A novel splice variant of Fc¦ÃRIIa: A?risk factor for anaphylaxis in patients with hypogammaglobulinemia

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• 作者：Joris van der Heijden ; MSc^a ; Judy Geissler^a ; ^b ; Edwin van Mirre ; PhD^a ; Marcel van Deuren ; MD ; PhD^c ; Jos W.M. van der Meer ; MD ; PhD^c ; Abdulgabar Salama ; MD ; PhD^d ; Timo K. van den Berg ; PhD^a ; Dirk Roos ; PhD^a ; Taco W. Kuijpers ; MD ; PhD^a ; ^b ; ^{t.w.kuijpers@amc.nl}
• 关键词：Anaphylaxis ; common variable immunodeficiency ; idiopathic thrombocytopenia ; intravenous immunoglobulin ; Fc¦Ã receptors ; Kawasaki disease ; splice variant ; neutrophils ; elastase
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：131
• 期：5
• 页码：1408-1416.e5
• 全文大小：659 K

文摘

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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 Fc¦Ã receptor (Fc¦ÃR) IIa in IVIg-induced anaphylactoid reactions.

Methods

Neutrophils and PBMCs were isolated from healthy subjects and IVIg-treated patients. Fc¦ÃRIIa 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 Fc¦ÃRIIa containing an expressed cryptic exon 6* (Fc¦ÃRIIa^exon6?) was identified in our index patient. This exon is normally spliced out of all Fc¦ÃRII isoforms, except the inhibitory Fc¦ÃRIIb1. 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, Fc¦ÃRIIa^exon6? was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by Fc¦ÃRIIa^exon6? compared with its native form, as shown by increased elastase release and intracellular calcium mobilization.

Conclusion

A novel splice variant, Fc¦ÃRIIa^exon6?, was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, Fc¦ÃRIIa^exon6? can contribute to anaphylaxis in patients with CVID.