Molecular pathogenesis of neuromyelitis optica

Abstract

Neuromyelitis optica (NMO) is a rare autoimmune disorder, distinct from multiple sclerosis, causing inflammatory lesions in the optic nerves and spinal cord. An autoantibody (NMO IgG) against aquaporin-4 (AQP4), a water channel expressed on astrocytes is thought to be causative. Peripheral production of the antibody is triggered by an unknown process in genetically susceptible individuals. Anti-AQP4 antibody enters the central nervous system (CNS) when the blood brain barrier is made permeable and has high affinity for orthogonal array particles of AQP4. Like other autoimmune diseases, Th17 cells and their effector cytokines (such as interleukin 6) have been implicated in pathogenesis. AQP4 expressing peripheral organs are not affected by NMO IgG, but the antibody causes extensive astrocytic loss in specific regions of the CNS through complement mediated cytotoxicity. Demyelination occurs during the inflammatory process and is probably secondary to oligodendrocyte apoptosis subsequent to loss of trophic support from astrocytes. Ultimately, extensive axonal injury leads to severe disability. Despite rapid advances in the understanding of NMO pathogenesis, unanswered questions remain, particularly with regards to disease mechanisms in NMO IgG seronegative cases. Increasing knowledge of the molecular pathology is leading to improved treatment strategies.

Figure 1

NMO positive Immunofluorescence on a composite of mouse cerebellum, midbrain and kidney (serum dilution 1:40, goat anti-human IgG F(ab)2 fluorescein isothiocyanate, 200× magnification). (a) and (b) staining of subpial surface and microvessels of the midbrain. (c) Microvessel staining of cerebellar granular layer, molecular layer and white matter. (d) Staining of the papillary tubules of the kidney.

Figure 2

Schematic diagram of the immunopathogenesis of NMO. APC: antigen presenting cell; B prec: precursor B cell; Plasm: Plasma cell; Mem B: memory B cell; Mem Th17: memory Th17 cell; Neut: neutrophil; BBB: blood brain barrier; CDC: complement dependant cytotoxicity; CDCC: complement dependant cell mediated cytotoxicity; Astr: astrocyte; Olig: oligodendrocyte; Macro: macrophage; Eos: eosinophil.

Figure 3

Serial sections from a biopsy of an early brain white matter NMO lesion immunostained for (a) C3d and (b) GFAP. (a) Typical perivascular complement deposition around numerous small vessels; (b) Particulate GFAP-positive debris with a perivascular accentuation indicating massive astrocyte destruction in a region with relatively preserved myelin architecture. Note that no normal astrocytes are visible.