The immunopathogenesis of narcolepsy type 1

Liblau, Roland; Latorre, Daniela; Kornum, Birgitte Rahbek; Dauvilliers, Yves; Mignot, Emmanuel

doi:10.1038/s41577-023-00902-9

Cited by 27 publications

(7 citation statements)

References 202 publications

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“…DQ molecules consist of αβ heterodimers that can be formed as both cis and trans variants depending on whether the α and β chains are encoded by the DQA1 and DQB1 genes on the same ( cis ) or opposite ( trans ) chromosomes, but not all combinations can form stable DQαβ heterodimers. Interestingly, the HLA-DQA1 and HLA-DQB1 alleles that can pair effectively fall into two mutually exclusive groups hereinafter designed as the DQ1 group (any DQA1*01 allele which can pair with any DQB1*05 or DQB1*06 allele) and the non-DQ1 group (any non-DQA1*01 allele which can pair with any DQB1*02, 03 or 04 allele) 20,21 .…”

Section: Resultsmentioning

confidence: 99%

Germline HLA-DQ genotype influences response to CAR T-cell therapy in patients with large B-cell lymphoma

Le Mene,

Allain,

Villemonteix

et al. 2024

Preprint

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CD19-directed chimeric antigen receptor (CAR) T cells have greatly improved the prognosis of relapsed/refractory large B-cell lymphoma (rrLBCL), yet treatment failure occurs in more than half of patients, usually in the first 3 months after treatment. While they primarily act through CAR-dependent, HLA-independent recognition of tumor targets, CAR-T cells may also indirectly contribute to long-term tumor immunosurveillance by stimulating endogenous immunity. We hypothesized that HLA diversity, measured by the HLA evolutionary divergence (HED) metric which reflects the breadth of the immunopeptidome presented to host T cells, could influence antitumor response after CAR T-cell therapy, as seen after immune chekpoint inhibitor treatment. We studied 127 rrLBCL patients treated with commercial CAR-T cells in our center, of whom 50 % achieved durable response. We observed no impact of diversity at any HLA locus, except for HED-DQA1 that was surprisingly negatively associated with response. Analysis of the distribution of HLA-DQ alleles according to clustering of HED values pointed to the DQ1/DQ1 genotype as an independent predictor of durable response and lower incidence of relapse/progression. These findings highlight the unsuspected role of germline HLA-DQ molecules in the response to CAR-T cells and suggest an important contribution of cross-talk between CAR-T cells and endogenous immune cells.

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Section: Resultsmentioning

confidence: 99%

Germline HLA-DQ genotype influences response to CAR T-cell therapy in patients with large B-cell lymphoma

Le Mene,

Allain,

Villemonteix

et al. 2024

Preprint

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“…NT1 remains a complex disorder, and its formal classification as an autoimmune disease is still under discussion [ 27 ]. However, emerging evidence has been accumulating to support the hypothesis of an autoimmune component in the pathogenesis of NT1.…”

Section: Discussionmentioning

confidence: 99%

Absence of specific autoantibodies in patients with narcolepsy type 1 as indicated by an unbiased random peptide-displayed phage screening

Tran,

Nguyen,

Dauvilliers

et al. 2024

PLoS ONE

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Narcolepsy type 1 (NT1) is an enigmatic sleep disorder characterized by the selective loss of neurons producing orexin (also named hypocretin) in the lateral hypothalamus. Although NT1 is believed to be an autoimmune disease, the orexinergic neuron-specific antigens targeted by the pathogenic immune response remain elusive. In this study, we evaluated the differential binding capacity of various peptides to serum immunoglobin G from patients with NT1 and other hypersomnolence complaints (OHCs). These peptides were selected using an unbiased phage display technology or based on their significant presence in the serum of NT1 patients as identified from previous studies. Although the subtractive biopanning strategy successfully enriched phage clones with high reactivity against NT1 serum IgG, the 101 randomly selected individual phage clones could not differentiate the sera from NT1 and OHC. Compared to the OHC control group, serum from several NT1 patients exhibited increased reactivity to the 12-mer peptides derived from TRBV7, BCL-6, NRXN1, RXRG, HCRT, and RTN4 proteins, although not statistically significant. Collectively, employing both unbiased and targeted methodologies, we were unable to detect the presence of specific autoantibodies in our NT1 patient cohort. This further supports the hypothesis that the autoimmune response in NT1 patients likely stems primarily from T cell-mediated immunity rather than humoral immunity.

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“…Notably, previous instances of various autoimmune antibodies, including anti-Ma antibodies ( 25 – 30 ), anti-Hu antibodies ( 31 ), AQP4 antibodies ( 32 , 33 ) and anti-NMDA receptor antibodies ( 34 ) have been associated with decreased hypocretin, indicating a common yet unidentified antigen that attacked by multiple autoimmune antibodies in hypocretin-producing neurons. HLA DQB1*06:02 , the main genetic factor responsible for susceptibility to NT1 ( 35 ), may also play a role in the development of an autoimmune response, ultimately resulting in the onset of secondary NT1 in the patient.…”

Section: Discussionmentioning

confidence: 99%

Case report: Excessive daytime sleepiness as a presenting manifestation of autoimmune glial fibrillary acidic protein astrocytopathy

Tang,

Huang,

Guo

et al. 2023

Front. Immunol.

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Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a recently discovered autoimmune inflammatory disease of the central nervous system. It presents with a variety of clinical symptoms, including fever, seizures, psychiatric symptoms, limber weakness, and sensory symptoms. However, the symptoms of sleep disorders have not been sufficiently addressed. Here, we report a case of GFAP-A in which the patient complained of excessive daytime sleepiness and an excessive need for sleep. Our patient was a 58-year-old male who experienced excessive daytime sleepiness for 50 days following SARS-CoV-2 infection. He was diagnosed with coronavirus disease 2019 on June 1st. On the 7th of June, he experienced excessive daytime sleepiness, nausea, reduced food intake, lower limb weakness, and dysuria. Subsequently, his sleepiness significantly deteriorated on July 21st. Five months prior, the patient underwent laparoscopic partial right nephrectomy for clear-cell renal cell carcinoma. Brain MRI revealed abnormal hyperintense lesions in the pontine brain and around the mesencephalic aqueduct on T2 and T2-fluid attenuated inversion recovery (T2-FLAIR) sequences However, these lesions did not exhibit any pathological enhancement. Spinal cord MRI revealed lesions in the C6–C7 and T2–T3 segments on the T2 sequence. His Epworth Sleepiness Scale (ESS) score was 16 (reference range, <10), and 24-hour polysomnography supported the diagnosis of rapid-eye-movement sleep disorder and severe sleep apnea-hypopnea syndrome. Glial fibrillary acidic protein IgG antibodies were detected in the cerebrospinal fluid (1:32, cell-based assay) but not in the serum. The level of hypocretin in the cerebrospinal fluid was 29.92 pg/mL (reference range ≥110 pg/mL), suggesting narcolepsy type 1. After treatment with corticosteroids for approximately 1 month, the patient showed considerable clinical and radiological improvement, as well as an increase in hypocretin levels. Although repeated polysomnography and multiple sleep latency tests suggested narcolepsy, his ESS score decreased to 8. Our findings broaden the range of clinical manifestations associated with GFAP-A, thereby enhancing diagnostic and therapeutic strategies for this disease. Additionally, our results indicate a potential common autoimmune mechanism involving GFAP-A and orexin system dysregulation, warranting further investigation.

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The immunopathogenesis of narcolepsy type 1

Cited by 27 publications

References 202 publications

Germline HLA-DQ genotype influences response to CAR T-cell therapy in patients with large B-cell lymphoma

Germline HLA-DQ genotype influences response to CAR T-cell therapy in patients with large B-cell lymphoma

Absence of specific autoantibodies in patients with narcolepsy type 1 as indicated by an unbiased random peptide-displayed phage screening

Case report: Excessive daytime sleepiness as a presenting manifestation of autoimmune glial fibrillary acidic protein astrocytopathy

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