NeCCIN

Chronic inflammatory neuropathies (CIN) are rare auto-immune disorders affecting peripheral myelinated axons that lead to significant disabilities. Distinct CIN groups have been distinguished according to disease course, sensory-motor presentation, symmetric/asymmetric distribution, and the presence of biological markers. Nonetheless, these groups are still heterogeneous entities with unwell defined borders, and a heterogeneous therapeutic response to conventional therapies. Identifying specific biomarkers of these pathologies is a major challenge and could improve diagnosis and therapeutic choice. During the past years, our group have shown that accurate examination of medical imaging and electrophysiology can help better individualize subgroups of patients and define specific therapeutic approaches. In addition, we recently identified autoantibody targets in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These autoantibodies have clinical benefits and help orientate patients’ treatment. One group of CIDP patients show IgG4 antibodies against contactin-1, Caspr-1, or neurofascin-155, and specific alterations of paranodes. Another subgroup present IgG4 targeting neurofascin-186, a cell adhesion molecule of the node of Ranvier. Interestingly, this latter group appears to form a distinct entity, Nodopathy, showing a severe presentation and conduction defects suggesting alterations at the nodes of Ranvier. These findings demonstrated that autoantibodies can help better delineate CIN subgroups together with specific clinical and biological markers. In keeping with this view, we observed that some patients with painful chronic neuropathies presented an immunoreactivity against small fibers and a good response to immunomodulatory treatments. Also, we identified a group of CIN patients with clear demyelinating features on EMG and nerve biopsies presenting a strong IgG or IgM reactivity against Schwann cell. Our concept is that CIN are triggered by diverse immune mechanisms that are targeting distinct nerve antigens. Here, we propose to characterize the physiopathogenic mechanisms in order to extract explicit clinical, biological, morphological and electrophysiological features that will serve to better delineate CIN entities. Our goals are as follows: 1. Identify new antigen targets by proteomic approaches: We have selected CIN patients (n > 50) presenting strong reactivities against specific nerve compartments. Our recent methodological progresses will enable us to isolate the target antigens directly from nerve samples. These novel antigens will be identified by mass spectrometry, and thoroughly characterized. 2. Characterization of blood markers for CIN: We have constituted a large bank of CIN sera with clinical data (n >650). We will determine the prevalence and specificity of all the newly identified autoantibodies to better define their clinical correlate. 3. Define novel clinical biomarkers in CIN: Electrophysiology and clinical imagery strongly help CIN diagnosis. We propose to perform refined electrophysiological examinations as well as quantitative muscle and nerve MRI to improve CIN stratification by combining these to serological and biological data. 4. Measure morphological alterations in biopsies: Skin and sural nerve biopsies are used to evaluate gross nerve alterations. Here, we will scrutinize fine structural alterations of nodes, paranodes, and myelin compartments to establish novel selective markers of pathology. 5. Correlate specific biomarkers with different subgroups of CIN patients: We will perform a combinatorial analysis of the gathered data to identify groups of markers that will be specific of CIN entities. This work will help revise the actual diagnostic criteria for CIN and better delineate novel entities such as nodopathy or chronic painful inflammatory neuropathies. This study will help elucidate the immune processes responsible for CIN and improve diagnosis and treatment.