Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica
Hua Zhang, A.S. Verkman
Hua Zhang, A.S. Verkman
Published April 8, 2013
Citation Information: J Clin Invest. 2013;123(5):2306-2316. https://doi.org/10.1172/JCI67554.
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Research Article Ophthalmology

Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica

Abstract

Eosinophils are abundant in inflammatory demyelinating lesions in neuromyelitis optica (NMO). We used cell culture, ex vivo spinal cord slices, and in vivo mouse models of NMO to investigate the role of eosinophils in NMO pathogenesis and the therapeutic potential of eosinophil inhibitors. Eosinophils cultured from mouse bone marrow produced antibody-dependent cell-mediated cytotoxicity (ADCC) in cell cultures expressing aquaporin-4 in the presence of NMO autoantibody (NMO-IgG). In the presence of complement, eosinophils greatly increased cell killing by a complement-dependent cell-mediated cytotoxicity (CDCC) mechanism. NMO pathology was produced in NMO-IgG–treated spinal cord slice cultures by inclusion of eosinophils or their granule toxins. The second-generation antihistamines cetirizine and ketotifen, which have eosinophil-stabilizing actions, greatly reduced NMO-IgG/eosinophil–dependent cytotoxicity and NMO pathology. In live mice, demyelinating NMO lesions produced by continuous intracerebral injection of NMO-IgG and complement showed marked eosinophil infiltration. Lesion severity was increased in transgenic hypereosinophilic mice. Lesion severity was reduced in mice made hypoeosinophilic by anti–IL-5 antibody or by gene deletion, and in normal mice receiving cetirizine orally. Our results implicate the involvement of eosinophils in NMO pathogenesis by ADCC and CDCC mechanisms and suggest the therapeutic utility of approved eosinophil-stabilizing drugs.

Authors

Hua Zhang, A.S. Verkman

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Figure 5

Eosinophil-dependent NMO pathology in mice.

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Eosinophil-dependent NMO pathology in mice. (A) Mice were intraperitonea...
(A) Mice were intraperitoneally administered anti–IL-5 or anti-Ly6G antibodies, alone or together, to deplete eosinophils and/or neutrophils, followed by a 3-day NMO-IgG/hc infusion (top). Peripheral neutrophil (Nϕ) and eosinophil counts in control and treated mice (bottom) (SEM; 5 mice per group; P < 0.001). (B) Mice were infused for 3 days with 3.3 μg/day NMO-IgG and 16.7 μl/day hc, and sacrificed on day 3. Immunofluorescence staining of AQP4 and MBP (scale bar: 2 mm); Siglec F and Ly6G (scale bar: 100 μm). (C) Lesion severity assessed by loss of AQP4, myelin, and numbers of eosinophils and neutrophils in lesions (SEM; 4–8 mice per group; *P < 0.05; **P < 0.01). (D) Control and hypereosinophilic IL-5 Tg mice were infused for 3 days with NMO-IgG (3.3 μg/day) and submaximal hc (3.4 μl/day). Immunofluorescence staining of AQP4 (scale bar: 2 mm), Siglec F, and Ly6G (scale bar: 100 μm). Summary of lesion scores (SEM; 4 mice per group; *P < 0.05). (E) Control and Tg hypoeosinophilic ΔdblGata1 mice were infused for 3 days with NMO-IgG (3.3 μg/day) and hc (16.7 μl/day). AQP4 immunofluorescence and loss of AQP4 immunofluorescence are shown (SEM; 5 mice per group; *P < 0.05). Scale bar: 2 mm.