Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

Luo, Guopei; Ambati, Aditya; Li, Gang; Bonvalet, Mélodie; Partinen, Markku; Ji, Xuhuai; Maecker, Holden T.; Mignot, Emmanuel

doi:10.1073/pnas.1818150116

Cited by 165 publications

(168 citation statements)

References 59 publications

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“…A final question which we attempted to address is to explain the abundance of cross-reactive CTL against displayed pGR, pVIPR, or pLMP2 in B * 27:05 + individuals and the scarcity of such CTL in B * 27:09 + individuals (16). Molecular mimicry has been proven to exist in the HLA-B27 as well as other contexts (60,61) and may contribute also to the emergence of cross-reactive CTL in certain subtypes. It remains still unknown whether these cells do really play a decisive role in the development of HLA-B * 27-associated diseases (62).…”

Section: Discussionmentioning

confidence: 99%

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

et al. 2020

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The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.

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Section: Discussionmentioning

confidence: 99%

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

et al. 2020

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“…The present study could not confirm humoural autoimmunity to any of the candidate antigens of the hypocretin transmitter system. Two recent studies found autoreactive Tcells against hypocretin peptides to be linked to NT1 [9,10]. Further studies are warranted to clarify if the immune response in NT1 is HLA DR rather than DQ-restricted [10] as well as if NT1-autoimmunity is restricted towards c-amidated but not against naive HCRT peptides [9].…”

Section: Discussionmentioning

confidence: 99%

“…The preprohypocretin and the hypocretin neuropeptides have been hypothesised as target autoantigens because of the autoimmune reaction directed towards hypocretin neurons. T-cell reactivity [9,10] but no autoantibodies have been demonstrated to hypocretin [11][12][13]. NT1-specific autoantibodies towards the Hypocretin receptor 2 (HCRT2R) have been investigated with conflicting results [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies in Pandemrix^®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test

et al. 2019

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Study objectives: Narcolepsy type 1 (NT1) is a chronic sleep disorder characterized by loss of hypocretin-producing neurons. Increased NT1 incidence was observed in Sweden following mass-vaccination with Pandemrix V R . Genetic association to HLA DQB1 Ã 06:02 implies an autoimmune origin, but target autoantigen remains unknown. Candidate autoantigens for NT1 have previously been identified in solid-phase immunoassays, while autoantibodies against conformation-dependent epitopes are better detected in radiobinding assays. The aims are to determine autoantibody levels against nine candidate autoantigens representing (1) proteins of the hypocretin transmitter system; Preprohypocretin (ppHypocretin), Hypocretin peptides 1 and 2 (HCRT1 and HCRT2) and Hypocretin receptor 2 (HCRTR2);(2) proteins previously associated with NT1; Tribbles homologue 2 (TRIB2), Pro-opiomelanocortin/ alpha-melanocyte-stimulating-hormone (POMC/a-MSH) and Prostaglandin D2 Receptor DP1 (DP1); (3) proteins suggested as autoantigens for multiple sclerosis (another HLA DQB1 Ã 06:02-associated neurological disease); ATP-dependent Inwardly Rectifying Potassium Channel Kir4.1 (KIR4.1) and Calcium-activated chloride channel Anoctamin 2 (ANO2). Methods: Serum from post-Pandemrix V R NT1 patients (n ¼ 31) and their healthy first-degree relatives (n ¼ 66) were tested for autoantibody levels in radiobinding assays separating autoantibody bound from free labelled antigen with Protein A-Sepharose. 125 I-labelled HCRT1 and HCRT2 were commercially available while 35 S-methionine-labelled ppHypocretin, HCRTR2, TRIB2, a-MSH/POMC, DP1, KIR4.1 or ANO2 was prepared by in vitro transcription translation of respective cDNA. In-house standards were used to express data in arbitrary Units/ml (U/ml). Results: All radiolabelled autoantigens were detected in a concentration-dependent manner by respective standard sera. Levels of autoantibodies in the NT1 patients did not differ from healthy firstdegree relatives in any of the nine candidate autoantigens. Conclusions: None of the nine labelled proteins proposed to be autoantigens were detected in the radiobinding assays for conformation-dependent autoantibodies. The results emphasise the need of further studies to identify autoantigen(s) and clarify the mechanisms in Pandemrix V R -induced NT1. ARTICLE HISTORY

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“…As for pMHC class II molecules on the other hand, it has been more challenging to develop efficient peptide exchange assays. However, Day et al were able to achieve peptide exchange for MHC class II molecules by thrombin‐cleavage of the peptide‐linker, a technique which also seems to work for some HLA‐DQ molecules but not all. Of note, techniques that improve the production efficacy of MHC class I and class II molecules, such as through in vivo biotinylation, have also been featured …”

Section: High‐throughput Production Of Pmhc Tetramersmentioning

confidence: 99%

Peptide‐MHC class I and class II tetramers: From flow to mass cytometry

Christophersen

2020

HLA

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Funding information Stiftelsen KG JebsenTo develop better vaccines and more targeted treatments for cancer and autoimmune disorders, the disease-specific T cells and their cognate antigens need to be better characterized. For more than two decades, peptide-major histocompatibility complex (pMHC) tetramers and flow cytometry have been the gold standard for detection of CD8+ and CD4+ T cells specific to antigens in the context of MHC class I and class II, respectively. Nonetheless, more recent studies combining such reagents with mass cytometry, that is, cytometry by time of flight (CyTOF), have offered far more comprehensive profiling of antigen-specific T-cell responses. In addition, mass cytometry has enabled ex vivo screening of CD8+ T-cell reactivities against hundreds of MHC class I restricted candidate epitopes. MHC class II molecules, on the other hand, have been challenging to combine with mass cytometry as they are more complex and bind with lower affinities to cognate T-cell receptors than MHC class I molecules. In this review, I discuss how techniques originally developed to improve the staining capacity of pMHC tetramers in flow cytometry led to the successful combination of such reagents with mass cytometry. Especially, I will highlight very recent advances facilitating the combination with pMHC class II tetramers. Together, these mass cytometry-based studies can help develop more targeted treatments for cancer and autoimmune disorders.

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Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

Cited by 165 publications

References 59 publications

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

Autoantibodies in Pandemrix^®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test

Peptide‐MHC class I and class II tetramers: From flow to mass cytometry

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Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

Cited by 165 publications

References 59 publications

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

Autoantibodies in Pandemrix®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test

Peptide‐MHC class I and class II tetramers: From flow to mass cytometry

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Autoantibodies in Pandemrix^®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test