Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

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• 作者：Julien Ratelade ; Alex J. Smith ; A.S. Verkman ; ^{Alan.Verkman@ucsf.edu" class="auth_mail} ;
• 关键词：ADCC ; antibody-dependent cellular cytotoxicity ; AQP4 ; aquaporin-4 ; BSA ; bovine serum albumin ; CDC ; complement-dependent cytotoxicity ; CNS ; central nervous system ; dSTORM ; direct stochastic reconstruction microscopy ; EDSS ; expanded disability status scale ; Fc纬R ; Fc纬 receptor ; GFAP ; glial fibrillary acidic protein ; hIgG ; human immunoglobulin G ; ITP ; idiopathic thrombocytopenic purpura ; MAC ; membrane attack complex ; MBP ; myelin basic protein ; NK-cell ; natural killer cell ; NMO ; neuromyelitis optic
• 刊名：Experimental Neurology
• 出版年：May, 2014
• 年：2014
• 卷：255
• 期：Complete
• 页码：145-153
• 全文大小：2032 K

文摘

Neuromyelitis optica (NMO) pathogenesis involves binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) present in serum to AQP4 on astrocytes, which causes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Human immunoglobulin G (hIgG) is effective for treatment of humorally mediated neurological autoimmune diseases and has been reported to improve disease outcome in a limited number of NMO patients. Here, we investigated hIgG actions on NMO-IgG pathogenicity using an in vivo rat model of NMO and in vitro assays. In rats administered NMO-IgG by intracerebral injection, the size of neuroinflammatory demyelinating lesions was reduced by ~ 50% when hIgG was administered by intraperitoneal injection to reach levels of 10-25 mg/mL in rat serum, comparable with human therapeutic levels. In vitro, hIgG at 10 mg/mL reduced by 90% NMO-IgG-mediated CDC following addition of NMO-IgG and human complement to AQP4-expressing cells. The hIgG effect was mainly on the classical complement pathway. hIgG at 10 mg/mL also reduced by up to 90% NMO-IgG-mediated ADCC as assayed with human natural killer cells as effector cells. However, hIgG at up to 40 mg/mL did not affect AQP4 cell surface expression or its supramolecular assembly in orthogonal arrays of particles, nor did it affect NMO-IgG binding to AQP4. We conclude that hIgG reduces NMO-IgG pathogenicity by inhibition of CDC and ADCC, providing a mechanistic basis to support further clinical evaluation of its therapeutic efficacy in NMO.