HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease

人类白细胞抗原 等位基因 疾病 HLA-DQB1 人类白细胞抗原-DR 自身免疫性脑炎 基因型 HLA-DQ 生物 免疫学 遗传学 医学 单倍型 内科学 抗体 基因 自身抗体 抗原
作者
Selina Yogeshwar,Sergio Muñiz‐Castrillo,Lidia Sabater,Vicente Peris-Sempere,Vamsee Mallajosyula,Luo Guo,Han Yan,Eric Yu,Jing Zhang,Ling Lin,Flavia Fagundes Bueno,Xuhuai Ji,Géraldine Picard,Véronique Rogemond,Anne Laurie Pinto,Anna Heidbreder,Romana Höftberger,Francesc Graus,Josep Dalmau,Joan Santamaría,Alex Iranzo,Bettina Schreiner,Maria Pia Giannoccaro,Rocco Liguori,Takayoshi Shimohata,Akio Kimura,Yoya Ono,Sophie Binks,Sara Mariotto,Alessandro Dinoto,Michael Bonello,Christian Hartmann,Nicola Tambasco,Pasquale Nigro,Harald Prüß,Andrew McKeon,Mark M. Davis,Sarosh Irani,Jérôme Honnorat,Carles Gaig,Carsten Finke,Emmanuel Mignot
出处
期刊:Brain [Oxford University Press]
被引量:7
标识
DOI:10.1093/brain/awae048
摘要

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. 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.
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