A novel splice variant of FcγRIIa: a risk factor for anaphylaxis in patients with hypogammaglobulinemia

Joris van der Heijden, Judy Geissler, Edwin van Mirre, Marcel van Deuren, Jos W M van der Meer, Abdulgabar Salama, Timo K van den Berg, Dirk Roos, Taco W Kuijpers

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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 Fcγ receptor (FcγR) IIa in IVIg-induced anaphylactoid reactions.

METHODS: Neutrophils and PBMCs were isolated from healthy subjects and IVIg-treated patients. FcγRIIa 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 FcγRIIa containing an expressed cryptic exon 6* (FcγRIIa(exon6∗)) was identified in our index patient. This exon is normally spliced out of all FcγRII isoforms, except the inhibitory FcγRIIb1. 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, FcγRIIa(exon6∗) was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by FcγRIIa(exon6∗) compared with its native form, as shown by increased elastase release and intracellular calcium mobilization.

CONCLUSION: A novel splice variant, FcγRIIa(exon6∗), was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, FcγRIIa(exon6∗) can contribute to anaphylaxis in patients with CVID.

Original languageEnglish
Pages (from-to)1408-16.e5
JournalJournal of allergy and clinical immunology
Issue number5
Publication statusPublished - May 2013


  • Adult
  • Agammaglobulinemia/etiology
  • Anaphylaxis/complications
  • Animals
  • Female
  • Humans
  • Male
  • Mice
  • Neutrophils/immunology
  • Protein Isoforms/immunology
  • Receptors, IgG/genetics
  • Risk Factors

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