Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

Journal of Neuroinflammation, Dec 2011

Background Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. Results We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. Conclusions We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

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Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

Simone Mader 0 Viktoria Gredler 0 Kathrin Schanda 0 Kevin Rostasy Irena Dujmovic Kristian Pfaller Andreas Lutterotti 0 Sven Jarius Franziska Di Pauli 0 Bettina Kuenz 0 Rainer Ehling 0 Harald Hegen 0 Florian Deisenhammer 0 Fahmy Aboul-Enein Maria K Storch Peter Koson Jelena Drulovic Wolfgang Kristoferitsch Thomas Berger 0 Markus Reindl 0 0 Clinical Department of Neurology, Innsbruck Medical University , Innsbruck , Austria Background: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. Results: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. Conclusions: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HRNMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4directed humoral immune response. - Background Neuromyelitis optica (NMO), a severe inflammatory demyelinating disorder, has gained increasing interest since the discovery of serum NMO-IgG autoantibodies targeting the aquaporin-4 (AQP4) water channel protein [1,2]. The detection of this highly specific biomarker resulted in the incorporation of the NMO-IgG serostatus in the diagnostic criteria of NMO [3]. An early differentiation from multiple sclerosis (MS) is highly important, due to differences in prognosis and therapy of NMO patients. The target antigen AQP4 is localized on astrocytic endfeet [4] and is expressed as full length M1 or shorter M23 AQP4 isoform [5,6]. Recently, serum anti-AQP4 antibodies were shown to bind primarily to the shorter M23 AQP4 isoform [7-9], which is of high diagnostic relevance due to an increased sensitivity of NMO-IgG analysis. Antibodies to AQP4 are also frequently detected in so called High-risk NMO (HR-NMO) patients not fulfilling all diagnostic criteria for NMO, who present with NMOassociated symptoms like recurrent optic neuritis (ON) or longitudinally extensive transverse myelitis (LETM) extending more than three vertebral segments [10]. NMO-IgG seropositivity was shown to be predictive for a poor visual outcome and the development of NMO in patients with recurrent ON [11,12]. Furthermore, the detection of AQP4-IgG in patients with a first episode of LETM extending three vertebral segments was associated with further relapses of LETM or ON, in some cases even within half a year [13]. Therefore, NMO and HR-NMO patients (recurrent ON or monophasic/recurrent LETM) are also classified as NMO-spectrum disorders (NMOSD) [10]. However, AQP4-IgG are missing in 5-40% of these patients, depending on the immunoassay used [9,12,14-16]. It is not yet known whether autoantibodies to other central nervous system (CNS) specific antigens are present in patients with NMO and HR-NMO [17]. Recent experimental studies indicated that myelin oligodendrocyte glycoprotein (MOG), a glycoprotein localized on the outer surface of the myelin sheath and oligodendrocytes [18], might be a target antigen in NMO. Two in vivo studies demonstrated spontaneous development of NMOlike symptoms with severe opticospinal experimental autoimmune encephalomyelitis (EAE) in a double-tr (...truncated)


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Simone Mader, Viktoria Gredler, Kathrin Schanda, Kevin Rostasy, Irena Dujmovic, Kristian Pfaller, Andreas Lutterotti, Sven Jarius, Franziska Di Pauli, Bettina Kuenz, Rainer Ehling, Harald Hegen, Florian Deisenhammer, Fahmy Aboul-Enein, Maria K Storch, Peter Koson, Jelena Drulovic, Wolfgang Kristoferitsch, Thomas Berger, Markus Reindl. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders, Journal of Neuroinflammation, 2011, pp. 184, 8, DOI: 10.1186/1742-2094-8-184