Antibody signatures in patients with histopathologically defined multiple sclerosis patterns

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.

Evaluation of diagnostic criteria and red flags of myelin oligodendrocyte glycoprotein encephalomyelitis in a clinical routine cohort

“…Postinfectious disease onset is likely to be underdiagnosed, especially if MOG-EM occurs within weeks after a common trivial infection. With the negative MOG-IgG result of the patient during EHEC sepsis, disease manifestation of MOG-EM with RION phenotype 7 weeks later and sequential confirmed positive MOG-IgG, our work may imply a possible underlying pathogenesis that involves triggering a general immune response29 or molecular mimicry processes 30. …”

Relationship between blood-brain permeability and antibodies against aquaporins in neuromyelitis optica spectrum disorders and multiple sclerosis patients

“…The inconsistent results of various studies indicate that there is a need for further exploration of the AQP1-Ab in patients with demyelinating diseases. Interestingly, higher AQP1-Ab levels were found in immunopathological pattern III of demyelination, which suggests a relation to astrocytic damage [40]. Thus, AQP1-Ab may be associated with disruption at the level of BBB rather than with primary immunological response.…”

Cerebrospinal Fluid IgM and Oligoclonal IgG Bands in Multiple Sclerosis: A Meta-Analysis of Prevalence and Prognosis

“…Pathological studies described four different patterns of demyelination [ 37 ]. These patterns are stable within individual patients [ 38 ], and only pattern II shows antibody-mediated demyelination [ 37 , 39 ]. Both IgG and IgM localized on oligodendrocytes and axons, and they co-localized with complement and foamy macrophages [ 40 ].…”