Viability of autoantibody-targets: how to tackle pathogenetic heterogeneity as an obstacle for treatment of multiple sclerosis.
ABSTRACT The growing complexity number of multiple sclerosis (MS) therapy emphasizes the need for an individualized approach, tailoring therapy to the needs of the individual patient. There is evidence supporting the immunopathological heterogeneity of MS, based on the analysis of biopsy and autopsy tissues. In clinical practice it is impossible to differentiate between the pathological subtypes of MS, because blood or CSF markers of pathological heterogeneity are lacking. Identification of such markers would be important, because "tailored therapy" and "biomarkers for patient stratification" may be considered as two sides of the same coin. In this article, we discuss the emerging role of autoantibodies as potential biomarkers, focusing on myelin oligodendrocyte glycoprotein (MOG) as one of the best characterized autoantigens in MS. In addition, we discuss several strategies for the identification of novel candidate autoantigens.
- SourceAvailable from: Vaibhav Singh[Show abstract] [Hide abstract]
ABSTRACT: B lymphocytes play a pivotal role in multiple sclerosis pathology, possibly via both antibody dependent and independent pathways. Intrathecal immunoglobulin G production in multiple sclerosis is produced by clonally expanded B cell populations. Recent studies indicate that the complementarity determining regions of immunoglobulins specific for certain antigens are frequently shared between different individuals. In this study, our main objective was to identify specific proteomic profiles of mutated complementarity determining regions of immunoglobulin G present in multiple sclerosis patients but absent in healthy controls. To achieve the above objective, from cerebrospinal fluid of 29 multiple sclerosis patients and 30 healthy controls we purified immunoglobulin G and separated the corresponding heavy and light chains by SDS - PAGE. Subsequently, bands were excised, trypsinized and measured with high - resolution mass spectrometry. We sequenced 841 heavy and 771 light chain variable region peptides. We observed 24 heavy and 26 light chain complementarity determining regions that were solely present in a number of multiple sclerosis individuals. Using stringent criteria for the identification of common peptides, we found five complementarity determining regions shared in three or more patients and not in controls. Interestingly, one complementarity determining region with a single mutation was found to be in common in six patients. Additionally, one other patient carrying a similar complementarity determining region with another mutation was observed. In addition, we found a skew in kappa to lambda ratio and in the usage of certain variable heavy region which was previously being observed at the transcriptome level. At the protein level, cerebrospinal fluid immunoglobulin G share common characteristics in the antigen binding region between different multiple sclerosis patients. The indication of a shared fingerprint may indicate common antigens for B cell activation.Molecular & Cellular Proteomics 08/2013; · 7.25 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease.Clinical Immunology 03/2014; · 3.77 Impact Factor