MS one disease or should we suggest one syndrome or are we going to split it into smaller diseases based on different targets.

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns. Stork L, Ellenberger D, Ruprecht K, Reindl M, Beißbarth T, Friede T, Kümpfel T, Gerdes LA, Gloth M, Liman T, Paul F, Brück W, Metz I. Acta Neuropathol. 2020 Jan 16. doi: 10.1007/s00401-019-02120-x. [Epub ahead of print]

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 (This depends in part on which study you read). Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition (yet some people with pattern I respond to plasma exchange,which is done to remove antibody…go figure). In pattern III lesions, which include Baló’s concentric sclerosis, primary oligodendrocyte damage was proposed (A pre-active lesion could be another definition). Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. (Not sure of the logic here) We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases (However, it needs to be said, it is well known that antibodies typically recognise conformational shapes of proteins and not linear sequences as found in peptide fragments of proteins), 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 (Well it would have been a real surprise if it did we must have had over firfty studies saying that it never happens). 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) (aquaporin1 is a water channel like aquaporin4, which is target in neuromyelitis optica. These are bith expressed by astrocytes however aquaporin 1 is expressed all over the nervous system and also at high levels in the kidnies and there you would ask why would this be of importance in MS and suggests that the antibody may be made secondary to damage. The authors argue that the damage to astrocytes may trigger oligodendrocytes. 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.

So different antigens may be a targeted in different people with different lesions, but before we split it up, I think that this needs to be repeated by others.We have been here before and indeed with a quick check antibodies to Aquaporin 1 occur infrequenctly in MS and are more common in NMO.

AQP1 is found in NMO

Now it is argued that this is not reproducible, but until this work is reproduced the jury needs to be out. However the antibody signatures do not allow allocation of single patients to patterns I–III or Baló’s concentric sclerosis, their findings explain some of the heterogeneity of MS lesion