Research:Prineas lesion was it NMO?


Point-of-view: Prineas & Parratt. Oligodendrocytes and the early multiple sclerosis lesion J Neurol: 24 APR 2012.

There is little agreement amongst neuropathologists regarding the timing and nature of oligodendrocyte loss in MS. The oligodendrocyte is the cell that makes myelin or the insulation around nerve fibres. This review describes changes that accompany acute oligodendrocyte loss in new MS lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic (before myelin debris is ingested by microglia) lesions exhibit cytopathic changes that include apoptosis (type of cell death) of oligodendrocytes immunoreactive for caspase 3 (an enzyme that triggers cell death), phagocytosis of apoptotic oligodendrocytes (ingestion of dead cells by microglia), swelling of cells with abnormal nuclei, complement deposition (proteins that damage cells), and lysis (popping of the cell membrane). These are non – specific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged IgG + microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood brain barrier, and the presence of rare CD8 T cells (these are a type of white blood cell  that mainly target viruses). Myelin contacted by IgG+ macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and grey matter plaques is scavenging activity directed at non- vital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica, including the fact that demyelination in both is secondary to a loss of caspase 3 – positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component. 

With this in mind it is interesting that this pathology paper has been produced.

Brück et al. Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate. J Neurology: 14 APR 2012. 

Objective: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are considered inflammatory demyelinating diseases with distinguishing pathological characteristics. NMO pathology shows perivascular immunoglobulin G (IgG) and complement deposition, as well as an astrocytopathy (disease of astrocytes) with aquaporin-4 (AQP4) loss (aquaporins are channels that control water flow into cells). MS lesions reveal a profound, interindividual heterogeneity (different pathology between individuals) in immunopathological patterns of active demyelination,which has been challenged by the description of stage-dependent sequences of pathological features. The aim of our study was to compare the histological characteristics of early active demyelinating NMO and MS brain lesions.

Methods: 13 cases with supraspinal active demyelinating NMO lesions were analyzed using immunohistochemistry (technique for staining tissue). Results were compared with the published characteristics of MS lesions.

Results: A subset of supraspinal lesions (above the spinal cord, in other words from the brain) from AQP4 seropositive NMOers revealed both 1) complement deposition within macrophages at sites of active demyelination and 2) oligodendrocyte apoptosis and a preferential loss of myelin associated glycoprotein (MAG). These characteristics resemble features previously associated with both MS lesion patterns II and III (a classification system that was put forward by these authors 8 years ago), respectively and were present in addition to characteristic histopathological NMO features, namely AQP4 and astrocyte loss.

Interpretation: Early active demyelinating NMO lesions may show both complement deposition within macrophages and oligodendrocyte apoptosis associated with a selective loss of minor myelin proteins, in addition to typical NMO features. We hypothesize these features may occur simultaneously only in a subset of active demyelinating NMO lesions and the description by Barnett and Prineas should be re-evaluated. These observations could further support the concept of inter-individual heterogeneity in MS.

There are questions of whether NMO is MS, many say it is not but there are clearly overlaps. Was the idea that oligodendrocytes as the initial target for disease by Barnett and Prineas due to the study of NMO rather than MS?, but the central question is what drives the death of the oligos. Could it be a virus? Prof. G thinks so and John Prineas has hinted as this possibility in many of his talks. Only time will tell.

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