Several immunological studies have shown that antibodies in mammals not only perform a receptor function by binding to foreign antigens and activating the immune response, but also exhibit catalytic activity, so called “abzymes”. Abzymes are found mainly in the blood serum of patients with autoimmune diseases and hydrolyse nucleic acids, polysaccharides, oligopeptides, and proteins. Recently, significant changes in the immune system have been observed in schizophrenia patients. Moreover, a number of abzymes from the blood stream of schizophrenia patients exhibited catalase activity, superoxide dismutase activity, nuclease activity, and proteolytic activity to myelin basic protein (MBP), histones, and collagen. However, the unambiguous pathogenic role and structural features that provide the catalytic properties of antibodies have remained unknown. In this study, common peptide sets of immunoglobulin G (IgG) that exhibit high proteolytic activity against MBP were investigated. Compared with healthy individuals, 12 sequences from the antibodies that hydrolyse MBP were identified in the blood serum of patients with acute schizophrenia. Among these 12 sequences, two sequences from the variable regions of the heavy chain, FQ(+0.98)GWVTMTR and LYLQMN(+0.98)SLR, showed an increase in proteolytic activity to MBP with increasing concentration. Collectively, the study provided insights into the mechanism of the catalytic properties of IgG molecules in schizophrenia patients.
How was PEAKS used?
IgGs were isolated from the blood serum of eight patients with schizophrenia and six healthy individuals, and mass spectrometry data of the tryptic peptides of IgGs were collected in both data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes. DIA data were searched against a sequence library composed of sequences of IgG light and heavy chains from the GenBank database in PEAKS Studio. A precursor mass tolerance of 5 ppm and a fragment mass tolerance of 0.01 Da were applied. A fixed modification of carbamidomethylation (C) and variable modifications of deamidation (NQ) and oxidation (M) were added. The predicted de novo sequences were compared using BLAST with human protein sequences from the UniProtKB database to determine whether they belong to class G immunoglobulins. Refined sequence variants were manually validated.
Zavialova, Maria, et al. “Some structural features of the peptide profile of myelin basic protein-hydrolyzing antibodies in schizophrenic patients.” PeerJ 11 (2023): e15584. https://doi.org/10.7717/peerj.15584
Abstract
The antibodies of schizophrenic patients that hydrolyze myelin basic protein (MBP) have been actively studied recently, but the mechanism of the catalytic properties of immunoglobulin molecules remains unknown. Determination of specific immunoglobulin sequences associated with the high activity of MBP proteolysis will help to understand the mechanisms of abzyme catalysis. In the course of comparative mass spectrometric analysis of IgG peptides from the blood serum of patients with acute schizophrenia and healthy people, 12 sequences were identified, which were found only in antibodies that hydrolyze MBP. These sequences belong to IgG heavy chains and κ– and λ-type light chains, with eight of them belonging to variable domains. The content of peptides from the variable regions of the light chains does not correlate with the proteolytic activity of IgG to MBP in patients with schizophrenia, whereas for two sequences from the variable regions of the heavy chains (FQ(+0.98)GWVTMTR and *LYLQMN(+0.98)SLR), an increase in activity with increasing their concentration. The results suggest that these sequences may be involved in one way or another in MBP hydrolysis.