Abstract
Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I–III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló’s concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I n = 12; II n = 29; III n = 25, including 8 with Baló’s), healthy controls, patients with Sjögren’s syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (p = 0.02) and III (p = 0.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I p = 0.002, pattern II p = 0.001) and varicella zoster virus (VZV, compared to pattern II p = 0.05). In patients with Baló’s, AQP1 reactivity was also significantly higher compared to patients without Baló’s (p = 0.04), and the former revealed distinct antibody signatures. Histologically, Baló’s patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Baló’s patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating CNS disease with heterogeneous clinical, radiological and pathological features that suggest different mechanisms of disease development
We focused on early disease stages with a median disease duration of less than 1 year
One patient was treated with cyclosporine due to liver transplantation and another patient received ipilimumab, an antibody targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), to treat melanoma
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating CNS disease with heterogeneous clinical, radiological and pathological features that suggest different mechanisms of disease development. Multiple drugs are available for MS treatment [56, 57], but we still lack biomarkers for stratification of particular subgroups of MS patients and specific pathogenic pathways. Lucchinetti et al describe three main subgroups of MS patients that show different histopathological patterns of early active inflammatory demyelinating lesions (patterns I–III, Fig. 1) and suggest diverse pathophysiological mechanisms of lesion development [42]. These patterns are stable within the individual patient [35, 52] and imply a specific and sustained pathogenic pathway for newly developing lesions during the entire disease course of that patient
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