Expression of the high responder/non‐responder human FcγRII. Analysis by PCR and transfection into FcR COS cells

Abstract

Summary Distinct differences in the capacity of monocyte FcyRII of different individuals to bind or not bind mouse IgGl defines a polymorphism ot FcyRIIa and has previously been defined as the high responder (HR) or low responder (LR) polymorphism of FcyRII. The precise definition of the molecular basis of the human HR/LR polymorphism of FcyRIIa from the peripheral blood mononuclear cells of normal individuals has been determined by anti-CD3 induction of T cell proliferation, the polymerase chain reaction {PCR), nucleotide sequencing, transfection and IgG binding. Amplification of first strand cDNA from mRNA isolated from mononuclear cells was performed by PCR using primers specific for the sequences encoding the leader and cytoplasmic sequences of FcyRUa, which is normally expressed in monocytes. Sequencing of the PCR products and transfection of these to FcyR cells indicated that in FcyRIIa of HR or LR individuals; (i) three nucieotide substitutions (CA to TG and G to A) resulted in the change of glutamine to tryptophan at position 27 {first extracellular domain) and arginine to histidine at position 131 (second extracellular domain); (ii) expression of cDNA encoding the various combinations of these indicated that arginine at position 131 was essential for IgGl binding whereas the amino acid changes at position 27 had no effect; and (iii) IgGl at high concentration bound to al! allomorphic forms of FcyRIIa. These results indicate that position 131 in the second extracellular domain of FcyRIIa is intimately involved in immunoglobulin binding. Furthermore, the apparent inability oi IgGl to bind to FcyRIIa of non-responder individuals is not absolute in that immune complexes sensitized with a high concentration of MlgGl will bind to non-responder-type FcyRIIa.

No association between neutrophil FcγRIIa allelic polymorphism and anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis

“…Homozygous FcgRIIa-R131 donors produced more than three-fold greater respiratory burst compared with the homozygous FcgRIIa-H131 donors in response to a murine monoclonal MPO-ANCA. However, this increased neutrophil activation in FcgRIIa-R131 donors almost certainly reflects the greater avidity of these receptors for murine IgG1 [10,[17][18][19][20][21][22]. The situation with human IgG is unclear.…”

“…This polymorphism results from a single base substitution from guanidine to adenine at nucleotide 494 of the coding region in exon 4 [14][15][16], which leads to an amino acid change from arginine to histidine at position 131 of the second extracellular domain [17][18][19][20]. The H131 allele (494A) codes for histidine at position 131 and has a high affinity for human IgG2 and a low affinity for murine IgG1, whilst the R131 allele (494G) has arginine at position 131 and has little or no affinity for human IgG2 but has a high affinity for murine IgG1 [17][18][19][20][21][22]. To a lesser extent, the two allotypes also differ in their ability to ligate human IgG3, with the homozygous FcgRIIa-H131 allotype having the higher affinity for IgG3 [17][18][19][20][21][22].…”

“…The H131 allele (494A) codes for histidine at position 131 and has a high affinity for human IgG2 and a low affinity for murine IgG1, whilst the R131 allele (494G) has arginine at position 131 and has little or no affinity for human IgG2 but has a high affinity for murine IgG1 [17][18][19][20][21][22]. To a lesser extent, the two allotypes also differ in their ability to ligate human IgG3, with the homozygous FcgRIIa-H131 allotype having the higher affinity for IgG3 [17][18][19][20][21][22]. Thus, this polymorphism may influence susceptibility to diseases, especially in situations where IgG2, and to a lesser extent IgG3, are the predominant antibody subclasses produced.…”

Gain-of-function mutations in FcγRI of NOD mice: implications for the evolution of the Ig superfamily

“…This implies that N1 must interact with other residues novel in the FcγRI-NOD allele to achieve the IgG2b and IgG3 binding pattern observed. It is interesting to note that one unique difference between FcγRI-NOD and FcγRI-BALB is an Asp135→Gly136 alteration that corresponds to an Ig interactive region defined for other FcR, namely FcγRII and FcεRI (Warmerdam et al, 1991;Tate et al, 1992;Hulett et al, 1993Hulett et al, , 1995.…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…The High Responder (HR) and low responder (LR) polymorphism at amino acid position 131 [89] is a highly significant risk factor for SLE [90][91][92], idiopathic thrombocytopenia [93] colitis [94] and rheumatoid arthritis [87,95,96], malarial parasitemia levels [97] and aggressive periodontal disease [98]. The protective effect of the H131 polymorphism for severe infection by encapsulated bacteria relates to this receptor being the only human FcγR that functionally binds IgG2 [99].…”