**6. Acknowledgment**

The authors wish to thank the ARGE NMO Austria for excellent co-operation and Kathrin Schanda and Viktoria Gredler for their help and encouragement. This work was financially supported by Innsbruck Medical University and the Austrian MS society.

#### **7. References**

178 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

demonstrated a causal relationship between anti-NMDA-R autoantibodies with impairment in cognition and behavior (Diamond et al., 2009). A recent study provided evidence of a positive modulating effect on receptor function by low concentrations of anti-NMDA-R antibodies, resulting in an increase of NMDA-R mediated excitatory postsynaptic potentials. However, at high concentrations, these antibodies promote excitotoxicity through enhanced mitochondrial permeability transition. These findings might be an explanation for the either transient or permanent neuropsychiatric clinical course observed in SLE patients. In conclusion, antibodies to the NR2 isoform of NMDA-R could play an important role in the

Many studies focusing on the detection of antibodies to the NMDA-R NR2A and NR2B subunits in SLE have used the ELISA technique. It is now essential that studies regarding antibody specificity in patient serum/CSF are confirmed using live cell-based assays

Interestingly, antibodies against NMDA-type glutamate receptors were also detected in both serum and CSF of patients with NMOSD (Ishikawa et al., 2007; Kruer et al., 2010). As previously described, the discovery of anti-AQP4 IgG antibodies in the serum of patients with NMOSD enables an early diagnosis and specific treatment of the disease. Despite the high percentage of AQP4-IgG seropositive NMO patients, several studies report on AQP4- IgG seronegative NMO patients who, however, show no differences in their clinical presentation. It might well be that AQP4-IgG seronegative patients represent a distinct subgroup of NMO patients, in whom the disease is triggered by other autoantibodies, such as antibodies to NMDA-R or yet unknown targets. So far, in literature there is a lack of information regarding the presence of anti-NMDA-R antibodies in other CNS demyelinating diseases, such as MS. Up to now, one case report speculates on a possible association of the rarely occurring epileptic seizures in MS (Catenoix et al., 2010) with anti-NMDA-R antibody

The discovery of autoantibodies in different CNS diseases can support an early diagnosis and treatment monitoring. Moreover, antibodies can contribute to a better understanding of the disease pathogenesis. However, an antibody seronegative result should be handled with care, as this can be linked to the assay methodology, study population or to therapeutic intervention. In contrast to the high sensitivity and specificity of anti-AQP4 autoantibodies in NMO patients, antibodies to MOG are discovered "only" in a subgroup of ADEM patients. Hence, there is a lack of a specific biomarker for more than half of patients diagnosed with ADEM. Future studies focusing on these seronegative patients might facilitate a reclassification of CNS diseases through the identification of novel biomarkers. Finally, antibodies to NMDA-R are highly specific for NMDA-receptor encephalitis, whereas their role

The authors wish to thank the ARGE NMO Austria for excellent co-operation and Kathrin Schanda and Viktoria Gredler for their help and encouragement. This work was financially

in other neurological diseases has to be confirmed by specific assays.

supported by Innsbruck Medical University and the Austrian MS society.

**4.3 Anti-NMDA receptor antibodies in inflammatory demyelinating diseases** 

pathogenesis of neuropsychiatric lupus.

seropositivity (Johnston et al., 2010).

**5. Conclusion** 

**6. Acknowledgment** 

expressing native NMDA-R or single subunits.


Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases 181

Di Pauli, F., Mader, S., Rostasy, K., Schanda, K., Bajer-Kornek, B., Ehling, R., Deisenhammer,

Diamond, B., Huerta, P.T., Mina-Osorio, P., Kowal, C., and Volpe, B.T. (2009). Losing your nerves? Maybe it's the antibodies. *Nat Rev Immunol*, 9, 6, Jun, 449-456. Dujmovic, I., Mader, S., Schanda, K., Deisenhammer, F., Stojsavljevic, N., Kostic, J., Berger,

Emmer, B.J., van der Grond, J., Steup-Beekman, G.M., Huizinga, T.W., and van Buchem,

Florance, N.R., Davis, R.L., Lam, C., Szperka, C., Zhou, L., Ahmad, S., Campen, C.J., Moss,

Fragoso-Loyo, H., Cabiedes, J., Orozco-Narvaez, A., Davila-Maldonado, L., Atisha-Fregoso,

Freedman, M.S., Thompson, E.J., Deisenhammer, F., Giovannoni, G., Grimsley, G., Keir, G.,

Furman, C.S., Gorelick-Feldman, D.A., Davidson, K.G., Yasumura, T., Neely, J.D., Agre, P.,

and M23 isoforms. *Proc Natl Acad Sci U S A*, 100, 23, Nov 11, 13609-13614. Gaertner, S., de Graaf, K.L., Greve, B., and Weissert, R. (2004). Antibodies against

Genain, C.P., Cannella, B., Hauser, S.L., and Raine, C.S. (1999). Identification of

Genain, C.P., Nguyen, M.H., Letvin, N.L., Pearl, R., Davis, R.L., Adelman, M., Lees, M.B.,

children and adolescents. *Annals of neurology*, 66, 1, Jul, 11-18.

diseases. *J Neuroimmunol*, 200, 1-2, Aug 30, 125-128.

*Neurology*, 63, 12, Dec 28, 2381-2383.

*medicine*, 5, 2, Feb, 170-175.

2966-2974.

870.

CNS demyelinating diseases. *Clin Immunol*, 138, 3, Mar, 247-254.

disorders. *J Neuroimmunol*, Feb 10.

erythematosus. *PLoS Med*, 3, 12, Dec, e499.

F., Reindl, M., and Berger, T. (2011). Temporal dynamics of anti-MOG antibodies in

T., Drulovic, J., and Reindl, M. (2011). Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum

M.A. (2006). Selective involvement of the amygdala in systemic lupus

H., Peter, N., Gleichman, A.J., Glaser, C.A., Lynch, D.R., Rosenfeld, M.R., and Dalmau, J. (2009). Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in

Y., Diamond, B., Llorente, L., and Sanchez-Guerrero, J. (2008). Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. *PloS one*, 3, 10, e3347. Franciotta, D., Columba-Cabezas, S., Andreoni, L., Ravaglia, S., Jarius, S., Romagnolo, S.,

Tavazzi, E., Bergamaschi, R., Zardini, E., Aloisi, F., and Marchioni, E. (2008). Oligoclonal IgG band patterns in inflammatory demyelinating human and mouse

Ohman, S., Racke, M.K., Sharief, M., Sindic, C.J., Sellebjerg, F., and Tourtellotte, W.W. (2005). Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. *Arch Neurol*, 62, 6, Jun, 865-

and Rash, J.E. (2003). Aquaporin-4 square array assembly: opposing actions of M1

glycosylated native MOG are elevated in patients with multiple sclerosis.

autoantibodies associated with myelin damage in multiple sclerosis. *Nature* 

Linington, C., and Hauser, S.L. (1995). Antibody facilitation of multiple sclerosislike lesions in a nonhuman primate. *The Journal of clinical investigation*, 96, 6, Dec,


Callen, D.J., Shroff, M.M., Branson, H.M., Li, D.K., Lotze, T., Stephens, D., and Banwell, B.L.

Catenoix, H., Marignier, R., Ritleng, C., Dufour, M., Mauguiere, F., Confavreux, C., and

Collongues, N., Marignier, R., Zephir, H., Papeix, C., Blanc, F., Ritleng, C., Tchikviladze, M.,

Colombo, M., Dono, M., Gazzola, P., Roncella, S., Valetto, A., Chiorazzi, N., Mancardi, G.L.,

Cree, B. (2008). Neuromyelitis optica: diagnosis, pathogenesis, and treatment. *Curr Neurol* 

Cree, B.A., Lamb, S., Morgan, K., Chen, A., Waubant, E., and Genain, C. (2005). An open

Dale, R.C., de Sousa, C., Chong, W.K., Cox, T.C., Harding, B., and Neville, B.G. (2000). Acute

Dale, R.C., Irani, S.R., Brilot, F., Pillai, S., Webster, R., Gill, D., Lang, B., and Vincent, A.

Dalmau, J., Gleichman, A.J., Hughes, E.G., Rossi, J.E., Peng, X., Lai, M., Dessain, S.K.,

Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M.R., and Balice-Gordon, R.

Dalmau, J., Tuzun, E., Wu, H.Y., Masjuan, J., Rossi, J.E., Voloschin, A., Baehring, J.M.,

DeGiorgio, L.A., Konstantinov, K.N., Lee, S.C., Hardin, J.A., Volpe, B.T., and Diamond, B.

multiple sclerosis in children. *Brain*, 123 Pt 12, Dec, 2407-2422.

encephalitis lethargica. *Annals of neurology*, 66, 5, Nov, 704-709.

NMDAR encephalitis. *Lancet neurology*, 10, 1, Jan, 63-74.

72, 11, Mar 17, 968-973.

2789.

12, 1270-1272.

12, Dec, 1091-1098.

Jan, 25-36.

*(Houndmills, Basingstoke, England)*, Sep 22.

*Neurosci Rep*, 8, 5, Sep, 427-433.

study of 125 patients. *Neurology*, 74, 9, Mar 2, 736-742.

(2009). Role of MRI in the differentiation of ADEM from MS in children. *Neurology*,

Vukusic, S. (2010). Multiple sclerosis and epileptic seizures. *Multiple sclerosis* 

Outteryck, O., Vukusic, S., Fleury, M., Fontaine, B., Brassat, D., Clanet, M., Milh, M., Pelletier, J., Audoin, B., Ruet, A., Lebrun-Frenay, C., Thouvenot, E., Camu, W., Debouverie, M., Creange, A., Moreau, T., Labauge, P., Castelnovo, G., Edan, G., Le Page, E., Defer, G., Barroso, B., Heinzlef, O., Gout, O., Rodriguez, D., Wiertlewski, S., Laplaud, D., Borgel, F., Tourniaire, P., Grimaud, J., Brochet, B., Vermersch, P., Confavreux, C., and de Seze, J. (2010). Neuromyelitis optica in France: a multicenter

and Ferrarini, M. (2000). Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. *J Immunol*, 164, 5, Mar 1, 2782-

label study of the effects of rituximab in neuromyelitis optica. *Neurology*, 64, 7, Apr

disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and

(2009). N-methyl-D-aspartate receptor antibodies in pediatric dyskinetic

Rosenfeld, M.R., Balice-Gordon, R., and Lynch, D.R. (2008). Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. *Lancet neurology*, 7,

(2011). Clinical experience and laboratory investigations in patients with anti-

Shimazaki, H., Koide, R., King, D., Mason, W., Sansing, L.H., Dichter, M.A., Rosenfeld, M.R., and Lynch, D.R. (2007). Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. *Annals of neurology*, 61, 1,

(2001). A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. *Nature medicine*, 7, 11, Nov, 1189-1193.


Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases 183

Jarius, S., Franciotta, D., Bergamaschi, R., Wildemann, B., and Wandinger, K.P. (2010a).

Jarius, S., Franciotta, D., Paul, F., Ruprecht, K., Bergamaschi, R., Rommer, P.S., Reuss,

Jarius, S., Paul, F., Franciotta, D., Aktas, O., Hohlfeld, R., Zipp, F., and Vincent, A. (2007).

Jarius, S., Paul, F., Franciotta, D., Waters, P., Zipp, F., Hohlfeld, R., Vincent, A., and

Johnston, J., Ali, K., Pearson, O.R., Rickards, C., and Vincent, A. (2010). POI14 Multiple

Kabat, E.A., Glusman, M., and Knaub, V. (1948). Quantitative estimation of the albumin and

Kalluri, S.R., Rothhammer, V., Staszewski, O., Srivastava, R., Petermann, F., Prinz, M.,

Kerlero de Rosbo, N., Honegger, P., Lassmann, H., and Matthieu, J.M. (1990). Demyelination

Kinoshita, M., Nakatsuji, Y., Kimura, T., Moriya, M., Takata, K., Okuno, T., Kumanogoh, A.,

Kinoshita, M., Nakatsuji, Y., Kimura, T., Moriya, M., Takata, K., Okuno, T., Kumanogoh, A.,

Kira, J. (2006). [Epidemiology of multiple sclerosis in Japanese: with special reference to opticopsinal multiple sclerosis]. *Rinsho Shinkeigaku*, 46, 11, Nov, 859-862. Kira, J., Kanai, T., Nishimura, Y., Yamasaki, K., Matsushita, S., Kawano, Y., Hasuo, K.,

myelin/oligodendrocyte glycoprotein. *J Neurochem*, 55, 2, Aug, 583-587. Kesselring, J., Miller, D.H., Robb, S.A., Kendall, B.E., Moseley, I.F., Kingsley, D., du

neuromyelitis optica. *Nature clinical practice*, 4, 4, Apr, 202-214.

encephalitis. *J Neurol Neurosurg Psychiatry*, 81, 11, Nov, e56.

disorders. *Clin Chem Lab Med*, 48, 5, May, 659-663.

status. *Nat Clin Pract Neurol*, 3, 5, May, E1.

methods. *Am J Med*, 4, 5, May, 653-662.

*Brain*, 113 ( Pt 2), Apr, 291-302.

*communications*, 386, 4, Sep 4, 623-627.

*Biochem Biophys Res Commun*, 394, 1, Mar 26, 205-210.

e16083.

*Neuroinflammation*, 7, 52.

Immunoglobulin M antibodies to aquaporin-4 in neuromyelitis optica and related

R., Probst, C., Kristoferitsch, W., Wandinger, K.P., and Wildemann, B. (2010b). Cerebrospinal fluid antibodies to aquaporin-4 in neuromyelitis optica and related disorders: frequency, origin, and diagnostic relevance. *J* 

Revised diagnostic criteria for neuromyelitis optica--incorporation of NMO-IgG

Wildemann, B. (2008b). Mechanisms of disease: aquaporin-4 antibodies in

sclerosis: a potential association with anti-N-methyl-d-aspartate receptor

gamma globulin in normal and pathologic cerebrospinal fluid by immunochemical

Hemmer, B., and Korn, T. (2011). Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica. *PLoS One*, 6, 1,

induced in aggregating brain cell cultures by a monoclonal antibody against

Boulay, E.P., and McDonald, W.I. (1990). Acute disseminated encephalomyelitis. MRI findings and the distinction from multiple sclerosis.

Kajiyama, K., Yoshikawa, H., and Sakoda, S. (2009). Neuromyelitis optica: Passive transfer to rats by human immunoglobulin. *Biochemical and biophysical research* 

Kajiyama, K., Yoshikawa, H., and Sakoda, S. (2010). Anti-aquaporin-4 antibody induces astrocytic cytotoxicity in the absence of CNS antigen-specific T cells.

Tobimatsu, S., and Kobayashi, T. (1996). Western versus Asian types of multiple


Gielen, M., Siegler Retchless, B., Mony, L., Johnson, J.W., and Paoletti, P. (2009). Mechanism

Goverman, J. (2009). Autoimmune T cell responses in the central nervous system. *Nat Rev* 

Graus, F., Saiz, A., and Dalmau, J. (2010). Antibodies and neuronal autoimmune disorders of

Greeve, I., Sellner, J., Lauterburg, T., Walker, U., Rosler, K.M., and Mattle, H.P. (2007). Anti-

Hanly, J.G., Robichaud, J., and Fisk, J.D. (2006). Anti-NR2 glutamate receptor antibodies and

Hauser, S.L., Waubant, E., Arnold, D.L., Vollmer, T., Antel, J., Fox, R.J., Bar-Or, A., Panzara,

Hinson, S.R., McKeon, A., Fryer, J.P., Apiwattanakul, M., Lennon, V.A., and Pittock, S.J.

Hughes, E.G., Peng, X., Gleichman, A.J., Lai, M., Zhou, L., Tsou, R., Parsons, T.D., Lynch,

of anti-NMDA receptor encephalitis. *J Neurosci*, 30, 17, Apr 28, 5866-5875. Hynson, J.L., Kornberg, A.J., Coleman, L.T., Shield, L., Harvey, A.S., and Kean, M.J. (2001).

Irani, S.R., Bera, K., Waters, P., Zuliani, L., Maxwell, S., Zandi, M.S., Friese, M.A., Galea, I.,

Ishikawa, N., Tajima, G., Hyodo, S., Takahashi, Y., and Kobayashi, M. (2007). Detection of

Jarius, S., Aboul-Enein, F., Waters, P., Kuenz, B., Hauser, A., Berger, T., Lang, W., Reindl, M.,

term course of neuromyelitis optica. *Brain*, 131, Pt 11, Nov, 3072-3080.

children. *Neurology*, 56, 10, May 22, 1308-1312.

*a journal of neurology*, 133, Pt 6, Jun, 1655-1667.

analysis of 25 patients. *Arch Neurol*, 65, 11, Nov, 1443-1448.

sclerosis in a Swiss cohort. *Acta Neurol Scand*, 116, 4, Oct, 207-210.

7247, Jun 4, 703-707.

1558.

*Immunol*, 9, 6, Jun, 393-407.

358, 7, Feb 14, 676-688.

Sep, 1164-1167.

the CNS. *J Neurol*, 257, 4, Apr, 509-517.

of differential control of NMDA receptor activity by NR2 subunits. *Nature*, 459,

myelin antibodies in clinically isolated syndrome indicate the risk of multiple

cognitive function in systemic lupus erythematosus. *J Rheumatol*, 33, 8, Aug, 1553-

M., Sarkar, N., Agarwal, S., Langer-Gould, A., and Smith, C.H. (2008). B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. *N Engl J Med*,

(2009). Prediction of neuromyelitis optica attack severity by quantitation of complement-mediated injury to aquaporin-4-expressing cells. *Arch Neurol*, 66, 9,

D.R., Dalmau, J., and Balice-Gordon, R.J. (2010). Cellular and synaptic mechanisms

Clinical and neuroradiologic features of acute disseminated encephalomyelitis in

Kullmann, D.M., Beeson, D., Lang, B., Bien, C.G., and Vincent, A. (2010). N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. *Brain :* 

autoantibodies against NMDA-type glutamate receptor in a patient with recurrent optic neuritis and transient cerebral lesions. *Neuropediatrics*, 38, 5, Oct, 257-260. Jacob, A., Weinshenker, B.G., Violich, I., McLinskey, N., Krupp, L., Fox, R.J., Wingerchuk,

D.M., Boggild, M., Constantinescu, C.S., Miller, A., De Angelis, T., Matiello, M., and Cree, B.A. (2008). Treatment of neuromyelitis optica with rituximab: retrospective

Vincent, A., and Kristoferitsch, W. (2008a). Antibody to aquaporin-4 in the long-


sclerosis: immunogenetically and clinically distinct disorders. *Ann Neurol*, 40, 4, Oct, 569-574.

Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases 185

Lennon, V.A., Kryzer, T.J., Pittock, S.J., Verkman, A.S., and Hinson, S.R. (2005). IgG marker

Lennon, V.A., Wingerchuk, D.M., Kryzer, T.J., Pittock, S.J., Lucchinetti, C.F., Fujihara, K.,

Linington, C., Berger, T., Perry, L., Weerth, S., Hinze-Selch, D., Zhang, Y., Lu, H.C.,

response in the central nervous system. *Eur J Immunol*, 23, 6, Jun, 1364-1372. Lotze, T.E., Northrop, J.L., Hutton, G.J., Ross, B., Schiffman, J.S., and Hunter, J.V. (2008). Spectrum of pediatric neuromyelitis optica. *Pediatrics*, 122, 5, Nov, e1039-1047. Lucchinetti, C., Bruck, W., Parisi, J., Scheithauer, B., Rodriguez, M., and Lassmann, H.

Lucchinetti, C.F., Bruck, W., Rodriguez, M., and Lassmann, H. (1996). Distinct patterns of

Lucchinetti, C.F., Mandler, R.N., McGavern, D., Bruck, W., Gleich, G., Ransohoff, R.M.,

Mader, S., Lutterotti, A., Di Pauli, F., Kuenz, B., Schanda, K., Aboul-Enein, F., Khalil, M.,

, R., De Seze, J., Vukusic, S., Durand-Dubief, F., Zephir, H., Vermersch, P., Cabre, P.,

Matiello, M., Lennon, V.A., Jacob, A., Pittock, S.J., Lucchinetti, C.F., Wingerchuk, D.M., and

Mikaeloff, Y., Adamsbaum, C., Husson, B., Vallee, L., Ponsot, G., Confavreux, C., Tardieu,

inflammatory demyelination in childhood. *Brain*, 127, Pt 9, Sep, 1942-1947. Mikaeloff, Y., Caridade, G., Husson, B., Suissa, S., and Tardieu, M. (2007). Acute

pathogenesis of demyelination. *Ann Neurol*, 47, 6, Jun, 707-717.

*Journal of experimental medicine*, 202, 4, Aug 15, 473-477.

17, 2106-2112.

6, 3, Jul, 259-274.

e10455.

75, 4, Jul 27, 310-315.

neuritis. *Neurology*, 70, 23, Jun 3, 2197-2200.

*Paediatr Neurol*, 11, 2, Mar, 90-95.

*Brain*, 125, Pt 7, Jul, 1450-1461.

of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. *The* 

Nakashima, I., and Weinshenker, B.G. (2004). A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. *Lancet*, 364, 9451, Dec 11-

Lassmann, H., and Wekerle, H. (1993). T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory

(2000). Heterogeneity of multiple sclerosis lesions: implications for the

multiple sclerosis pathology indicates heterogeneity on pathogenesis. *Brain Pathol*,

Trebst, C., Weinshenker, B., Wingerchuk, D., Parisi, J.E., and Lassmann, H. (2002). A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica.

Storch, M.K., Jarius, S., Kristoferitsch, W., Berger, T., and Reindl, M. (2010). Patterns of antibody binding to aquaporin-4 isoforms in neuromyelitis optica. *PloS one*, 5, 5,

Cavillon, G., Honnorat, J., and Confavreux, C. (2008). NMO-IgG and Devic's neuromyelitis optica: a French experience. *Mult Scler*, 14, 4, May, 440-445. Matiello, M., Kim, H.J., Kim, W., Brum, D.G., Barreira, A.A., Kingsbury, D.J., Plant, G.T.,

Adoni, T., and Weinshenker, B.G. (2010). Familial neuromyelitis optica. *Neurology*,

Weinshenker, B.G. (2008). NMO-IgG predicts the outcome of recurrent optic

M., and Suissa, S. (2004). MRI prognostic factors for relapse after acute CNS

disseminated encephalomyelitis cohort study: prognostic factors for relapse. *Eur J* 


Klawiter, E.C., Alvarez, E., 3rd, Xu, J., Paciorkowski, A.R., Zhu, L., Parks, B.J., Cross, A.H.,

Kowal, C., Degiorgio, L.A., Lee, J.Y., Edgar, M.A., Huerta, P.T., Volpe, B.T., and Diamond, B.

Kruer, M.C., Koch, T.K., Bourdette, D.N., Chabas, D., Waubant, E., Mueller, S., Moscarello,

Krupp, L.B., Banwell, B., and Tenembaum, S. (2007). Consensus definitions proposed for

Kuhle, J., Lindberg, R.L., Regeniter, A., Mehling, M., Hoffmann, F., Reindl, M., Berger, T.,

Kuhle, J., Pohl, C., Mehling, M., Edan, G., Freedman, M.S., Hartung, H.P., Polman, C.H.,

and progression to multiple sclerosis. *N Engl J Med*, 356, 4, Jan 25, 371-378. Lalive, P., Hausler, M., Maurey, H., Mikaeloff, Y., Tardieu, M., Wiendl, H., Schroeter, M.,

Lalive, P.H., Menge, T., Delarasse, C., Della Gaspera, B., Pham-Dinh, D., Villoslada, P., von

Lapteva, L., Nowak, M., Yarboro, C.H., Takada, K., Roebuck-Spencer, T., Weickert, T.,

Leake, J.A., Albani, S., Kao, A.S., Senac, M.O., Billman, G.F., Nespeca, M.P., Paulino, A.D.,

viral encephalitis in children. *Mult Scler*, 17, 3, Mar, 297-302.

*of America*, 103, 7, Feb 14, 2280-2285.

*Pediatr Infect Dis J*, 23, 8, Aug, 756-764.

optica. *Neurology*, 72, 12, Mar 24, 1101-1103.

*America*, 103, 52, Dec 26, 19854-19859.

Oct, 569-574.

1473-1475.

254, 2, Feb, 160-168.

Aug, 2505-2514.

S7-12.

sclerosis: immunogenetically and clinically distinct disorders. *Ann Neurol*, 40, 4,

and Naismith, R.T. (2009). NMO-IgG detected in CSF in seronegative neuromyelitis

(2006). Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. *Proceedings of the National Academy of Sciences of the United States of* 

M.A., Dalmau, J., Woltjer, R.L., and Adamus, G. (2010). NMDA receptor encephalitis mimicking seronegative neuromyelitis optica. *Neurology*, 74, 18, May 4,

pediatric multiple sclerosis and related disorders. *Neurology*, 68, 16 Suppl 2, Apr 17,

Radue, E.W., Leppert, D., and Kappos, L. (2007a). Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF. *J Neurol*,

Miller, D.H., Montalban, X., Barkhof, F., Bauer, L., Dahms, S., Lindberg, R., Kappos, L., and Sandbrink, R. (2007b). Lack of association between antimyelin antibodies

Hartung, H., Kieseier, B., and Menge, T. (2011). Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from

Budingen, H.C., and Genain, C.P. (2006). Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis. *Proceedings of the National Academy of Sciences of the United States* 

Bleiberg, J., Rosenstein, D., Pao, M., Patronas, N., Steele, S., Manzano, M., van der Veen, J.W., Lipsky, P.E., Marenco, S., Wesley, R., Volpe, B., Diamond, B., and Illei, G.G. (2006). Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. *Arthritis and rheumatism*, 54, 8,

Quintela, E.R., Sawyer, M.H., and Bradley, J.S. (2004). Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features.


Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases 187

Owens, G.P., Ritchie, A.M., Burgoon, M.P., Williamson, R.A., Corboy, J.R., and Gilden, D.H.

Palace, J., Leite, M.I., Nairne, A., and Vincent, A. (2010). Interferon Beta treatment in

Papais-Alvarenga, R.M., Miranda-Santos, C.M., Puccioni-Sohler, M., de Almeida, A.M.,

Papeix, C., Vidal, J.S., de Seze, J., Pierrot-Deseilligny, C., Tourbah, A., Stankoff, B., Lebrun,

Paul, F., Jarius, S., Aktas, O., Bluthner, M., Bauer, O., Appelhans, H., Franciotta, D.,

Pavone, P., Pettoello-Mantovano, M., Le Pira, A., Giardino, I., Pulvirenti, A., Giugno, R.,

Pellkofer, H.L., Suessmair, C., Schulze, A., Hohlfeld, R., and Kuempfel, T. (2009). Course of

Pittock, S.J., Lennon, V.A., de Seze, J., Vermersch, P., Homburger, H.A., Wingerchuk, D.M.,

Pittock, S.J., Weinshenker, B.G., Lucchinetti, C.F., Wingerchuk, D.M., Corboy, J.R., and

Pohl, M., Fischer, M.T., Mader, S., Schanda, K., Kitic, M., Sharma, R., Wimmer, I., Misu, T.,

Popescu, B.F., Lennon, V.A., Parisi, J.E., Howe, C.L., Weigand, S.D., Cabrera-Gomez, J.A.,

Qin, Y., Duquette, P., Zhang, Y., Talbot, P., Poole, R., and Antel, J. (1998). Clonal expansion

multiple sclerosis. *The Journal of clinical investigation*, 102, 5, Sep 1, 1045-1050.

*Immunol*, 171, 5, Sep 1, 2725-2733.

optica. *Mult Scler*, 13, 2, Mar, 256-259.

analysis. *Neuropediatrics*, 41, 6, Dec, 246-255.

rituximab. *Mult Scler*, 15, 8, Aug, 1006-1008.

aquaporin 4 expression. *Arch Neurol*, 63, 7, Jul, 964-968.

responses against aquaporin 4. *Acta Neuropathol*, Apr 6.

pathogenic implications. *Neurology*, Mar 2.

*PLoS Med*, 4, 4, Apr 17, e133.

*Neurol*, 67, 8, Aug, 1016-1017.

Oct, 429-435.

78-83.

(2003). Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid. *J* 

neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. *Arch* 

Oliveira, S., Basilio De Oliveira, C.A., Alvarenga, H., and Poser, C.M. (2002). Optic neuromyelitis syndrome in Brazilian patients. *J Neurol Neurosurg Psychiatry*, 73, 4,

C., Moreau, T., Vermersch, P., Fontaine, B., Lyon-Caen, O., and Gout, O. (2007). Immunosuppressive therapy is more effective than interferon in neuromyelitis

Bergamaschi, R., Littleton, E., Palace, J., Seelig, H.P., Hohlfeld, R., Vincent, A., and Zipp, F. (2007). Antibody to Aquaporin 4 in the Diagnosis of Neuromyelitis Optica.

Parano, E., Polizzi, A., Distefano, A., Ferro, A., Pavone, L., and Ruggieri, M. (2010). Acute disseminated encephalomyelitis: a long-term prospective study and meta-

neuromyelitis optica during inadvertent pregnancy in a patient treated with

Lucchinetti, C.F., Zephir, H., Moder, K., and Weinshenker, B.G. (2008). Neuromyelitis optica and non organ-specific autoimmunity. *Arch Neurol*, 65, 1, Jan,

Lennon, V.A. (2006). Neuromyelitis optica brain lesions localized at sites of high

Fujihara, K., Reindl, M., Lassmann, H., and Bradl, M. (2011). Pathogenic T cell

Newell, K., Mandler, R.N., Pittock, S.J., Weinshenker, B.G., and Lucchinetti, C.F. (2011). Neuromyelitis optica unique area postrema lesions: Nausea, vomiting, and

and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in


Minagar, A., Alexander, J.S., Fowler, M.R., Long, A.C., and Kelley, R.E. (2002). Devic

Mirsattari, S.M., Johnston, J.B., McKenna, R., Del Bigio, M.R., Orr, P., Ross, R.T., and Power,

Misu, T., Takano, R., Fujihara, K., Takahashi, T., Sato, S., and Itoyama, Y. (2009).

Neely, J.D., Christensen, B.M., Nielsen, S., and Agre, P. (1999). Heterotetrameric

Nelson, P.A., Khodadoust, M., Prodhomme, T., Spencer, C., Patarroyo, J.C., Varrin-Doyer,

Nicchia, G.P., Mastrototaro, M., Rossi, A., Pisani, F., Tortorella, C., Ruggieri, M., Lia, A.,

Nicchia, G.P., Nico, B., Camassa, L.M., Mola, M.G., Loh, N., Dermietzel, R., Spray, D.C.,

Nielsen, S., Nagelhus, E.A., Amiry-Moghaddam, M., Bourque, C., Agre, P., and Ottersen,

Nishiyama, S., Ito, T., Misu, T., Takahashi, T., Kikuchi, A., Suzuki, N., Jin, K., Aoki, M.,

O'Connor, K.C., McLaughlin, K.A., De Jager, P.L., Chitnis, T., Bettelli, E., Xu, C., Robinson,

Osuntokun, B.O. (1971). The pattern of neurological illness in tropical Africa. Experience at

sclerosis. *N Engl J Med*, 343, 13, Sep 28, 938-952.

Ibadan, Nigeria. *J Neurol Sci*, 12, 4, Apr, 417-442.

neuromyelitis optica. *Neurology*, 56, 3, Feb 13, 317-323.

*Psychiatry*, 80, 5, May, 575-577.

*PLoS One*, 5, 11, e15050.

Oct, 33.

11163.

1363-1373.

129, 4, 935-945.

Jan 1, 171-180.

2, Feb, 211-217.

disease: clinical course, pathophysiology, and management. *Pathophysiology*, 9, 1,

C. (2001). Aboriginals with multiple sclerosis: HLA types and predominance of

Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker. *J Neurol Neurosurg* 

composition of aquaporin-4 water channels. *Biochemistry*, 38, 34, Aug 24, 11156-

M., Ho, J.D., Stroud, R.M., and Zamvil, S.S. (2010). Immunodominant T cell determinants of aquaporin-4, the autoantigen associated with neuromyelitis optica.

Trojano, M., Frigeri, A., and Svelto, M. (2009). Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies. *Glia*, 57, 13, Oct,

Svelto, M., and Frigeri, A. (2004). The role of aquaporin-4 in the blood-brain barrier development and integrity: studies in animal and cell culture models. *Neuroscience*,

O.P. (1997). Specialized membrane domains for water transport in glial cells: highresolution immunogold cytochemistry of aquaporin-4 in rat brain. *J Neurosci*, 17, 1,

Fujihara, K., and Itoyama, Y. (2009). A case of NMO seropositive for aquaporin-4 antibody more than 10 years before onset. *Neurology*, 72, 22, Jun 2, 1960-1961. Noseworthy, J.H., Lucchinetti, C., Rodriguez, M., and Weinshenker, B.G. (2000). Multiple

W.H., Cherry, S.V., Bar-Or, A., Banwell, B., Fukaura, H., Fukazawa, T., Tenembaum, S., Wong, S.J., Tavakoli, N.P., Idrissova, Z., Viglietta, V., Rostasy, K., Pohl, D., Dale, R.C., Freedman, M., Steinman, L., Buckle, G.J., Kuchroo, V.K., Hafler, D.A., and Wucherpfennig, K.W. (2007). Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. *Nature medicine*, 13,


Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases 189

Takahashi, T., Fujihara, K., Nakashima, I., Misu, T., Miyazawa, I., Nakamura, M., Watanabe,

Tenembaum, S., Chamoles, N., and Fejerman, N. (2002). Acute disseminated

Tomassini, V., De Giglio, L., Reindl, M., Russo, P., Pestalozza, I., Pantano, P., Berger, T., and

Vincent, A., Irani, S.R., and Lang, B. (2010). The growing recognition of immunotherapy-

Wandinger, K.P., Stangel, M., Witte, T., Venables, P., Charles, P., Jarius, S., Wildemann,

Warabi, Y., Matsumoto, Y., and Hayashi, H. (2007). Interferon beta-1b exacerbates multiple

Watanabe, S., Nakashima, I., Misu, T., Miyazawa, I., Shiga, Y., Fujihara, K., and Itoyama, Y.

Waters, P., and Vincent, A. (2008). Detection of anti-aquaporin-4 antibodies in neuromyelitis

Weinshenker, B.G., Wingerchuk, D.M., Vukusic, S., Linbo, L., Pittock, S.J., Lucchinetti, C.F.,

longitudinally extensive transverse myelitis. *Ann Neurol*, 59, 3, Mar, 566-569. Weissert, R., Wallstrom, E., Storch, M.K., Stefferl, A., Lorentzen, J., Lassmann, H., Linington,

EAE in rats. *The Journal of clinical investigation*, 102, 6, Sep 15, 1265-1273. Wingerchuk, D.M. (2009). Neuromyelitis optica: effect of gender. *J Neurol Sci*, 286, 1-2, Nov

Wingerchuk, D.M., Hogancamp, W.F., O'Brien, P.C., and Weinshenker, B.G. (1999). The

Wingerchuk, D.M., Lennon, V.A., Lucchinetti, C.F., Pittock, S.J., and Weinshenker, B.G. (2007). The spectrum of neuromyelitis optica. *Lancet Neurol*, 6, 9, Sep, 805-815. Wingerchuk, D.M., and Weinshenker, B.G. (2003). Neuromyelitis optica: clinical predictors of a relapsing course and survival. *Neurology*, 60, 5, Mar 11, 848-853.

episode suggestive of MS. *Mult Scler*, 13, 9, Nov, 1086-1094.

neuromyelitis optica. *Mult Scler*, 13, 1, Jan, 128-132.

optica: current status of the assays. *Int MS J*, 15, 3, Sep, 99-105.

307-313.

1198-1200.

Jan 15, 57-61.

15, 18-23.

1107-1114.

titre. *Brain*, 130, Pt 5, May, 1235-1243.

*Curr Opin Neurol*, 23, 2, Apr, 144-150.

59, 8, Oct 22, 1224-1231.

human aquaporin-4 antibody in neuromyelitis optica. *Tohoku J Exp Med*, 210, 4, Dec,

S., Shiga, Y., Kanaoka, C., Fujimori, J., Sato, S., and Itoyama, Y. (2007). Antiaquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody

encephalomyelitis: a long-term follow-up study of 84 pediatric patients. *Neurology*,

Pozzilli, C. (2007). Anti-myelin antibodies predict the clinical outcome after a first

responsive seizure disorders with autoantibodies to specific neuronal proteins.

B., Probst, C., Iking-Konert, C., and Schneider, M. (2010). Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjogren's syndrome. *Arthritis Rheum*, 62, 4, Apr,

sclerosis with severe optic nerve and spinal cord demyelination. *J Neurol Sci*, 252, 1,

(2007). Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with

and Lennon, V.A. (2006). Neuromyelitis optica IgG predicts relapse after

C., and Olsson, T. (1998). MHC haplotype-dependent regulation of MOG-induced

clinical course of neuromyelitis optica (Devic's syndrome). *Neurology*, 53, 5, Sep 22,


Rash, J.E., Yasumura, T., Hudson, C.S., Agre, P., and Nielsen, S. (1998). Direct immunogold

Rauer, S., Euler, B., Reindl, M., and Berger, T. (2006). Antimyelin antibodies and the risk of

Reindl, M., Khalil, M., and Berger, T. (2006). Antibodies as biological markers for pathophysiological processes in MS. *J Neuroimmunol*, 180, 1-2, Nov, 50-62. Rivera, V.M., and Cabrera, J.A. (2001). Aboriginals with multiple sclerosis: HLA types and predominance of neuromyelitis optica. *Neurology*, 57, 5, Sep 11, 937-938. Roemer, S.F., Parisi, J.E., Lennon, V.A., Benarroch, E.E., Lassmann, H., Bruck, W.,

Rust, R.S. (2000). Multiple sclerosis, acute disseminated encephalomyelitis, and related

Saadoun, S., Waters, P., Bell, B.A., Vincent, A., Verkman, A.S., and Papadopoulos, M.C.

Sabater, L., Giralt, A., Boronat, A., Hankiewicz, K., Blanco, Y., Llufriu, S., Alberch, J.,

Schwarz, S., Mohr, A., Knauth, M., Wildemann, B., and Storch-Hagenlocher, B. (2001). Acute

Sellner, J., Boggild, M., Clanet, M., Hintzen, R.Q., Illes, Z., Montalban, X., Du Pasquier,

Sospedra, M., and Martin, R. (2005). Immunology of multiple sclerosis. *Annual review of* 

Storch, M.K., Piddlesden, S., Haltia, M., Iivanainen, M., Morgan, P., and Lassmann, H.

Stuve, O., Nessler, S., Hartung, H.P., Hemmer, B., Wiendl, H., and Kieseier, B.C. (2005).

Takahashi, T., Fujihara, K., Nakashima, I., Misu, T., Miyazawa, I., Nakamura, M., Watanabe,

conditions. *Semin Pediatr Neurol*, 7, 2, Jun, 66-90.

demyelination. *Ann Neurol*, 43, 4, Apr, 465-471.

prognosis]. *Nervenarzt*, 76, 6, Jun, 701-707.

11981-11986.

May, 1194-1205.

Feb, 349-361.

1019-1032.

56, 10, May 22, 1313-1318.

*immunology*, 23, 683-747.

35.

*Psychiatry*, 77, 6, Jun, 739-742.

labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. *Proc Natl Acad Sci U S A*, 95, 20, Sep 29,

relapse in patients with a primary demyelinating event. *J Neurol Neurosurg* 

Mandler, R.N., Weinshenker, B.G., Pittock, S.J., Wingerchuk, D.M., and Lucchinetti, C.F. (2007). Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. *Brain*, 130, Pt 5,

(2010). Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. *Brain*, 133, Pt 2,

Graus, F., and Saiz, A. (2009). Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: an in vitro study. *J Neuroimmunol*, 215, 1-2, Oct 30, 31-

disseminated encephalomyelitis: a follow-up study of 40 adult patients. *Neurology*,

R.A., Polman, C.H., Sorensen, P.S., and Hemmer, B. (2010). EFNS guidelines on diagnosis and management of neuromyelitis optica. *Eur J Neurol*, 17, 8, Aug,

(1998). Multiple sclerosis: in situ evidence for antibody- and complement-mediated

[Acute disseminated encephalomyelitis. Pathogenesis, diagnosis, treatment, and

S., Ishii, N., and Itoyama, Y. (2006). Establishment of a new sensitive assay for anti-

human aquaporin-4 antibody in neuromyelitis optica. *Tohoku J Exp Med*, 210, 4, Dec, 307-313.


Zaffaroni, M. (2004). Cerebrospinal fluid findings in Devic's neuromyelitis optica. *Neurol Sci*, 25 Suppl 4, Nov, S368-370.

**10** 

*Russia* 

**Preclinical and Predictive Algorithms in** 

 **Monitoring Patients with Autoimmune** 

**Diseases and Their Relatives-at-Risks** 

Sergey Suchkov1,2, Dmitry Kostyushev1, Dmitry Gnatenko1,

Millions of people all round the world suffer from various autoimmune disorders. T1D, MS, SLE, autoimmune diseases of the heart, liver, intestine and other internal organs, etc., all represent severe manifestations, which deteriorate the quality of life and cause physical disability and even death in patients with chronic illnesses. Every year, the largest world economies incur megabuck losses associated with medical services, insurance and drug procurement, not to mention the ever decreasing size of the able-bodied population. The development of preclinical diagnostic algorithms for autoimmune diseases, their implementation and introduction into routine clinical practice will help detect tissue or organ pathologies at the stages where their reversal is still possible. Early implementation of causal therapy allows the physician to compensate for the lack of one or another organ and ensures complete recovery or significant improvement of the patient's health status. However, in developing updated preventive protocols, the investigator is faced with a

 And, last but not least, what are the analytical procedures for mass-scale monitoring? While constructing preclinical monitoring algorithms, one should also take into consideration the diseases suffered by patients' relatives. One of the cornerstones in preventive and predictive medicine is screening for genetic abnormalities or hereditary predisposition. All-encompassing analysis of gene units and construction of individual genetic maps not only facilitate the assessment of individual risks for each concrete patient, but also allows prediction of disease development in first-degree-relatives. Therefore, today's objective demands include not only large-scale monitoring of definite cohorts of the general population, but, rather, identification of high risk cohorts coupled with genetic abnormalities and/or shifts and social factors (residence, place of employment, occupation, living conditions, etc.). However, even a comprehensive analysis is inadequate without a set

necessity to solve fundamental problems in order to understand:

 Who should be selected for examination? What exactly needs to be checked?

When should the examination be performed?

**1. Introduction** 

 Sevindzh Gadzhieva1 and Mikhail Paltsev3 *1I.M. Sechenov First Moscow State Medical University 2Moscow State Medical Dentistry University, National* 

*3Research Center "Kurchatov Institute"* 

Zhou, D., Srivastava, R., Nessler, S., Grummel, V., Sommer, N., Bruck, W., Hartung, H.P., Stadelmann, C., and Hemmer, B. (2006). Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. *Proceedings of the National Academy of Sciences of the United States of America*, 103, 50, Dec 12, 19057-19062.
