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Background: Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species., Methods: The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared., Results: Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG-. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG- children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration., Conclusions: Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.

We have previously identified eight novel autoantibody targets in the cerebrospinal fluid of multiple sclerosis (MS) patients, including sperm-associated Ag 16 (SPAG16). In the current study, we further investigated the autoantibody response against SPAG16-a protein with unknown function in the CNS-and its expression in MS pathology. Using isoelectric focusing, we detected SPAG16-specific oligoclonal bands in the cerebrospinal fluid of 5 of 23 MS patients (22%). Analysis of the anti-SPAG16 Ab reactivity in the plasma of a total of 531 donors using ELISA demonstrated significantly elevated anti-SPAG16 Ab levels (p = 0.002) in 32 of 153 MS patients (21%) compared with all other control groups with 95% specificity for the disease. To investigate the pathologic relevance of anti-SPAG16 Abs in vivo, anti-SPAG16 Abs were injected in mice with experimental autoimmune encephalomyelitis, resulting in a significant disease exacerbation. Finally, we demonstrated a consistent upregulation of SPAG16 in MS brain and experimental autoimmune encephalomyelitis spinal cord lesions, more specifically in reactive astrocytes. We conclude that SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. Furthermore, the pathologic relevance of anti-SPAG16 Abs was shown in vivo., (Copyright © 2014 by The American Association of Immunologists, Inc.)

To investigate whether AQP4 autoantibodies (AQP4-Ab) are causative for neuromyelitis optica (NMO), the production of AQP4-Ab and clinical experimental autoimmune encephalomyelitis (EAE) was investigated in mice administered with mouse AQP4 antigen or myelin oligodendrocyte glycoprotein (MOG35-55) alone, and in combination. Eight- to twelve-week-old female C57BL/6 mice were randomly immunized with encephalitogenic mixture containing 300 μg of MOG35-55 or AQP4 antigen alone, and in combination in complete Freund's adjuvant supplemented with H37Ra M. tuberculosis. The incidence of EAE, Weaver 15 scores, and body weight was evaluated. ELISA was used to detect serum mouse AQP4-Ab. Mice injected with MOG35-55 and MOG33-35 plus AQP4 antigen began to show EAE symptoms 12 days after immunization. The incidence of EAE was 91.6%, and 62.5%, for MOG35-55 alone and MOG33-35 plus AQP4 antigen groups, respectively, while AQP4 antigen alone didn't develop EAE. In all but the control group, serum AQP4-Ab levels were increased, and correlated positively with Weaver 15 score (rs=0.713, p=0.000) and negatively with body weight changes (rs=-0.415, p=0.011). Injection of human NMO sera positive for AQP4-Ab exacerbated MOG-induced EAE. Our results suggest that AQP4-Ab can be produced in MOG-induced MS model, and itself is not sufficient for the development of EAE, implying that NMO might be a subtype or transition from MS., (Published by Elsevier B.V.)

It is important to find biomarkers for autoimmune inflammation and demyelination in the CNS to monitor disease status in patients with multiple sclerosis (MS). For this purpose, we determined the titers of antibodies (Ab) reacting with native myelin oligodendrocyte glycoprotein (MOG)-expressing cells to evaluate the disease activity of chronic experimental autoimmune encephalomyelitis (EAE) in rats and the relationship between anti-MOGcme (cell membrane-expressed MOG), Ab titers and clinical and pathological parameters were evaluated. Consequently, we found that elevation of anti-MOGcme Ab titers was associated with clinical severity, except for some cases in very late stages and with severe and widespread demyelination but with dominant inflammation. In contrast, antibodies detected by standard ELISA using recombinant MOG were elevated in both symptomatic and asymptomatic rats and were not associated with parameters such as inflammation and demyelination. Longitudinal examination of anti-MOGcme Ab titers in individual rats revealed that Ab titers accurately reflect disease activity. Furthermore, anti-MOGcme Ab titer was not elevated in acute EAE without demyelination. These findings suggest that autoantibodies reacting with native and glycosylated MOG play an important role in the progression of demyelinating diseases and could be biomarkers for monitoring the status of patients with MS., (© 2010 Japanese Society of Neuropathology.)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. The numbers of autoimmune T cells and Abs specific for proteins of CNS myelin are increased in the blood in some patients with MS. The aim of this study was to investigate whether there are correlations between the specificity of the autoimmune responses in the blood, the HLA molecules carried by the patient, and the clinical features of MS, because studies on experimental autoimmune encephalomyelitis, an animal model of MS, indicate that autoimmune responses targeting particular myelin proteins and the genetic background of the animal play a role in determining the pattern of lesion distribution. We tested blood T cell immunoreactivity to myelin proteins in 100 MS patients, 70 healthy controls, and 48 patients with other neurological disorders. Forty MS patients had strongly increased T cell reactivity to one or more myelin Ags. In these 40 patients, the most robust correlation was between CD4(+) T cell reactivity to myelin proteolipid protein residues 184-209 (PLP(184-209)) and development of lesions in the brainstem and cerebellum. Furthermore, carriage of HLA-DR4, -DR7, or -DR13 molecules by MS patients correlated with increased blood T cell immunoreactivity to PLP(184-209), as well as the development of lesions in the brainstem and cerebellum. Levels of PLP(190-209)-specific Abs in the blood also correlated with the presence of cerebellar lesions. These findings show that circulating T cells and Abs reactive against specific myelin Ags can correlate with lesion distribution in MS and suggest that they are of pathogenic relevance.

The authors used a liquid-phase radiobinding assay to measure serum anti-myelin oligodendrocyte protein (MOG) immunoglobulin (Ig) G in 87 patients with multiple sclerosis (MS), in 12 patients with encephalomyelitis, and in 47 healthy subjects. Anti-MOG IgM was determined in samples obtained at onset from 40 of 87 patients with MS and in control subjects. The frequency of positive samples with low titers of anti-MOG IgG (< or =5.7%) and IgM (< or =8.3%) was similar in all the groups and subgroups. Binding competition experiments showed that these antibodies had low affinity. Anti-MOG antibodies are not disease specific.

Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO-related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S-nitrosocysteine (SNO-cysteine) and showed that anti-NO-cysteine Abs of the IgM isotype are in fact present in the sera of some MS patients (Boullerne et al., 1995). We report here the presence of a seemingly identical Ab response directed against SNO-cysteine in an acute model of MS, experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with the 68-84 peptide of guinea pig myelin basic protein (MBP(68-84)). Serum levels of anti-SNO-cysteine Abs peaked 1 week before the onset of clinical signs and well before the appearance of anti-MBP(68-84) Abs. The anti-SNO-cysteine Ab peak titer correlated with the extent of subsequent CNS demyelination, suggesting a link between Ab level and CNS lesion formation. In relapsing-remitting MS patients, we found elevated anti-SNO-cysteine Ab at times of relapse and normal values in most patients judged to be in remission. Two-thirds of patients with secondary progressive MS had elevated anti-SNO-cysteine Ab levels, including those receiving interferon beta-1b. The data show that a rise in circulating anti-SNO-cysteine Ab levels precedes onset of EAE. Anti-SNO-cysteine Abs are also elevated at times of MS attacks and in progressive disease, suggesting a possible role for these Abs, measurable in blood, as a biological marker for clinical activity.

T cell vaccination, the application of syngeneic attenuated T cells, has been shown to prevent effectively and treat experimental autoimmune diseases, but its mechanisms of action are poorly understood. Here we present data on the induction of a humoral anti-T cell response by T cell vaccination, capable of strongly inhibiting T cell proliferation and of ameliorating experimental autoimmune disease. T cell vaccination in the Lewis rat induced autoantibodies reactive with several syngeneic T cell proteins. These autoantibodies were not detectable in normal Lewis sera as assessed by immunoblotting and flow cytometry with intact syngeneic T cells. The autoantibody reactivity was not restricted to one idiotype, was detected as early as 1 week after vaccination and was dominated by IgG, suggesting the boosting of a naturally preformed humoral network by T cell vaccination. Recovery from passively or actively induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat, too, could be shown to be associated with the development of anti-T cell autoantibodies. In vitro, both the post-EAE and the post-vaccination sera had a strong suppressive effect on the proliferation of syngeneic T cell clones. This inhibition was shown to be mediated by antibodies and to be partly complement-dependent. In vivo, both kinds of sera were able to ameliorate EAE. This protective effect of the post-vaccination sera was not idiotype-specific, since sera obtained after T cell vaccination with an unrelated T cell clone were similarly effective in suppressing EAE. These results suggest that anti-lymphocytic antibodies might play an immunoregulatory role that can be positively manipulated by T cell vaccination.

Immunological parameters in rhesus monkeys, resistant and susceptible to experimental allergic encephalomyelitis (EAE), were studied. Monkeys immunized with complete Freund's adjuvant (CFA) alone and EAE resistant monkeys immunized with a low dose of bovine brain homogenate emulsified in CFA did not show significant fluctuations in numbers of granulocytes, lymphocytes and lymphocyte subsets (CD4; CD8; GM13, a subset of CD8) and anti-brain homogenate antibody titres remained low. EAE susceptible monkeys immunized with a high dose of myelin developed EAE significantly faster than monkeys immunized with a low dose of brain homogenate. During the induction phase all EAE susceptible monkeys, in contrast to the CFA controls and EAE resistant monkeys, showed an increase in the numbers of granulocytes and the CD4/CD8 ratios and had high antibody titres specific for the immunizing antigens. The most significant disease-related changes were observed after the onset of clinical signs. These included a granulocytosis, a lymphopenia and a decrease in the CD4/CD8 ratio, indicating a selective loss of CD4+ lymphocytes. A major difference between monkeys immunized with myelin and brain homogenate was the significant increase in the percentage of GM13+ lymphocytes after the onset of clinical signs in the latter group. Increases in the CD4/CD8 ratio and antibody titres during the induction phase may be prognostic factors for the subsequent development of EAE.

Titers of serum antibodies to myelin basic protein, cerebroside and ganglioside were determined in chronic relapsing experimental allergic encephalomyelitis in strain 13 guinea pigs at various intervals after inoculation with whole central nervous system (CNS) tissue. Levels of antibodies to cerebroside and ganglioside were higher in the animals with paralysis than those without paralysis during the early chronic stage. In the late chronic stage, these antibodies were still at high levels, but none of the levels correlated with clinical activity. Levels of antibody to cerebroside were significantly related to the amount of demyelination. The humoral response to the CNS antigens was monophasic, although the clinical course was polyphasic. Another factor seems to be required for clinical relapses in this animal model.

The myelin/oligodendrocyte glycoprotein (MOG) is a target antigen for autoantibody-mediated demyelination in chronic relapsing experimental allergic encephalomyelitis (CREAE) in the Strain 13 guinea pig. Anti-idiotypic antibodies directed against a demyelinating MOG-specific monoclonal antibody (8-18C5) have identified a cross-reactive idiotype in 10/10 CREAE sera. In nine of these sera inhibition studies demonstrated that this idiotype was at or in close proximity to the combination site of guinea pig anti-MOG autoantibodies. This cross-reactive anti-MOG idiotype may represent an important target for the anti-idiotypic regulation of demyelinating antibody responses in CREAE.