Abstract
BACKGROUND: Our index case was a patient with common variable immunodeficiency (CVID). She had anaphylactoid reactions on administration of intravenous immunoglobulin (IVIg) associated with the presence of IgG antibodies against IgA. OBJECTIVE: We sought to determine the role of Fcgamma receptor (FcgammaR) IIa in IVIg-induced anaphylactoid reactions. METHODS: Neutrophils and PBMCs were isolated from healthy subjects and IVIg-treated patients. FcgammaRIIa mRNA and DNA were analyzed by using real-time PCR and sequencing. IgG-mediated elastase release and intracellular Ca(2+) mobilization were determined in neutrophils and transfected cell lines, respectively. RESULTS: A novel splice variant of FcgammaRIIa containing an expressed cryptic exon 6* (FcgammaRIIa(exon6 *)) was identified in our index patient. This exon is normally spliced out of all FcgammaRII isoforms, except the inhibitory FcgammaRIIb1. Compared with healthy control subjects, the heterozygous FCGR2A(c.742+871A>G) mutation was more frequent in patients with CVID (n = 53, P < .013). Expression in patients with CVID was associated with anaphylaxis on IVIg infusion (P = .002). On screening of additional IVIg-treated patient cohorts, we identified 6 FCGR2A(c.742+871A>G) allele-positive patients with Kawasaki disease (n = 208) and 1 patient with idiopathic thrombocytopenia (n = 93). None had adverse reactions to IVIg. Moreover, FcgammaRIIa(exon6 *) was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by FcgammaRIIa(exon6 *) compared with its native form, as shown by increased elastase release and intracellular calcium mobilization. CONCLUSION: A novel splice variant, FcgammaRIIa(exon6 *), was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, FcgammaRIIa(exon6 *) can contribute to anaphylaxis in patients with CVID.
