Identification of peptides specific for cerebrospinal fluid antibodies in multiple sclerosis by using phage libraries.

Abstract

The study of the origin and pathogenetic relevance of the oligoclonal antibodies present in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients has been hampered by a lack of specific ligands. We recently reported a general strategy, based on phage-displayed random peptide libraries, to identify ligands for disease-specific antibodies even in the absence of any information on the nature of the pathologic antigen. With this procedure, we identified several peptides specifically recognized by antibodies present in the CSF of MS patients. Using these peptides as reagents, we demonstrated that they mimic different natural epitopes and react with antibodies enriched in the CSF of MS patients.Antibodies recognizing the selected peptides are commonly found with equal frequency in the sera of MS patients and of normal individuals. In contrast, the repertoire of CSF antibodies appears to be individual-specific and is probably the result of a nonspecific immunodysregulation rather than a stereotyped response to a single antigen/agent. (2-6). The IgG patterns differ from one patient to another but remain fairly constant in each individual during the course of the disease (7-10) and do not appear to be affected by treatment with immunomodulatory drugs (11). These data seem to imply a specific immune response, developed within the CNS, against persistent epitopes.OB antibodies can also be found in other inflammatory neurological diseases such as tuberculous meningitis, neurosyphilis, progressive rubella panencephalitis, subacute sclerosing panencephalitis, and others (8,(12)(13)(14)(15)(16). In these pathologies, the majority of the oligoclonal IgG has been found to recognize the etiologic agent (17), whereas for MS there is no general consensus on the nature of the antigens that react with the oligoclonal antibodies present in the CSF (18-21). The failure to identify the natural antigens binding to the OB antibodies has brought the study of their origin and pathological relevance to a standstill.Over the last few years, random peptide libraries (RPLs) displayed on phage have been used as a source of ligands to antibodies and receptors. These ligands are not necessarily identical or even similar to the natural ones, but mimic their binding properties. RPLs have been extensively used to select peptides mimicking linear epitopes or folded protein domains, and even nonproteinaceous molecules (22-24). Since the binding properties of the selected peptides to antibodies are usually determined when they are displayed on the phage particle, we have introduced the term phagotope to refer to this special type of phage displayed epitope.Using a pool of sera from rheumatoid arthritis (RA) patients, Dybwad et al. (25) have been able to identify phagotopes displaying a higher frequency of reactivity with antibodies present in RA sera than in normal control sera. Recently, we have developed a novel and general strategy to identify phagotopes that bind to disease-specific antibodies present in the serum of patients th...

Screening Random Peptide Libraries with Subacute Sclerosing PanencephalitisBrain-Derived Recombinant Antibodies Identifies Multiple Epitopes in the C-Terminal Region of the Measles Virus Nucleocapsid Protein

“…Identifying the antigenic specificities of MS oligoclonal IgG has been problematic, and the use of random peptide screening as a tool for antigen identification in MS is not novel. Panning of libraries with MS CSF in these earlier studies enriched several peptide sequences (7,8). However, none of the selected peptides reacted universally and specifically with MS CSF and reactivity was also found in serum from a subset of MS patients and healthy controls.…”

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

“…Approaches involving phage display and expression libraries were used to dissect the IgG antibody specificity in the CSF (22)(23)(24)(25). These studies identified possible target peptides in single patients.…”

A comparative study of antibody expressions in primary biliary cirrhosis and autoimmune cholangitis using phage display

“…Thus, phage display could provide a means of discerning traces of an earlier etiologic agent that could have initiated an ongoing autoimmune disease. Disease-associated motifs have been sought by phage display in various autoimmune diseases, multiple sclerosis, 41 rheumatoid arthritis, 42 diabetes mellitus, 43 and idiopathic thrombocytopenic purpura. 44 However, these studies have used smaller numbers of patients, or pooled IgG, and although disease-associated motifs have been discerned, in no instance so far has the motif identified a response to a cryptic agent.…”