C-reactive protein binding to FcγRIIa on human monocytes and neutrophils is allele-specific
Mary-Pat Stein, … , Carolyn Mold, Terry W. Du Clos
Mary-Pat Stein, … , Carolyn Mold, Terry W. Du Clos
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):369-376. https://doi.org/10.1172/JCI7817.
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Article

C-reactive protein binding to FcγRIIa on human monocytes and neutrophils is allele-specific

Abstract

C-reactive protein (CRP) is involved in host defense, regulation of inflammation, and modulation of autoimmune disease. Although the presence of receptors for CRP on phagocytes has been inferred for years, their identity was determined only recently. FcγRIa, the high-affinity IgG receptor, binds CRP with low affinity, whereas FcγRIIa, the low-affinity IgG receptor, binds CRP with high affinity. Because the single nucleotide polymorphism in FcγRIIA — which encodes histidine or arginine at position 131 — strongly influences IgG2 binding, we determined this polymorphism’s effect on CRP binding. CRP bound with high avidity to monocytes and neutrophils from FcγRIIA R-131 homozygotes, and binding was inhibited by the R-specific mAb 41H16. CRP showed decreased binding to cells from FcγRIIA H-131 homozygotes (which bind IgG2 with high affinity). However, IFN-γ enhanced FcγRI expression by H-131 monocytes and increased CRP binding. FcγRIIa heterozygotes showed intermediate binding. CRP initiated increases in [Ca2+]i in PMN from R-131, but not from H-131 homozygotes. These data provide direct genetic evidence for FcγRIIa as the functional, high-affinity CRP receptor on leukocytes while emphasizing the reciprocal relationship between IgG and CRP binding avidities. This counterbalance may affect the contribution of FcγRIIA alleles to host defense and autoimmunity.

Authors

Mary-Pat Stein, Jeffrey C. Edberg, Robert P. Kimberly, Erin K. Mangan, Dwaipayan Bharadwaj, Carolyn Mold, Terry W. Du Clos

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CRP binding to human monocytes and PMN is FcγRIIa allele-specific. Human...
CRP binding to human monocytes and PMN is FcγRIIa allele-specific. Human monocytes and PMN from genotyped donors were isolated from peripheral blood by gradient separation using Mono-Poly Resolving Medium. Cells were washed in ice-cold PAB and incubated in the presence of CRP for 60 minutes on ice. After 2 washes, bound CRP was detected by flow cytometry using mAb 2C10 and PE-GAM. (a) CRP binding to PMN from R-131 homozygotes, R/H-131 heterozygotes, and H-131 homozygotes. (b) CRP binding to monocytes from R-131 homozygotes, R/H-131 heterozygotes, and H-131 homozygotes. Results are expressed as the change in GMFI. Data were analyzed by Student’s paired t-test and two-tailed P values were calculated using GraphPad Prism software. The P values for RR versus HH, RR versus RH, and RH versus HH monocytes were 0.004, 0.001, and 0.015, respectively. The P values for RR versus HH, RR versus RH, and RH versus HH neutrophils were 0.008, 0.005, and 0.018, respectively.