A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia - 29/04/13
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 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 Ca2+ mobilization were determined in neutrophils and transfected cell lines, respectively.
Results |
A novel splice variant of FcγRIIa containing an expressed cryptic exon 6* (FcγRIIaexon6) 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 FCGR2Ac.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 FCGR2Ac.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, FcγRIIaexon6 was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by FcγRIIaexon6 compared with its native form, as shown by increased elastase release and intracellular calcium mobilization.
Conclusion |
A novel splice variant, FcγRIIaexon6, was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, FcγRIIaexon6 can contribute to anaphylaxis in patients with CVID.
Le texte complet de cet article est disponible en PDF.Key words : Anaphylaxis, common variable immunodeficiency, idiopathic thrombocytopenia, intravenous immunoglobulin, Fcγ receptors, Kawasaki disease, splice variant, neutrophils, elastase
Abbreviations used : [Ca2+]i, CVID, FcγR, FITC, fMLP, IMIg, ITP, IVIg, KD, SNP
Plan
Supported in part by a grant from the Netherlands Organization for Scientific Research (NWO; HORIZON 050-71-034). Also supported by Sanquin. |
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 5
P. 1408 - mai 2013 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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