DR。具体来说，我们确定了与 HLA-DQA1*01:05∼DQB1*05:01、HLA-DQA1*01:01∼DQB1*05:01 和 HLA-DQA1*01:04∼DQB1*05 的易感排序关联:03 85% 的患者。这三个 DQ 异二聚体的 HLA 序列和结合核心相似，与相连的 DRB1 等位基因不同，支持与 HLA-DQ 的因果联系。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，而非易感性 DQ1 等位基因存在时风险降低也表明 HLA-DQ 剂量依赖性效应。通过竞争结合测定研究了观察到的 HLA-DQ 分子的功能相关性。这些概念验证实验揭示了 IgLON5 在翻译后修饰而非天然状态下优先与所有三种风险相关的 HLA-DQ 受体结合。此外，与携带 HLA-DQA1*01:05∼DQB1*05:01 的一名对照患者相比，来自 IgLON5 Ig2 结构域的脱酰胺肽激活了两名患者的 T 细胞。总而言之，这些数据支持 HLA-DQ 介导的 T 细胞对 IgLON5 的反应，作为这种疾病中自身免疫启动的潜在关键步骤。