HLA and microtubule-associated protein tau H1 haplotype associations in anti-IgLON5 disease

Abstract

Objectives: We investigated the associations with HLA and microtubule-associated protein tau (MAPT) H1 haplotype in anti-IgLON5 disease, a recently identified disorder characterized by gait instability, brainstem dysfunction, and a prominent sleep disorder in association with IgLON5 antibodies and pathologic findings of a novel neuronal-specific tauopathy.

Methods: We compared the HLA alleles and MAPT H1/H1 genotype of 35 patients with anti-IgLON5 with healthy controls. The on-line server tool NetMHCIIpan 3.1 was used to predict the IgLON5 peptide binding to HLA Class II molecules.

Results: The HLA-DRB1*10:01-DQB1*05:01 haplotype was overrepresented in patients with anti-IgLON5 disease (OR = 54.5; 95% CI: 22.2-133.9, p < 0.0001). In addition, HLA-DQA was genotyped in 27 patients, and 25 (92.6%) of them had DQ molecules composed by DQA1*01 and DQB1*05 chains compared with 148/542 (27.3%) controls (OR = 43.9; 95% CI: 10.4-185.5, p < 0.0001). Patients DRB1*10:01 positive developed more frequently sleep or bulbar symptoms than those carrying other HLA alleles (70.0% vs 26.7%; p = 0.011). Prediction algorithms identified 2 IgLON5 peptides (1 located in the signal sequence) that showed strong binding to HLA-DRB1*10:01 and other HLA-DRB1, but not to HLA-DQA and HLA-DQB molecules. The MAPT H1/H1 homozygous genotype was present in 20/24 (83.3%) anti-IgLON5 Caucasian patients compared with 54/116 (46.5%) healthy controls (p = 0.0007).

Conclusions: The robust association of anti-IgLON5 disease with distinct HLA Class II molecules supports a primary autoimmune origin. The significant association of MAPT H1 haplotype also suggests that an underlying neurodegenerative process could be involved in anti-IgLON5 disease.

Figure. Modeling of the interaction between Class II molecules and IgLON5 peptides

Detail of the pockets P7 and P9 in the modeled complexes between peptides LRLLAAAAL (A) and IVHVPARIV (B) of IgLON5 and molecules HLA-DRB1*01:01 and HLA-DRB1*10:01. Residues 7–9 (from right to left) of the peptides are represented as sticks, with the carbons in golden yellow. Protein residues forming the pockets are represented as sticks, with carbon atoms in teal blue. Covering the protein atoms, their Connolly surface is represented to facilitate the visualization of the pockets. Noncarbon atoms are colored as follows: N-blue, H-light gray, O-red, and S-yellow. It can be observed that P9 (cavity at the left of each panel) is shallower in HLA-DRB1*10:01 than in HLA-DRB1*01:01. As a result, the aliphatic residues at position 9 of both peptides bind more deeply in HLA-DRB1*01:01. The models also show that the Arg (R) residue at position 7 in IVHVPARIV is too bulky for the small P7 and has to orient its side chain toward previous pockets, particularly in HLA-DRB1*10:01.