DIFFERENTIAL CLEARANCE OF GLYCOFORMS OF IGG IN NORMAL AND AUTOIMMUNE-PRONE MICE

In order to understand better the origins of the elevated levels of th e glycoform of IgG that lacks galactose on both arms of the oligosacch aride chain (G0%) located in the Fc, which occurs in man and mouse wit h age, and in particular in autoimmune disease, we investigated the cl earance of two glycosylated forms of IgG2a and IgG1 in normal (BALB/c) and autoimmune-prone (MRL/lpr, MRL/+, and non-obese diabetic (NOD)) m ice. To investigate the possibility of different rates of catabolism, enzymatically generated glycoforms of monomeric IgG1 and IgG2a (fully glycosylated or G0%), were iodinated and injected into the tail vein o f the mice. We found that the G0% IgG2a remained in circulation signif icantly longer than the fully glycosylated variants, in all of the mou se strains tested. In contrast, the two forms of lgG1 had similar kine tics in all the autoimmune-prone mice, whereas in BALB/c, there was a longer half-life (t(1/2)) for G0% IgG1. These data suggest that there may be differences in the ability of the IgG glycoforms to bind to the Fc gamma receptors, in particular Fc gamma RI. The clearance rates we re found to vary among the strains studied, with MRL/lpr having the fa stest catabolic rates for all glycoforms and IgG subclasses tested. Th is appeared to be due to the presence of circulating IgG and IgM rheum atoid factors (RF). There were significantly increased frequencies and titres for both IgM and IgG RF in MRL/lpr mice compared with the othe r strains. In contrast, interferon-gamma, known to induce the Fc gamma RI, was found to be similar in the sera, in all of the strains of mic e examined. These results suggest that RF probably play an important b iological function in the MRL/lpr mice and aid in the clearance of cir culating IgG. Our study shows that the state of glycosylation of IgG a ffects the t(1/2) in vivo, and that by removing the terminal sugars (s ialic acid and galactose), the antibody (IgG2a) will remain in circula tion significantly longer. These observations may thus provide a parti al explanation for the increase in relative percentage of this glycofo rm that occurs with age.