Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP (original) (raw)
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A rapid ELISA-based serum assay for myelin basic protein in multiple sclerosis
Journal of Immunological Methods, 2002
We have developed a sensitive, ELISA-based assay to detect autoantibodies to myelin basic protein (MBP) in human serum. Autoantibody levels were measured in 98 normal healthy adults (age range 20-66) and 94 clinically definite multiple sclerosis (MS) cases (age range 18-63). Of the MS patients, 77% had elevated levels of MBP autoantibodies (IgG) whereas only five normal individuals had antibody levels increased over normal. From the receiver-operator curve (ROC), the mean ± 2SD as clinical decision limit offers high sensitivity (77%) and specificity (95%). No change in assay performance was observed when hemoglobin, triglycerides or bilirubin were added to serum samples. The success of the assay is dependent on the use of heparin, an anionic molecule, which neutralizes the positive charge on the highly cationic MBP.
Journal of Neuroimmunology, 1994
Irrespective of the large body of literature on the putative role of antibodies in the development of multiple sclerosis (MS), the detection of specific antibody-forming B cells (AFCs) in the central nervous system (CNS) tissues has not been described. In this study we show that autoantigen-specific AFCs can be found in CNS tissue sections of MS patients. Applying a newly developed myelin basic protein (MBP)-enzyme conjugate technique, we have detected MBP-specific AFCs in autopsy periventricular white matter and cerebellum tissue sections of MS patients. We demonstrated the presence of MBP-specific AFCs in CNS tissue sections in five out of 12 MS patients. No MBP-specific AFCs were detected in CNS tissue sections of 11 patients with other neurological diseases, such as Parkinson's and Alzheimer's disease, or in brain tissue sections of eight deceased persons without neurological diseases. In MS patients, anti-MBP AFCs were present in brain tissue sections both with and without plaques. The proportion of MBP-specific AFCs in some of the MS patient brain tissues reached over 50% of all AFCs. The high relative frequency of the anti-MBP AFCs and their localization in periventricular white matter and cerebellum of MS patients only, suggests that anti-MBP AFCs represent a cell population, which could play an important role in MS immunopathology.
Autoantibodies to Non-myelin Antigens as Contributors to the Pathogenesis of Multiple Sclerosis
Journal of clinical & cellular immunology, 2013
For years, investigators have sought to prove that myelin antigens are the primary targets of autoimmunity in multiple sclerosis (MS). Recent experiments have begun to challenge this assumption, particularly when studying the neurodegenerative phase of MS. T-lymphocyte responses to myelin antigens have been extensively studied, and are likely early contributors to the pathogenesis of MS. Antibodies to myelin antigens have a much more inconstant association with the pathogenesis of MS. Recent studies indicate that antibodies to non-myelin antigens such as neurofilaments, neurofascin, RNA binding proteins and potassium channels may contribute to the pathogenesis of MS. The purpose of this review is to analyze recent studies that examine the role that autoantibodies to non-myelin antigens might play in the pathogenesis of MS.
International Immunology, 2009
MBP-specific autoreactive T cells are considered pro-inflammatory T cells and thought to play an important role in the pathogenesis of multiple sclerosis (MS). Here, we report that MBP 83-99-specific T cells generated from MS patients (n 5 7) were comprised of pro-inflammatory and regulatory subsets of distinct phenotypes. The pro-inflammatory phenotype was characterized by high production of IFN-g, IL-6, IL-21 and IL-17 and low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and exhibited potent regulatory functions. The regulatory subset of MBP-specific T cells appeared to expand from the CD4 1 CD25 2 T-cell pool. Their FOXP3 expression was stable, independent of the activation state and it correlated with suppressive function and inversely with the production of IFN-g, IL-6, IL-21 and IL-17. In contrast, the phenotype and function of FOXP3 low MBP-specific T cells were adaptive and dependent on IL-6. The higher frequency of FOXP3 high MBP-specific T cells was observed when IL-6 was neutralized in the culture of PBMC with MBP. The study provides new evidence that MBP-specific T cells are susceptible to pro-inflammatory cytokine milieu and act as either pro-inflammatory or regulatory T cells.
Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis
The Journal of Immunology, 2004
Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8 ؉ T cell responses and their functional properties in patients with MS. There were significantly increased CD8 ؉ T cell responses to 9-mer MBP peptides, in particular MBP 111-119 and MBP 87-95 peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8 ؉ T cell lines were of the Th1 phenotype, producing TNF-␣ and IFN-␥ and belonged to a CD45RA ؊ /CD45RO ؉ memory T cell subset. Further characterization indicated that the CD8 ؉ T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP 111-119) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8 ؉ T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8 ؉ CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.
PLoS ONE, 2014
It was found that antibodies (Abs) against myelin basic protein (MBP) are the major components of the antibody response in multiple sclerosis (MS) patients. We have recently shown that IgGs from sera of MS patients are active in the hydrolysis of MBP. However, in literature there are no available data concerning possible MBP-hydrolyzing Abs in cerebrospinal fluid (CSF) of MS patients. We have shown that the average content of IgGs in their sera is about 195-fold higher than that in their CSF. Here we have compared, for the first time, the average content of lambda-and kappa-IgGs as well as IgGs of four different subclasses (IgG1-IgG4) in CSF and sera of MS patients. The average relative content of lambda-IgGs and kappa -IgGs in the case of CSFs (8.0 and 92.0%) and sera (12.3 and 87.7%) are comparable, while IgG1, IgG2, IgG3, and IgG4: CSF -40.4, 49.0, 8.2, and 2.5% of total IgGs, respectively and the sera -53.6, 36.0, 5.6, and 4.8%, decreased in different order. Electrophoretically and immunologically homogeneous IgGs were obtained by sequential affinity chromatography of the CSF proteins on protein G-Sepharose and FPLC gel filtration. We present first evidence showing that IgGs from CSF efficiently hydrolyze MBP and that their average specific catalytic activity is unpredictably ,54-fold higher than that of Abs from sera of the same MS patients. Some possible reasons of these findings are discussed. We suggest that anti-MBP abzymes of CSF may promote important neuropathologic mechanisms in this chronic inflammatory disorder and in MS pathogenesis development. Citation: Doronin VB, Parkhomenko TA, Castellazzi M, Padroni M, Pastore M, et al. (2014) Comparison of Antibodies Hydrolyzing Myelin Basic Protein from the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis. PLoS ONE 9(9): e107807.
Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis
Journal of the Neurological Sciences, 2003
An autoimmune response to one or more myelin-protein components is thought to be part of the pathogenesis of multiple sclerosis (MS). The immunodominant-autoantibody epitope may be localized on a linear peptide segment, on a conformation-sensitive epitope, or on an epitope resulting from post-translational modifications. Primary, secondary, and tertiary structures of myelin proteins may determine the specific site for binding of autoantibodies. A myelin protein-specific autoantibody can bind to either a linear or conformational epitope, whereas all of the T cell epitopes are linear. At present, the conformational epitopes of myelin proteins have not been identified; most of the methods used to identify the myelin-protein epitopes corresponding to the pathogenesis of multiple sclerosis are involved in the linear epitope mapping. Polymorphism or mutations may cause inappropriate expression of the myelin proteins with alterations to their linear and/or conformational epitopes, and make them susceptible to autoantibody binding, especially if these changes occur at the surface of the protein. This review focuses on the specificity of autoantibodies to the epitopes of myelin proteins and correlates this to the structures of proteins. Factors that influence the expression of myelin-protein epitopes such as the a-helical or h-sheet structure of the protein, the tri-proline site, and the post-translational modifications as well as physicochemical properties of amino acid changed are included.
CSF myelin basic protein in multiple sclerosis
Acta Neurologica Scandinavica, 2009
Cerebrospinal fluid (CSF) from 221 patients with multiple sclerosis (MS) and 85 patients with other neurological disorders (OND) was examined using a competitive radioimmunoassay for myelin basic protein (MBP) immunoreactivity. MBP was found in 46 of 55 MS patients (84%) examined within six weeks of relapse but in only 11 of 85 patients (13%) with OND. There was a significant correlation between the concentration of MBP in the CSF and relapse severity in patients seen within four weeks of the onset of symptoms (p < 0.01). Of 44 patients in remission, MBP was detected in 12, and these patients had a significantly higher tendency to subsequent relapse (p < 0.05). In 72 patients with progressive disease the presence of MBP in the CSF reflected the confidence of clinical diagnosis.