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

Objectives We investigated the associations with HLA and microtubule-associated protein tau (MAPT) H1 haplotype in anti-IgLONS disease, a recently identified disorder characterized by gait instability, brainstem dysfunction, and a prominent sleep disorder in association with IgLONS 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-IgLONS with healthy controls. The on-line server tool NetMHCIIpan 3.1 was used to predict the IgLONS peptide binding to HLA Class II molecules. Results The HLA-DRB1*10:01-DQB1*05:01 haplotype was overrepresented in patients with antiIgLONS 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 DQmolecules 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 IgLONS 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%) antiIgLONS Caucasian patients compared with 54/116 (46.5%) healthy controls (p = 0.0007). Conclusions The robust association of anti-IgLONS 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-IgLONS disease.