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The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1.

ABSTRACT: FcγRIIa is an activating FcγR, unique to humans and non-human primates. It induces antibody-dependent proinflammatory responses and exists predominantly as FcγRIIa1. A unique splice variant, we designated FcγRIIa3, has been reported to be associated with anaphylactic reactions to intravenous immunoglobulins (IVIg) therapy. We aim to define the functional consequences of this FcγRIIa variant associated with adverse responses to IVIg therapy and evaluate the frequency of associated SNPs. FcγRIIa forms from macaque and human PBMCs were investigated for IgG-subclass specificity, biochemistry, membrane localization, and functional activity. Disease-associated SNPs were analyzed by sequencing genomic DNA from 224 individuals with immunodeficiency or autoimmune disease. FcγRIIa3 was identified in macaque and human PBMC. The FcγRIIa3 is distinguished from the canonical FcγRIIa1 by a unique 19-amino acid cytoplasmic insertion and these two FcγRIIa forms responded distinctly to antibody ligation. Whereas FcγRIIa1 was rapidly internalized, FcγRIIa3 was retained longer at the membrane, inducing greater calcium mobilization and cell degranulation. Four FCGR2A SNPs were identified including the previously reported intronic SNP associated with anaphylaxis, but in only 1 of 224 individuals. The unique cytoplasmic element of FcγRIIa3 delays internalization and is associated with enhanced cellular activation. The frequency of the immunodeficiency-associated SNP varies between disease populations but interestingly occurred at a lower frequency than previously reported. None-the-less enhanced FcγRIIa3 function may promote a proinflammatory environment and predispose to pathological inflammatory responses.

SUBMITTER: Anania JC

PROVIDER: S-EPMC6109644 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1.

Anania Jessica C JC Trist Halina M HM Palmer Catherine S CS Tan Peck Szee PS Kouskousis Betty P BP Chenoweth Alicia M AM Kent Stephen J SJ Mackay Graham A GA Hoi Alberta A Koelmeyer Rachel R Slade Charlotte C Bryant Vanessa L VL Hodgkin Philip D PD Aui Pei Mun PM van Zelm Menno C MC Wines Bruce D BD Hogarth P Mark PM

Frontiers in immunology 20180820

FcγRIIa is an activating FcγR, unique to humans and non-human primates. It induces antibody-dependent proinflammatory responses and exists predominantly as FcγRIIa1. A unique splice variant, we designated FcγRIIa3, has been reported to be associated with anaphylactic reactions to intravenous immunoglobulins (IVIg) therapy. We aim to define the functional consequences of this FcγRIIa variant associated with adverse responses to IVIg therapy and evaluate the frequency of associated SNPs. FcγRIIa f ...[more]

PMID: 30177930

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Project description:IntroductionThe pathogenesis of cold urticaria (ColdU) and cold-induced anaphylaxis (ColdA) remains poorly understood, and ColdA is underrepresented in anaphylaxis literature. Laboratory features to guide management are largely unknown. This study evaluated basal serum tryptase (BST) and total immunoglobulin E (IgE) levels in ColdU and ColdA, their associations with clinical features, and the utility of testing for the KIT p.D816V variant in blood leukocytes and hereditary α-tryptasemia (HαT).MethodsNinety-two adults with ColdU were enrolled. ColdA was defined as a reaction involving skin and/or visible mucosal tissue with cardiovascular, respiratory, or gastrointestinal manifestations. Evaluations included patient history, standard cold stimulation testing (sCST) using an ice cube and TempTest®, and laboratory tests.ResultsColdA was diagnosed in 35.9% of patients. ColdU phenotypes based on sCST included typical ColdU (52.2%), localized cold-reflex urticaria (5.4%), and ColdU with negative sCST (42.4%). Negative sCST, compared to typical ColdU, was associated with fewer ColdA cases (p = 0.004) but more spontaneous wheals (p < 0.001). ColdA patients more frequently exhibited generalized wheals (p = 0.047), skin angioedema (p = 0.007), oropharyngeal/laryngeal manifestations (p < 0.001), and itchy earlobes (p = 0.002) than non-ColdA patients. Elevated BST levels (>11.4 ng/mL) in 9.8% of patients were attributed to KIT p.D816V and/or HαT. KIT p.D816V was detected in 6.6% of ColdU and 6.3% of ColdA patients. HαT prevalence was higher in ColdU (10.9%) and ColdA (15.2%) than the general population (estimated at 5.7%; p = 0.041 and p = 0.038). Total IgE levels were significantly higher in ColdA than non-ColdA (p = 0.021).DiscussionThis study confirmed clinical features linked to ColdA previously identified by the multicenter COLD-CE study, including generalized wheals, skin angioedema, oropharyngeal/laryngeal manifestations, and itchy earlobes. We identified new high-risk features. ColdA is more frequently associated with typical ColdU than with ColdU with negative sCST, the latter being linked to spontaneous wheals. ColdA is additionally associated with higher total IgE levels. Furthermore, patients with ColdU and ColdA exhibit higher prevalence of KIT p.D816V and HαT compared to general population data, a finding not previously reported. Further research is needed to explore their clinical implications.

Dataset Information

The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1.

Publications

The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1.

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