TY - JOUR
T1 - A novel splice variant of FcγRIIa
T2 - a risk factor for anaphylaxis in patients with hypogammaglobulinemia
AU - van der Heijden, Joris
AU - Geissler, Judy
AU - van Mirre, Edwin
AU - van Deuren, Marcel
AU - van der Meer, Jos W M
AU - Salama, Abdulgabar
AU - van den Berg, Timo K
AU - Roos, Dirk
AU - Kuijpers, Taco W
N1 - Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
PY - 2013/5
Y1 - 2013/5
N2 - 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.
AB - 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.
KW - Adult
KW - Agammaglobulinemia/etiology
KW - Anaphylaxis/complications
KW - Animals
KW - Female
KW - Humans
KW - Male
KW - Mice
KW - Neutrophils/immunology
KW - Protein Isoforms/immunology
KW - Receptors, IgG/genetics
KW - Risk Factors
U2 - 10.1016/j.jaci.2013.02.009
DO - 10.1016/j.jaci.2013.02.009
M3 - Article
C2 - 23545275
VL - 131
SP - 1408-16.e5
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 5
ER -