Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody-dependent cellular cytotoxicity

Abstract

Cellular injury in AQP4-IgG seropositive neuromyelitis spectrum disorder (herein called NMO) involves AQP4-IgG binding to astrocytes, resulting in astrocyte injury by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mechanisms. The rapid disease progression, severe tissue damage, and abundant leukocyte infiltration seen in some NMO patients suggest a more direct mechanism for demyelination and neurologic deficit than secondary injury from astrocyte loss. Here, we report evidence for an ‘ADCC bystander mechanism’ in NMO involving injury to nearby cells by leukocytes following their activation by AQP4-bound AQP4-IgG on astrocytes. In model cocultures containing AQP4-expressing and null CHO cells, AQP4-IgG and complement killed bystander null cells to ~ 100 μm away from AQP4-expressing cells; AQP4-IgG and NK cells produced bystander killing to ~ 300 μm, with perforin deposition seen on injured null cells. Bystander cytotoxicity was also seen with neutrophil-mediated ADCC and in astrocyte-neuron cocultures. Mechanistic studies, including real-time imaging, suggested that leukocytes activated by an AQP4-dependent ADCC mechanism injure bystander cells by direct targeted exocytosis on neighboring cells and not by diffusion of soluble granule contents. In support of this conclusion, ADCC bystander injury was preferentially reduced by an RGDS peptide that inhibits integrin adhesion. Evidence for ADCC bystander injury to oligodendrocytes and neurons was also found in mice following intracerebral injection of AQP4-IgG and NK cells, which was inhibited by RGDS peptide. These results establish a novel cellular pathogenesis mechanism in AQP4-IgG seropositive NMO and provide evidence that inflammatory mechanisms can cause widespread tissue damage in NMO independently of the secondary effects from astrocyte loss. Electronic supplementary material The online version of this article (10.1186/s40478-019-0766-7) contains supplementary material, which is available to authorized users.

Triglyceride Level Is an Independent Risk Factor in First-Attacked Neuromyelitis Optica Spectrum Disorders Patients

“…In line with this research, our univariate analysis also found that age of onset was positively associated with outcomes in first-attacked NMOSD patients. AQP4-IgG was a specific biomarker for the diagnosis of NMO, which can cause demyelination and neurologic deficit by binding to astrocytes and leading to astrocyte injury (41). Positive AQP4 status was closely related to rapid progress, severe tissue damage, and abundant infiltration of leukocyte in some NMO patients (42).…”

Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology

“…3 AQP4-IgG binding to astrocytic AQP4 leads to classical complement cascade activation and granulocyte and lymphocyte infiltration that combine to damage neural tissues. 4,5 IL-6 may drive disease activity in NMOSD by promoting plasmablast survival, stimulating AQP4-IgG secretion, reducing blood-brain barrier (BBB) integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation (figure A). CSF and serum IL-6 levels are significantly elevated in patients with NMOSD, and IL-6 inhibition has been shown to improve disease control (table 1).…”

“… 3 AQP4-IgG binding to astrocytic AQP4 leads to classical complement cascade activation and granulocyte and lymphocyte infiltration that combine to damage neural tissues. 4 , 5 …”

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

“…These findings, taken together with the observation of a penumbra lesion in rats as mentioned above , support a role for ADCC in NMO pathogenesis and suggested ADCC as a potential therapeutic target. In a follow‐on study, in vivo evidence was reported for an “ADCC bystander” mechanism of killing involving leukocyte activation by astrocyte‐bound AQP4‐IgG and killing of nearby cells (Figure B) .…”