JCI – Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.
Research Article
Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica
Departments of Medicine and Physiology, UCSF, San Francisco, California, USA.
Address correspondence to: Alan S. Verkman, 1246 Health Sciences East Tower, University of California, San Francisco, California 94143-0521, USA. Phone: 415.476.8530; Fax: 415.665.3847; E-mail: Alan.Verkman@ucsf.edu.
Published April 8, 2013
Received for publication October 26, 2012, and accepted in revised form February 12, 2013.
Introduction
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that primarily affects the spinal cord and optic nerves, leading to paralysis and visual impairment (1, 2). Serum autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called NMO immunoglobulin G (NMO-IgG), are present in most NMO patients and are believed to be pathogenic (3–5). Human NMO lesions show marked cellular infiltration with eosinophils, neutrophils, and macrophages, loss of astrocyte AQP4 and glial fibrillary acidic protein, perivascular deposition of activated complement, and demyelination (6–9). Current NMO therapies include immunosuppression, plasma exchange and B cell depletion (10, 11).
Eosinophil infiltration is a prominent feature in NMO lesions but not in other demyelinating diseases including multiple sclerosis (2, 7). Eosinophils are also found in cerebrospinal fluid in NMO (9). They can damage cells by the release of toxins contained in intracellular granules, including eosinophilic granule major basic protein (MBPe), eosinophil cationic protein (ECP), eosinophil peroxidase, and eosinophil-derived neurotoxin (12). Eosinophil degranulation can be triggered by immunoglobulin binding to Fc receptors and by soluble effectors such as complement anaphylotoxins C3a and C5a, chemokines, and lipid mediators (13). Differentiation and maturation of eosinophils in bone marrow is under the control of transcription factor GATA-1, as well as IL-3, IL-5, and GM-CSF (12). Eosinophils are normally present in the gastrointestinal tract, as well as in the thymus, mammary gland, and uterus. Eosinophilia and exaggerated eosinophil responses occur in some infections, asthma, hypereosinophilic syndrome, eosinophilic gastrointestinal diseases, and certain tumors (14). Eosinophil-based therapies target eosinophil production or eosinophil-derived products, which broadly include glucocorticoids, myelosuppressive drugs, leukotriene antagonists and inhibitors, some second-generation antihistamines, cromoglycate, tyrosine kinase inhibitors, IFN-α, and anti–IL-5 antibodies (13, 14).
Here, we utilize mouse models of NMO, including ex vivo spinal cord slice cultures (15) and a new in vivo intracerebral infusion model, as well as cell cultures, to investigate the mechanisms of eosinophil-dependent NMO pathology. We report evidence of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cell-mediated cytotoxicity (CDCC), in which eosinophil toxins secreted upon degranulation injure target cells. We also show protection against eosinophil-dependent NMO pathology by small-molecule inhibitors of eosinophil degranulation, including 2 widely used second-generation antihistamines.
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