INCREASED CLEARANCE OF IGG IN MICE THAT LACK BETA(2)-MICROGLOBULIN - POSSIBLE PROTECTIVE ROLE OF FCRN

The mechanisms that regulate immunoglobulin G (IgG) catabolism are lit tle understood. We have previously found unusually low IgG concentrati ons in sera of mice homozygous for a targeted disruption of the beta(2 )-microglobulin gene. We therefore investigated whether this might res ult, at least in part, from increased clearance of IgG from the system ic circulation in mice lacking beta(2)-microglobulin. We compared the half-lives of radiolabelled mouse IgG1 injected intravenously into bet a(2)-microglobulin(-/-) mice and wild-type or heterozygous siblings. T he clearance of I-125-labelled IgG1 was strikingly more rapid in the m ice lacking beta(2)-microglobulin. beta(2)-microglobulin(-/-) mice lac k functional molecules of the MHC class I-related Fc receptor, FcRn. S ome mutations in mouse IgG1 that increase its clearance have recently been shown to prevent binding to FcRn in the gut. To determine whether the slower degradation of immunoglobulin in mice with beta(2)- microg lobulin correlated with the ability of the antibody to bind FcRn, we m easured the clearance of chicken IgY, which does not bind this recepto r. The I-125-labelled IgY was catabolized equally rapidly in beta(2)-m icroglobulin-deficient and wild-type mice. We compared the half-lives of the four subclasses of mouse IgG in beta(2)-microglobulin(-/-), (+/ -), and (+/+) mice to determine whether the difference we had noted fo r IgG1 was peculiar to this subclass. The I-125-labelled IgG of all su bclasses, with the possible exception of IgG2b, was degraded more rapi dly in the beta(2)-microglobulin-deficient mice than in heterozygous o r wild-type siblings. These data suggest that FcRn can protect IgG fro m degradation, and is therefore important in maintaining IgG levels in the circulation.