Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: An in vitro study

Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases

“…This deposition of NMO antibodies and complement on astrocytes at the glia limitans was accompanied by a loss of the AQP4 water channel protein (Lennon et al, 2004;Roemer et al, 2007). The cytotoxic effect of anti-AQP4 antibodies has been demonstrated in several studies so far (Jarius et al, 2008b;Hinson et al, 2009;Sabater et al, 2009;Kinoshita et al, 2010). The binding of the anti-AQP4 antibody led to an activation of the classical complement cascade, resulting in lysis of NMO antibody opsonized and AQP4-transfected cells and astrocytes (Jarius et al, 2008b).…”

Pathogenesis, diagnosis and treatment of neuromyelitis optica: Changing concept of an old disease

“…In addition, NMO-IgG-negative sera of patients with NMO resulted in a significantly higher percentage of astrocyte death than that of MS patients and healthy controls in the presence of active complement, which might suggest the presence of other autoantibodies in such cases. 24 Indeed, anti-MOG antibodies and MOG-specific T cell responses in double-transgenic mice can evoke clinical signs of NMO (''Devic mice''), nevertheless pathology more closely resembles MS than NMO. 55 2.…”

“…61 In addition, the response to plasma exchange was also independent of NMO-IgG positivity, and NMO-IgG-negative sera of patients with NMO resulted in a significantly higher percentage of astrocyte death than that of MS patients and healthy controls in the presence of active complement, which might suggest similar pathogenesis and presumed pathogenecity of other autoantibodies in NMO-IgG-negative cases as well. 24,158 The upcoming European guidelines support the notion of similar treatment decisions (in press).…”

“…8,9 Outside the CNS, AQP4 is expressed in skeletal muscles, distal collecting tubules of the kidney, parietal cells of the stomach, colon epithelium, tracheal and bronchial epithelium, and glandular epithelia of breast and salivary glands. 10,11 Several data show that anti-AQP4 antibodies are pathogenic: (i) antibodies binding to AQP4 are present in a substantial portion of patients with NMO; (ii) NMO-IgG titers in sera might correlate with clinical disease activity; 6,12 (iii) in CNS plaques of NMO characterized by antibody and complement deposition, AQP4 molecules are absent in contrast to MS, 6,[14][15][16] and glial fibrillary acidic protein (GFAP) (an astrocyte marker) immunoreactivity is lost along with increased cerebrospinal fluid (CSF) levels of soluble GFAP; [17][18][19] (iv) sera containing NMO-IgG induces complement-dependent necrosis of astrocytes in vitro; [20][21][22][23][24] (v) human NMO sera recognize an extracellular epitope of AQP4 and induce AQP4 endocytosis in transfected cell lines. 17,20,21,23,25,26 The third extracellular loop of AQP4 might be the major epitope for antibodies in NMO; 27 (vi) IgG isolated from sera or recombinant antibodies generated from CSF of NMO patients were able to transfer disease.…”

“…39,40 As anti-AQP4 antibodies predominantly belong to a major complement-activating IgG1 subclass, binding to antigen activates a classical complement pathway on astrocytes, resulting in complementdependent cytotoxicity and necrosis in vitro. [20][21][22][23][24] Sera of patients with NMO induces endocytosis of AQP4, even in the absence of complement and perturbate glutamate homeostasis, which might contribute to neuron and oligodendrocyte injury; the astrocytic Na + -dependent excitatory amino acid transporter 2 (EAAT2), which is responsible for more than 90% of glutamate uptake in the CNS, is reduced in AQP4-deficient mice and NMO-IgGinduced endocytosis of AQP4 is associated with EAAT2 downregulation. 21,22 Chemotactic complement factors can induce the recruitment of inflammatory cells, which can play a part in astrocyte damage by antibody-dependent cellular cytotoxicity.…”