title: A novel splice variant of FcγRIIa: a risk factor for anaphylaxis in patients with hypogammaglobulinemia.
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 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Blood Cell Research, Sanquin Research at CLB and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: van der Heijden
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.forename: Edwin
authors.initials: E
authors.lastname: van Mirre
authors.forename: Marcel
authors.initials: M
authors.lastname: van Deuren
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Abdulgabar
authors.initials: A
authors.lastname: Salama
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000328:Adult; D000361:Agammaglobulinemia / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D000707:Anaphylaxis / Q000150:complications / Q000235:genetics* / Q000276:immunology; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D020033:Protein Isoforms / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics*; D012307:Risk Factors
chemical_list: C080568:Fc gamma receptor IIA; D020033:Protein Isoforms; D017452:Receptors, IgG