DEFECTIVE FC-GAMMA-RII GENE-EXPRESSION IN MACROPHAGES OF NOD MICE - GENETIC-LINKAGE WITH UP-REGULATION OF IGG1 AND IGG2B IN SERUM

A quantitative trait locus for increased Ige serum levels in the NOD m ouse strain was mapped to distal chromosome 1, close to the fcgr2 locu s encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII), Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gam ma RIIb1) isoform was only slightly decreased and Fc gamma RIII was no t altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr 2 or by a closely linked locus, occurred at the mRNA level, and was as sociated with multiple mutations in the fcgr2 gene promoter. In relati on with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsoniz ed RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severe ly impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mi ce, indicating that Fc gamma RII plays a nondispensable role in bindin g of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 con genic mice. These findings indicate that macrophage Fc gamma RII may r egulate serum IgG1 and IgG2b through their catabolism, and validate th e NOD strain as a model to investigate the functions of Fc gamma RII i soforms.