Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling

Abstract

BackgroundNeuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive.MethodsHere we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3.FindingsOur data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1.InterpretationWe propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.

Role of the L-PGDS-PGD2-DP1 receptor axis in sleep regulation and neurologic outcomes

“…Recently, the role of DP1R in narcolepsy type 1 patients was investigated. By performing a comprehensive antigenic repertoire analysis of sera from patients, it was found that patients with narcolepsy type 1 exhibit a specific immune response to epitopes of DP1R [152]. These results further support the importance of the L-PGDS-PGD 2 -DP1R pathway in regulating sleep-wake homeostasis [53,153].…”

Personalization of Medical Device Interfaces: Decreasing Implant-Related Complications by Modular Coatings and Immunoprofiling

“…However, in order to delve into the background of an individual’s adaptive immune response to a given material, antibody-level information is necessary. For this end, use of mimotope variance analysis [ 10 ] provides a unique opportunity to not only determine the generic responses to new biomaterials, but also patient-specific response to biomaterials, which can guide the development of immune-compatible, patient-specific implant surfaces. Such immunoprofiling based pre-implantation and postimplantation diagnostics can improve the functional outcomes of different implants by aiding in the implant type selection and can also significantly decrease the implant-related complications.…”

Screening for autoantibody targets in post‐vaccination narcolepsy using proteome arrays

“…28 Follow-up studies have not been able to associate HCRTR2 autoantibodies to NT1. 29,30 Other suggested autoantigens in NT1 include prostaglandin D2 receptor 31 and the glutamic acid-isoleucine/α-melanocyte-stimulating hormone, which is a peptide hormone that is cleaved from proopiomelanocortin. 32 Antigen-arrays have previously been used to screen for NT1 autoantigens.…”