A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica

Abstract

Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3(+) and CD8(+) T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.

Fig. 1

Histopathology of NMO. (A) Spinal cord cross-section demonstrating extensive demyelination involving both the grey and white matter (Luxol fast blue and PAS myelin stain, mag × 10). (B) The lesion is filled with numerous macrophages (KiM1P pan-macrophage stain). (C) There is a sharp demarcation between the periplaque white matter and the plaque edge (Luxol fast blue and PAS myelin, mag × 100). (D) Macrophages within the actively demyelinated lesion contain myelin debris within the cytoplasm (arrow; immunocytochemistry for MOG, mag × 600).

Fig. 2

Histopathology of neuromyelitis optica. (A, B, mag × 200) The perivascular infiltrate contains numerous CD3⁺ T lymphocytes (A) and CD8⁺ T lymphocytes (B). (C). There is a marked reduction in axonal density and acute axonal pathology consisting of swellings and spheroids (Bielschowsky silver impregnation, mag × 400). (D) There is a marked reduction in oligodendrocytes within the lesion [PLP mRNA in situ hybridization (black); double-labelled with immunocytochemistry for PLP protein (red, mag × 200)].

Fig. 3

Inflammatory infiltrate in NMO. Numerous perivascular eosinophils (A) and granulocytes (B) are located within the lesion (haematoxylin–eosin, mag × 600). Intact perivascular and parenchymal eosinophils are present within the lesion (haematoxylin-eosin, mag × 100) (C). Eosinophil MBP immunofluorescence of corresponding serial section (mag × 200) (D). Eosinophils are also present within the meninges with evidence of degranulation demonstrated by the irregular punctate granular staining [haematoxylin–eosin stain (E) with eosinophil MBP immunofluorescence of corresponding serial section (F), mag × 100].

Fig. 4

Evidence for humoral immunity in NMO. (A) Actively demyelinating NMO lesion shows massive deposition of complement C9neo-antigen (red staining) in a rim pattern on the outer surface of thickened blood vessels, as well as in a rosette perivascular pattern (mag × 200). (B) There is pronounced perivascular immunoglobulin reactivity (human Ig). (C) Immunocytochemistry for IgM demonstrates a rosette perivascular staining pattern. Higher power view of staining for complement activation with C9neo-antigen (red) demonstrates this rim (D) and rosette (E) pattern of staining. Macrophages co-localize in a similar rim (F) and rosette (G) pattern (KiM1P pan-macrophage stain) (mag × 400).

Fig. 5

Vessel pathology in NMO. (A) There is an apparent increase in numbers and prominence of thickened hyahnized blood vessels within the lesion (Movat, mag × 100). (B) Higher power view emphasizes collagen infiltration of vessel wall (green with Movat, mag × 400).