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Novel Immunological and Therapeutic Insights in Guillain-Barre Syndrome and CIDP.

ABSTRACT: Inflammatory neuropathies are a heterogeneous group of rare diseases of the peripheral nervous system that include acute and chronic diseases, such as Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The etiology and pathophysiological mechanisms of inflammatory neuropathies are only partly known, but are considered autoimmune disorders in which an aberrant immune response, including cellular and humoral components, is directed towards components of the peripheral nerve causing demyelination and axonal damage. Therapy of these disorders includes broad-spectrum immunomodulatory and immunosuppressive treatments, such as intravenous immunoglobulin, corticosteroids, or plasma exchange. However, a significant proportion of patients do not respond to any of these therapies, and treatment selection is not optimized according to disease pathophysiology. Therefore, research on disease pathophysiology aiming to reveal clinically and functionally relevant disease mechanisms and the development of new treatment approaches are needed to optimize disease outcomes in CIDP and GBS. This topical review describes immunological progress that may help guide therapeutic strategies in the future in these two disorders.

SUBMITTER: Querol L

PROVIDER: S-EPMC8455117 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute inflammatory demyelinating polyneuropathy (AIDP) - one of the forms of Guillain-Barre syndrome (GBS) - is a rare and severe disorder of the peripheral nervous system that also has an unknown etiology. One of the hallmarks of AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level in comparison with the peptidome/proteome profile of a representative number of CSF samples obtained from AIDP and multiple sclerosis (MS) patients and control patients. In total, 2355 peptide fragments related to 795 proteins were found in CSF samples from AIDP patients, 1066 peptide fragments of 253 proteins in samples from MS patients, and 774 peptide fragments of 220 proteins from control patients. Proteomic studies detected 1103 proteins in the control cohort and 1402 proteins in the AIDP cohort. Our dataset suggests that the proteome of the CSF from AIDP and control patients overlaps by as much as 67%, whereas the peptidome is only 21.5% identical. Comparison of the peptidomic and proteomic data revealed that 80% of the peptides in the CSF of AIDP patients correspond to proteins that are not present in proteomic dataset. Importantly, a considerable number of differentially represented peptides are related to the proteins involved in the arrangement of the axonal domains. The observed peptidomic dataset indicates that specific proteins, which participate in the arrangement of the myelin sheath in the nodes of Ranvier, are degraded in the course of AIDP. Here, we show that the proteins that are overrepresented in the CSF of AIDP patients are partially linked with defensive responses to bacteria and viruses. These observations are in line with the upregulation of CSF cytokines associated with innate immunity, which in turn surprisingly suggests that the destruction of axons is not accompanied by any indications of a distinct adaptive autoimmune process. We believe that the presented proteomic and peptidomic dataset of the CSF from AIDP patients will provide useful information regarding the mechanisms of AIDP pathogenesis in comparison with MS, which is the prolonged but incurable autoimmune degradation of the central nervous system.

Project description:BackgroundGuillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome.MethodsAutoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed.ResultsNone of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors.ConclusionOur study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

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Novel Immunological and Therapeutic Insights in Guillain-Barre Syndrome and CIDP.

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