The Pathogenesis of the Demyelinating Form of Guillain-Barre Syndrome (GBS): Proteo-peptidomic and Immunological Profiling of Physiological Fluids

Rustam H Ziganshin,Olga M Ivanova,Yakov A Lomakin,Alexey A Belogurov,Sergey I Kovalchuk,Igor V Azarkin,Georgij P Arapidi,Nikolay A Anikanov,Victoria O Shender,Mikhail A Piradov,Natalia A Suponeva,Anna A Vorobyeva,Alexander G Gabibov,Vadim T Ivanov,Vadim M Govorun

doi:10.1074/mcp.m115.056036

Abstract

Acute inflammatory demyelinating polyneuropathy (AIDP) - the main form of Guillain-Barre syndrome-is a rare and severe disorder of the peripheral nervous system with an unknown etiology. One of the hallmarks of the AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level. In this paper CSF peptidome and proteome in AIDP were analyzed and compared with multiple sclerosis and control patients. A total protein concentration increase was shown to be because of even changes in all proteins rather than some specific response, supporting the hypothesis of protein leakage from blood through the blood-nerve barrier. The elevated CSF protein level in AIDP was complemented by activization of protein degradation and much higher peptidome diversity. Because of the studies of the acute motor axonal form, Guillain-Barre syndrome as a whole is thought to be associated with autoimmune response against neurospecific molecules. Thus, in AIDP, autoantibodies against cell adhesion proteins localized at Ranvier's nodes were suggested as possible targets in AIDP. Indeed, AIDP CSF peptidome analysis revealed cell adhesion proteins degradation, however no reliable dependence on the corresponding autoantibodies levels was found. Proteome analysis revealed overrepresentation of Gene Ontology groups related to responses to bacteria and virus infections, which were earlier suggested as possible AIDP triggers. Immunoglobulin blood serum analysis against most common neuronal viruses did not reveal any specific pathogen; however, AIDP patients were more immunopositive in average and often had polyinfections. Cytokine analysis of both AIDP CSF and blood did not show a systemic adaptive immune response or general inflammation, whereas innate immunity cytokines were up-regulated. To supplement the widely-accepted though still unproven autoimmunity-based AIDP mechanism we propose a hypothesis of the primary peripheral nervous system damaging initiated as an innate immunity-associated local inflammation following neurotropic viruses egress, whereas the autoantibody production might be an optional complementary secondary process.

Highlights

From the ‡Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya str., 16/10, Moscow 117997, Russian Federation; §Moscow Institute of Physics and Technology, Institutskiy pereulok 9, Dolgoprudny 141700, Russian Federation; ¶Research Center of Neurology, Volokolamskoye highway, 80, Moscow 125367, Russian Federation; ʈResearch Institute of Physical Chemical Medicine, Malaya Pirogovskaya str., 1a, Moscow 119435, Russian Federation
The dispersion of the observed protein concentrations in the cerebrospinal fluid (CSF) of the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) patients was rather high, probably because of the different symptom dynamics and severity of the disease, but our sample library was not large enough to establish a reliable dependence. This effect must be always taken into account when the total protein content or individual proteins are analyzed in the CSF of Guillain-Barre syndrome (GBS) patients
The individual CSF proteome analysis was made for two pairs of the AIDP patients, whose CSF samples were taken at different time intervals from the peak of neurological symptoms

Summary

Introduction

Immunoglobulin blood serum analysis against most common neuronal viruses did not reveal any specific pathogen; AIDP patients were more immunopositive in average and often had polyinfections. Cytokine analysis of both AIDP CSF and blood did not show a systemic adaptive immune response or general inflammation, whereas innate immunity cytokines were up-regulated. Comparable methodologies have described the induction and immunological features of EAN as the GBS model of peripheral neurodegeneration and experimental allergic encephalomyelitis (EAE) as the model for multiple sclerosis (MS), which lead to neurodegeneration in the central nervous system and thereby provide additional opportunities for speculating about the etiology of these diseases [9, 10]. The precise incidence of each GBS subtype has not been elucidated, it is believed that AIDP accounts for about 90% of all GBS cases in Western countries [12]

Objectives

Methods

Results

Conclusion