Among post-translational modifications, glycosylation is the only one that requires structural characterization of the modifying moiety beyond noting its presence. It is well known that over 50% of all mammalian serum proteins and about 80% of cell membrane proteins are glycosylated and that glycans play crucial roles in various biological events. Glycans of glycoproteins, which are displayed on cell surface membranes, are structurally changed during carcinogenesis and rheumatism. Glycosylation can alter the charge, conformation and stability of proteins and induce heterogeneous profiles as a consequence of the production of variable glycoforms.
The oligosaccharide variants on glycoproteins (glycoforms) can lead to alterations in protein folding, stability, trafficking and immunogenicity, as well as modification of the protein's primary functional activity. Phosphorylation and glycosylation are the most common post translational modifications, which are topologically restricted from each other. Phosphorylation occurs in cytoplasm and nucleus of the cells and involves the reversible addition of phosphate molecules. On the other hand, glycosylation is mostly confined to the secretory pathway, involves the addition and removal of different monosaccharide linkages (termed glycans) to proteins and lipids that are bound to the cell surface and extracellular compartments. Although glycans are the most abundant and diverse of nature's biopolymers, much less is known about their functions than the other basic components of cells - nucleic acids (DNA and RNA), lipids, and proteins. Nevertheless, one percent of the mammalian genome encodes enzymes that produce and modify glycan structures among all cell types. Glycans bearing multiple monosaccharide linkages may exist as single or multi-antennary branched oligosaccharide structures. During embryogenesis, normal adult physiology, and in many diseased states, the appearance of different glycan linkages at the cell surface occurs in part by altered gene expression involving glycosyltransferases and glycosidases. Oligosaccharide variants thus occur on glycoproteins, can lead to alterations in protein activity and functions.
Human plasma is rich in glycoproteins, many of which exist in different glycoforms. Aberrant glycosylation of cell surface glycoconjugates and serum glycoproteins are known to be involved in a variety of biological phenomena such as inflammation, cell differentiation, infection, tumor progression, and metastasis. Protein glycosylation alterations indicate aberrant cellular changes in a number of diseases, providing diagnostic markers and vision into disease progression and pathogenesis. Glycosylation depends upon the biosynthetic cell type and protein core and results in a set glycoforms of a particular glycoprotein. Under diseased conditions, alteration of the glycosylation pattern of glycoproteins present in human plasma may occur. For example, degalactosylated IgA1 and IgG have been detected in IgA nephropathy and rheumatoid arthritis, respectively. Abnormally reduced sialylation and increased branching of oligosaccharide chains of alpha-fetoprotein, alpha-1-acid glycoprotein and transferrin, occurs in liver diseases. The alteration is specific of the disease studied, such as increased sialylation and fucosylation of acute-phase proteins are detected in cancer sera. Lectin-based methods are also used in clinical purposes, for improvement in the disease prognosis and diagnosis, or treatment.
Glycosylation alteration of IgG (agalactosylated IgG/IgG0) is involved in the RA pathogenesis. With the disease severity, the levels of IgG0 have also been increased proportionately. The characteristic autoantibodies known as rheumatoid factors, which bind to the Fc portion of agalactosylated IgG molecule, are found to be increased in the sera of patients with RA. Alpha-1-acid glycoprotein, another plasma protein, is found to be present in various glycoforms, and its glycosylation alteration has been reported in various pathological conditions including RA. One such protein, namely, mannose-binding lectin (MBL), has strong affinity for the exposed GlcNAc of IgG0 (agalactosyl IgG), has been found to stimulate the complement pathway and bind with IgG0. Such complexes are found in the synovial fluid of RA patients. Differential expression pattern of proteins, as acute phase response is significant in the pathogenesis of RA. The oligosaccharide patterns of acute phase proteins are altered in inflammatory diseases, without any changes in serum concentrations of these glycoproteins during acute inflammation. As example, several serum glycoproteins, like alpha-1-acid glycoprotein (AGP), and alpha-2-HS-glycoprotein, etc., number of branches get reduced during acute inflammation, whereas increases during chronic inflammation. These changes can be detected by crossed immuno-affinoelectrophoresis with Concanavalin-A. Aberrant glycosylation of glycoconjugates and glycoproteins are involved in several biological phenomena such as infection, inflammation, tumor progression, and metastasis.
From the above discussion, it can be concluded that the altered glycoproteins in the RA patients' plasma can be used as biomarker for diagnosis or prognosis of rheumatoid arthritis.
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Written by Debasis Sahu and Shikha Sharma
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