Increased Levels of Galactose-Deficient Anti-Gal Immunoglobulin G in the Sera of Hepatitis C Virus-Infected Individuals with Fibrosis and Cirrhosis

Abstract

Hepatitis B and C viruses are major causative agents of liver fibrosis, cirrhosis, and liver cancer. Using comparative glycoproteomics, we identified a glycoprotein that is altered both in amount and in glycosylation as a function of liver fibrosis and cirrhosis. Specifically, this altered glycoprotein is an immunoglobulin G (IgG) molecule reactive to the heterophilic alpha-Gal epitope [Gal␣-1-3Gal␤1-(3)4GlcNAc-R]. While similar changes in glycosylation have been observed in several autoimmune diseases, the specific immunoglobulins and their antigen recognition profiles were not determined. Thus, we provide the first report identifying the specific antigenic recognition profile of an immunoglobulin molecule containing altered glycosylation as a function of liver disease. This change in glycosylation allowed increased reactivity with several fucose binding lectins and permitted the development of a plate-based assay to measure this change. Increased lectin reactivity was observed in 100% of the more than 200 individuals with stage III or greater fibrosis and appeared to be correlated with the degree of fibrosis. The reason for the alteration in the glycosylation of anti-Gal IgG is currently unclear but may be related to the natural history of the disease and may be useful in the noninvasive detection of fibrosis and cirrhosis.

Multilectin Assay for Detecting Fibrosis-Specific Glyco-Alteration by Means of Lectin Microarray

“…3). These values were close to the values of the tests using the glyco-alteration in serum total IgG and specific IgG against ␣-Gal epitope, which are known to be high-performance biomarkers for liver fibrosis (30,31 ). AOL preferentially distinguished between F2 and F3.…”

“…We must construct a rapid and simple sandwich ELISA kit with the lectin set we optimized in this study, before the next validation phase toward a much larger cohort. The optimized assay could be compared with other recently introduced glyco-based test approaches by using the same sample set (30,31 ). a n ϭ 88 (chronic hepatitis: n ϭ 45, liver cirrhosis: n ϭ 43).…”

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

“…28 The heterophillic alpha-galactose epitope is most notably a major antigen on Gram-negative micro-organisms. Thus, although the natural source for the alpha-galactose antigen stimulating production of the AAL-reactive IgG is not currently known, given its correlation with the other markers of microbial translocation it is tempting to speculate that it is derived from translocated components of intestinal microorganisms.…”

“…Lectin FluorophoreLinked Immunosorbent Assay (FLISA): the amount of an altered IgG, itself specific for a heterophilic (alpha-galactose) epitope, has previously been strongly associated with stage of liver disease. 28 The altered (agalactosylated) antibody has an exposed fucose residue, which allows it to be detected by a fucose-binding lectin derived from Aleuria aurantia (AAL). An AAL-based FLISA was used to quantify the amount of this altered immunoglobulin.…”

Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma

“…6 Structural details of the attached glycans are of great physiological significance and are associated with many pathological conditions. 6,7 For example, levels of galactose-deficient IgG are increased in liver fibrosis, cirrhosis, and ovarian and lung cancer [8][9][10] and increased core fucosylated IgG was described as a diagnostic marker in ovarian cancer. 11 Additionally, individual variation in IgG glycosylation changes during acute systemic inflammation was associated with increased mortality risk.…”