Dataset Information

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.

SUBMITTER: Gaig C

PROVIDER: S-EPMC6705627 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Gaig Carles C Ercilla Guadalupe G Daura Xavier X Ezquerra Mario M Fernández-Santiago Ruben R Palou Eduard E Sabater Lidia L Höftberger Romana R Heidbreder Anna A Högl Birgit B Iranzo Alex A Santamaria Joan J Dalmau Josep J Graus Francesc F

Neurology(R) neuroimmunology & neuroinflammation 20190812 6

<h4>Objectives</h4>We investigated the associations with HLA and microtubule-associated protein tau (<i>MAPT</i>) 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.<h4>Methods</h4>We compared the HLA alleles and <i>MAPT</i> H1/H1 genotype of 35 patients with anti-IgLON5 with healthy controls ...[more]

PMID: 31454761

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Project description:Antibodies against IgLON5, a neuronal adhesion protein of unknown function, are markers of a novel neurological disorder termed anti-IgLON5 syndrome. The disorder shows a remarkable association with the HLA-DQB1*0501 and HLA-DRB1*1001 alleles, and postmortem studies demonstrate a novel neuronal tauopathy predominantly involving the hypothalamus and tegmentum of the brainstem. The role of IgLON5 antibodies in the pathogenesis of the disease is currently unknown. Here, we have determined the target epitopes of IgLON5 antibodies, the effects of the IgLON5 antibodies in rat hippocampal neurons, and the IgG subclass responsible for these effects.HEK293 cells expressing several deletion constructs of IgLON5 were used to determine the epitopes recognized by the serum of 15 patients with anti-IgLON5 syndrome. The role of glycosylation in immunogenicity was tested with PNGase F treatment of transfected cells. Dissociated hippocampal neuronal cultures were used to test by immunocytochemistry the effects of total IgG, IgG1, and IgG4 subclasses of IgLON5 antibodies.Patients' antibodies reacted with the immunoglobulin-like domain 2 of IgLON5. Glycosylation was not required for immunoreactivity. The predominant subclass of IgLON5 antibodies was IgG4 but all patients also had IgG1. The mean percentage of specific IgLON5 IgG4 and IgG1 of the samples analyzed by flow cytometry was 64 and 33 %, respectively. In cultures of hippocampal neurons, patients' antibodies caused a decrease of cell surface IgLON5 clusters that was not reversed after IgLON5 antibodies were removed from the media. The decrease of surface IgLON5 clusters correlated with the rate of antibody internalization. These effects were observed with purified IgG1 but not with the IgG4 antibodies.IgLON5 antibodies recognize the immunoglobulin-like domain 2 of the antigen, and the reactivity is not dependent on glycosylation. The effects observed on hippocampal neuronal cultures indicate an irreversible antibody-mediated internalization of surface IgLON5. These effects were mediated by specific IgLON5 IgG1 antibodies and suggest a pathogenic role of these antibodies in the disease.

Project description:We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.

Dataset Information

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

Publications

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

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