Dynamics of the interaction of human IgG subtype immune complexes with cells expressing R and H allelic forms of a low-affinity FcÎ³ receptor CD32A
CD32A, the major phagocytic FcÎ³R in humans, exhibits a polymorphism in the ligand binding domain. Individuals homozygous for the R allelic form of CD32A (CD32AR allele) are more susceptible to bacterial infections and autoimmune diseases as compared with H allelic CD32A (CD32AH) homozygous and CD32AR/H heterozygous individuals. To understand the mechanisms behind this differential susceptibility, we have investigated the dynamics of the interaction of these allelic forms of CD32A when they are simultaneously exposed to immune complexes (IC). Binding studies using Ig fusion proteins of CD32A alleles showed that the R allele has significantly lower binding not only to human IgG2, but also to IgG1 and IgG3 subtypes. Competition assays using purified molecules demonstrated that CD32AH-Ig outcompetes CD32AR-Ig for IC binding when both alleles simultaneously compete for the same ligand. CD32AH-Ig blocked the IC binding mediated by both the allelic forms of cell surface CD32A, whereas CD32A R-Ig blocked only CD32AR and was unable to cross-block IC binding mediated by CD32AH. Two-dimensional affinity measurements also demonstrated that CD32AR has significantly lower affinity toward all three subtypes as compared with CD32AH. Our data suggest that the lower binding of CD32AR not only to IgG2 but also to IgG1 and IgG3 might be responsible for the lack of clearance of IC leading to increased susceptibility to bacterial infections and autoimmune diseases. Our data further suggests that in humans, inflammatory cells from CD32AR/H heterozygous individuals may predominantly use the H allele to mediate Ab-coated target cell binding during phagocytosis and Ab-dependent cellular cytotoxicity, resulting in a phenotype similar to CD32AH homozygous individuals. Copyright Â© 2009 by The American Association of Immunologists, Inc.
Journal of Immunology
Shashidharamurthy, Rangaiah; Zhang, Fang; Amano, Aaron; Kamat, Aparna; Panchanathan, Ravichandran; Ezekwudo, Daniel; Zhu, Cheng; and Selvaraj, Periasamy, "Dynamics of the interaction of human IgG subtype immune complexes with cells expressing R and H allelic forms of a low-affinity FcÎ³ receptor CD32A" (2009). PCOM Scholarly Papers. 555.