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.
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.
Authors: María M Escribese; Domenico Rosace; Tomas Chivato; Tahia D Fernández; Angel L Corbí; Domingo Barber Journal: Front Immunol Date: 2017-05-08 Impact factor: 7.561
Authors: Jessica C Anania; Halina M Trist; Catherine S Palmer; Peck Szee Tan; Betty P Kouskousis; Alicia M Chenoweth; Stephen J Kent; Graham A Mackay; Alberta Hoi; Rachel Koelmeyer; Charlotte Slade; Vanessa L Bryant; Philip D Hodgkin; Pei Mun Aui; Menno C van Zelm; Bruce D Wines; P Mark Hogarth Journal: Front Immunol Date: 2018-08-20 Impact factor: 7.561