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Background: Transglutaminase-6 (TGM6), a member of the transglutaminase enzyme family, is found predominantly in central nervous system (CNS) neurons under physiological conditions. It has been proposed as an autoimmune target in cerebral palsy, gluten-sensitive cerebellar ataxia, and schizophrenia., Objective: To investigate TGM6 involvement in multiple sclerosis (MS)., Methods: Antibody levels against TGM6 (TGM6-IgG) were measured in the cerebrospinal fluid (CSF) of 62 primary progressive multiple sclerosis (PPMS), 85 secondary progressive multiple sclerosis (SPMS), and 50 relapsing-remitting multiple sclerosis (RRMS) patients and 51 controls. TGM6 protein expression was analyzed in MS brain autopsy, murine experimental autoimmune encephalomyelitis (EAE), and cultured astrocytes., Results: CSF levels of TGM6-IgG were significantly higher in PPMS and SPMS compared to RRMS and controls. Notably, patients with clinically active disease had the highest TGM6-IgG levels. Additionally, brain pathology revealed strong TGM6 expression by reactive astrocytes within MS plaques. In EAE, TGM6 expression in the spinal cord correlated with disease course and localized in reactive astrocytes infiltrating white matter lesions. Finally, knocking down TGM6 expression in cultured reactive astrocytes reduced their glial fibrillary acidic protein (GFAP) expression., Conclusion: TGM6-IgG may be a candidate CSF biomarker to predict and monitor disease activity in progressive MS patients. Furthermore, TGM6 expression by reactive astrocytes within both human and mouse lesions suggests its involvement in the mechanisms of glial scar formation.

Progressive multifocal leukoencephalopathy (PML) is a complication of natalizumab treatment. In order to identify natalizumab-treated patients at risk of developing PML, we assayed for anti-JC virus (JCV) antibody levels in cerebrospinal fluid (CSF). Serial CSF antibody levels were obtained, with 4 patients showing increases in anti-JCV levels indicating possibly viral activation. In patients with both CSF and serum antibody levels, a comparison showed only a moderate Spearman Rank Correlation Coefficient of 0.38. Our data suggests that serum anti-JCV antibody testing alone may not suffice in identifying at-risk patients because of the lack of uniform correlation with CSF titers., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We compared the binding of human antibodies from patients with neuropathy to the myelin-associated glycoprotein (MAG), to its cross-reactive glycolipid sulfoglucuronyl paragloboside (SGPG), and to sections of peripheral nerve. Titers were correlated with the clinical presentation and results of electrophysiological and pathological studies. Most patients had a predominantly sensory or sensorimotor demyelinating neuropathy and highly elevated antibodies to both MAG and SGPG, but 2 had highly elevated antibodies to MAG alone, and 1 to SGPG alone. Two patients had predominantly motor neuropathy and highly elevated antibodies to SGPG which reacted with MAG by Western blot but not by enzyme-linked immunosorbent assay. One patient had amyotrophic lateral sclerosis and antibodies to SGPG but not to MAG. These studies indicate that the neuropathic syndrome associated with anti-MAG or -SGPG antibodies are more heterogeneous than previously suspected, and that although most of the antibodies react with both MAG and SGPG, some may react with MAG or SGPG alone.

Anti-GM1 antibodies were measured in 22 patients with the Guillain-Barré syndrome (GBS) and compared with anti-GM1 antibody activity in patients with other neurological or immunological diseases and in normal subjects. Four out of 22 patients with GBS had raised IgM, IgG, or IgA anti-GM1 antibody activities. All four patients were tetraparetic with only minimal or no sensory deficit. Three of the patients had highly raised antibody activity and showed severe residual deficits, while of the remaining patients with GBS, only one remained severely affected. One patient had anti-GM1 antibodies specific for GM1, whereas the other three patients showed antibody activity with asialo-GM1 or GD1b. The presence of anti-GM1 antibodies may define a subgroup of patients with GBS who have a poor prognosis.

We compared anti-GM1 IgM antibody titers in patients with various neurologic diseases and in normal subjects. We found increased titers in patients with lower motor neuron disease, sensorimotor neuropathy, or motor neuropathy with or without multifocal conduction block. In patients with other diseases, titers are similar to those in normal individuals, suggesting that anti-GM1 antibody levels are not increased nonspecifically after neural injury or inflammatory diseases. Anti-GM1 antibodies in many of the patients occur as monoclonal gammopathies, predominantly of lambda light-chain type, but the antibodies are sometimes polyclonal with normal or increased serum IgM concentrations. Most of the anti-GM1 antibodies appear to react with the Gal(beta 1-3)GalNAc epitope which is shared with asialo-GM1 and GD1b, but in some patients the antibodies are more specific for GM1 and associated with motor neuropathy. Patients with motor or sensorimotor peripheral neuropathy or lower motor neuron disease should be tested for anti-GM1 antibodies or anti-Gal(beta 1-3)GalNAc antibodies, as therapeutic reduction in antibody concentrations was reported to result in clinical improvement in some patients.

An IgM monoclonal autoantibody (M-protein) with anti-Gal(beta 1-3)GalNAc activity from a patient with lower motor neuron disease bound to the surface of motoneurons isolated from bovine spinal cord. The Gal(beta 1-3)GalNAc epitope is shared by the gangliosides GM1 and GD1b and by several glycoproteins in the nervous system, and binding was abolished by preabsorbing the patient's serum with GM1. Antibodies specific for GM1, however, which do not bind to GaL(beta 1-3)GalNAc, did not bind to the motoneurons. This suggests that Gal(beta 1-3)GalNAc bearing glycoproteins or glycolipids other than GM1 are expressed on the surface of motoneurons, while GM1 may be absent or shielded, and that antibody binding to the cell surface might contribute to the development of the motor neuron disease.