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:Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as a surrogate CSF biomarker to identify HAM/TSP patients with a worse prognosis.

Dataset Information

The pathogenesis of Guillain-Barre syndrome: peptidomic profiling of physiological fluids

Publications

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

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