Cells producing antibodies specific for myelin basic protein region 70–89 are predominant in cerebrospinal fluid from patients with multiple sclerosis

Abstract

Cells secreting antibodies against guinea pig myelin and synthetic myelin basic protein (MBP) peptides were evaluated in cerebrospinal fluid (CSF) and blood from patients with multiple sclerosis (MS) and a variety of other neurological diseases (OND). The peptides used, reproducing amino acid sequences 1-20, 70-89, 108-126, or 157-166 of MBP, were selected on the basis of their hydrophilic and encephalitogenic properties. Low numbers of cells secreting IgG antibodies against myelin or each of the MBP peptides (about 1 per 50,000) were detected in peripheral blood, with no difference between MS and OND. In CSF, cells secreting IgG antibodies to MBP 70-89 were more frequently (p = 0.007) detected in patients with MS (1/380 IgG-secreting cells on average) than in patients with OND (1/2083 IgG-secreting cells on average). The frequencies of cells secreting antibodies against myelin or the three other MBP peptides were similar in MS and OND. Thus, evaluation of B cell immunity at the cellular level indicates that MBP 70-89 is an immunodominant B cell epitope in MS. It is not clear whether this intrathecal anti-MBP 70-89 IgG antibody response has any pathogenetic relevance in MS or is the result of myelin breakdown.

Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope

“…The T and B cells found in the CNS of MS patients show consistent specificity for this minimal epitope, and antibodies against it are found in both the brain and spinal fluid of MS patients, indicating both humoral and cellular immune responses in disease pathogenesis (34,35). Detailed requirements for the binding of this epitope to HLA class II molecules and autoimmune T cell receptor (TCR) were provided by the x-ray crystallographic analysis of this peptide complexed with the two MHC class II isotypes, HLADRa and HLA-DRb, and TCR (36,37).…”

Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS

“…Of the ten Fabs that were generated for this study from clonally expanded CSF B cells of three patients diagnosed with RRMS, nine of them were reactive to MBP in these three different screening approaches, although to varying degrees (summarized in Table 3). We had predicted that at least some of the clonally expanding B cells from the CSF of MS patients would be reactive to MBP, given the large body of established data indicating that MBP is a central candidate antigen in the pathogenesis of MS. For example, anti-MBP antibodies can be readily detected in the spinal fluid and brain tissues of MS patients (Martino et al, 1991) at higher concentrations than what is observed in healthy donors and patients with other neurological diseases. Furthermore, anti-MBP antibodies (and anti-PLP antibodies) can be detected in areas of myelin damage within lesion sites of MS patients (Wucherpfennig et al, 1997).…”

Genetic and Molecular Approaches to the Immunopathogenesis of Multiple Sclerosis: An Update

“…Two of the rFabs that recognized MBP did also recognize 2', 3'-cyclic nucleotide 3'-phosphodiesterase and glial fibrillary acidic protein, compatible with polyreactivity of these rFabs. Although low affinity anti-MBP antibodies as well as B cells producing antibodies against MBP peptides are present in the CSF of MS patients [255,256], the finding that the majority of Fabs recovered from CSF B cells recognize MBP was unexpected and was recently not reproduced [257].…”