Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions

Abstract

Neuromyelitis optica (NMO) is a chronic, mostly relapsing inflammatory demyelinating disease of the CNS characterized by serum anti-aquaporin 4 (AQP4) antibodies in the majority of patients. Anti-AQP4 antibodies derived from NMO patients target and deplete astrocytes in experimental models when co-injected with complement. However, the time course and mechanisms of oligodendrocyte loss and demyelination and the fate of oligodendrocyte precursor cells (OPC) have not been examined in detail. Also, no studies regarding astrocyte repopulation of experimental NMO lesions have been reported. We utilized two rat models using either systemic transfer or focal intracerebral injection of recombinant human anti-AQP4 antibodies to generate NMO-like lesions. Time-course experiments were performed to examine oligodendroglial and astroglial damage and repair. In addition, oligodendrocyte pathology was studied in early human NMO lesions. Apart from early complement-mediated astrocyte destruction, we observed a prominent, very early loss of oligodendrocytes and oligodendrocyte precursor cells (OPCs) as well as a delayed loss of myelin. Astrocyte repopulation of focal NMO lesions was already substantial after 1 week. Olig2-positive OPCs reappeared before NogoA-positive, mature oligodendrocytes. Thus, using two experimental models that closely mimic the human disease, our study demonstrates that oligodendrocyte and OPC loss is an extremely early feature in the formation of human and experimental NMO lesions and leads to subsequent, delayed demyelination, highlighting an important difference in the pathogenesis of MS and NMO.

The Treatment of Neuromyelitis Optica

“…In agreement with human lesions, experimental models demonstrate immediate and widespread astrocyte loss following co-injection of AQP4 autoantibody and human complement (36,49). Oligodendrocyte cell body death occurs a few hours later, possibly in part by apoptosis (28,50), and is subsequently followed by demyelination and inflammatory cell infiltration (49). Several sequelae of CDC- and ADCC-mediated astrocyte insult likely contribute this temporal progression.…”

“…As noted previously, acute NMO lesions in affected individuals and animal models show unique unipolar astrocytes that repopulate regions of astrocyte destruction (28,49). In some CNS locations, NMO lesions may demonstrate a relative preservation of myelin with no neuronal or axonal pathology (29,56), suggesting that noninflammatory mechanisms such as AQP4 internalization and altered water transport may contribute to lesion propagation.…”

“…CDC activation is critical for the development of lesions in NMO animal models (43,49). As CDC activation is dependent on OAP formation (46), disrupting OAP formation may limit CDC activation and represents a novel approach to decrease further immune activation in the presence of NMO IgG.…”

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies

“…39 The role of T cells—which, in addition to their involvement in initial AQP4-IgG generation, might be involved along with other factors in permeabilization of the blood–brain barrier—is also not well understood, 40 but current data suggest that these cells are probably not involved in the progressive stage of NMO lesion pathology. 41,42 Various propositions for alternative NMO pathogenesis mechanisms, such as excitotoxic injury, 43 AQP4-IgG-mediated inhibition of AQP4 water permeability and AQP4-induced AQP4 aggregation, 44 are controversial in light of the more-recent data.…”

Multiple Autoantibodies and Neuromyelitis Optica Spectrum Disorders

“…Recent studies have shown that the anti-aquaporin 4 antibody (AQP4-Ab), present in >80% of patients with NMOSD [3,4], causes astrocyte damage, inflammatory cell infiltration and myelin loss [5]. Humoral immune mechanisms are suggested to be involved in the pathogenesis of NMOSD [6,7].…”