%0 Journal Article
%T HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.
%A Yogeshwar SM
%A Muñiz-Castrillo S
%A Sabater L
%A Peris-Sempere V
%A Mallajosyula V
%A Luo G
%A Yan H
%A Yu E
%A Zhang J
%A Lin L
%A Fagundes Bueno F
%A Ji X
%A Picard G
%A Rogemond V
%A Pinto AL
%A Heidbreder A
%A Höftberger R
%A Graus F
%A Dalmau J
%A Santamaria J
%A Iranzo A
%A Schreiner B
%A Giannoccaro MP
%A Liguori R
%A Shimohata T
%A Kimura A
%A Ono Y
%A Binks S
%A Mariotto S
%A Dinoto A
%A Bonello M
%A Hartmann CJ
%A Tambasco N
%A Nigro P
%A Prüss H
%A McKeon A
%A Davis MM
%A Irani SR
%A Honnorat J
%A Gaig C
%A Finke C
%A Mignot E
%J Brain
%V 147
%N 7
%D 2024 Jul 5
%M 38425314
%F 15.255
%R 10.1093/brain/awae048
%X 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.