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Biomarkers in Polyradiculoneuropathies

Només els usuaris registrats poden traduir articles
Inicieu sessió / registreu-vos
L'enllaç es desa al porta-retalls
EstatReclutament
Patrocinadors
University Hospital, Montpellier
Col·laboradors
CHU de la Timone, Marseille, France
CHU Carémeau, Nîmes, France
CHU de Bordeaux, France
CH de Perpignan, France
CH de Narbonne, France
CH de Béziers France

Paraules clau

Resum

The nodes of Ranvier contain ion channels that enable the rapid propagation of the nerve impulse. Cell adhesion molecules and glycolipids play an important role in the formation of the nodes of Ranvier. Antibodies against glycolipids are detected in half of patients with Guillain-Barré syndrome, an acute inflammatory neuropathy affecting peripheral nerve. The investigators found that antibodies target cell adhesion molecules at nodes of Ranvier in 10% of patients with chronic inflammatory demyelinating neuropathy (CIDP), another disabling neuromuscular disease affecting peripheral nerves. In the majority of patients with GBS or CIDP, the mechanisms responsible for the neuromuscular disorders are unknown. Our goals are to identify novel targets of antibodies in patients, this in order to find novel bio-markers and to better understand the physiopathology of inflammatory neuropathies. This work will help patient diagnosis and treatment orientation.

Descripció

Background: Inflammatory demyelinating polyradiculoneuropathies are rare disabling autoimmune diseases affecting the peripheral nervous system. These neuropathies can be acute, when signs and symptoms raise in less than 1 month (Guillain-Barré syndrome, GBS), or chronic, when deteriorations continue over more than 2 months from onset (CIDP). About half of GBS patients present with IgG1 or IgG3 anti-gangliosides antibodies. Gangliosides are glycolipidic structures mainly localized at the node and paranode areas. In CIDP patients, IgG4 auto-antibodies directed against nodal (Nfasc-186) or paranodal (Nfasc-155, CNTN1, Caspr-1) proteins are found in 5 to 10 %. In most GBS and CIDP patients, the antigenic target are unknown and clinical biomarkers are critically lacking to help diagnosis and treatment orientation. The aim of the present study is to identify new biomarkers in AIDP and CIDP patients.

Methods : The investigators conduct a national retrospective and prospective study to identify new antigenic targets in GBS and CIDP patients. Since 2015, the Institute for Neurosciences of Montpellier and the University Hospitals of Montpellier collect clinical, immulogical, electrophysiological, and histological data of GBS and CIDP patients. Each patient whose serum has already been collected gave written informed consent. GBS and CIDP are diagnosed according to the current criteria. Anti-gangliosides antibodies (by immunodot-blot) and anti-Nfasc155, -CNTN1, -Nfasc186, and -Caspr-1 antibodies (by ELISA and cell-binding assay) are assessed in GBS and CIDP patients, respectively. Among CIDP patients with monoclonal gammapathy, those presenting with anti-MAG antibodies, increasing VEGF, AL amyloidosis, and neurolymphomatosis are excluded. Patients' serum are also tested by immunohistochemical staining on wild-type and GalNacT -/- mouse sciatic nerve fibres.

Clinical and electrophysiological phenotypes are compared between patients with positive and negative immunostaining. Localization of the staining (i.e. node of Ranvier, paranodal region, and/or myelin sheath) as the subclass and isotype of the autoantibody are specified.

The search for a new antigenic target is performed in GBS and CIDP patients which are i) seronegatives for antiganglioside and anti-Nfasc155, -CNTN1, -Nfasc186, and -Caspr-1 antibodies, and presenting with ii) a postive immunostaining on wild-type and GalNacT-/- mouse sciatic nerve fibres. Then, serums of these selected patients are incubated with neuronal and glial cells in culture (spinal dorsal ganglia, motoneurons, Schwann cells, oligodendrocytes and neocortical neurons). In the case of positivity against cell culture, an immunoprecipitation is performed and the antigen/antibody complex is separated on SDS-PAGE 4-12% gel and electrophoretic bands are analyzed by mass spectrometry.

The aim of this study is to identify new antigenic targets in seronegative GBS and CIDP patients displaying immunoreactivity. The knowledge of these new targets may improve our diagnostic tools and could help to develop targeted therapies.

Dates

Darrera verificació: 12/31/2019
Primer enviat: 01/08/2020
Inscripció estimada enviada: 01/28/2020
Publicat per primera vegada: 01/30/2020
Última actualització enviada: 01/28/2020
Publicació de l'última actualització: 01/30/2020
Data d'inici de l'estudi real: 12/31/2019
Data estimada de finalització primària: 12/31/2021
Data estimada de finalització de l’estudi: 01/29/2025

Condició o malaltia

Guillain-Barre Syndrome
CIDP

Fase

-

Grups de braços

BraçIntervenció / tractament
Group 1 with GBS patients
GBS patients
Group 2 with CIDP patients
with CIDP patients

Criteris d'elegibilitat

Edats elegibles per estudiar 18 Years Per a 18 Years
Sexes elegibles per estudiarAll
Mètode de mostreigNon-Probability Sample
Accepta voluntaris saludables
Criteris

Inclusion criteria:

- GBS or CIDP patients over 18 years old

- Signed informed consent

- With a positive immunostaining on wild-type and GalNacT-/- mouse sciatic nerve fibres.

- Subjects must be covered by public health insurance

Exclusion criteria:

- seropositive for anti-ganglioside, anti-MAG, and/or anti-Nfasc155, -CNTN1, -Nfasc186, and -Caspr-1 antibodies

Resultat

Mesures de resultats primaris

1. Correlation between clinical features and immunoreactivity findings in GBS and CIDP patients [24 months]

Correlation between the localization of the staining (i.e. node of Ranvier, paranodal region, and/or myelin sheath) and the axonal or demyelinating nature of the neuropathy (according to GBS and CIDP criteria).

Mesures de resultats secundaris

1. Screening and titration of antibodies against new antigenic targets in GBS and CIDP patients. [5 years]

The serums of patients will be considered seropositives when optical density value is ≥ 0.1 in ELISA

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