Frontiers in Immunology (Aug 2018)
The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1
- Jessica C. Anania,
- Jessica C. Anania,
- Halina M. Trist,
- Catherine S. Palmer,
- Catherine S. Palmer,
- Peck Szee Tan,
- Betty P. Kouskousis,
- Betty P. Kouskousis,
- Alicia M. Chenoweth,
- Alicia M. Chenoweth,
- Stephen J. Kent,
- Stephen J. Kent,
- Stephen J. Kent,
- Graham A. Mackay,
- Alberta Hoi,
- Rachel Koelmeyer,
- Charlotte Slade,
- Charlotte Slade,
- Charlotte Slade,
- Charlotte Slade,
- Vanessa L. Bryant,
- Vanessa L. Bryant,
- Vanessa L. Bryant,
- Vanessa L. Bryant,
- Philip D. Hodgkin,
- Philip D. Hodgkin,
- Pei Mun Aui,
- Pei Mun Aui,
- Menno C. van Zelm,
- Menno C. van Zelm,
- Bruce D. Wines,
- Bruce D. Wines,
- Bruce D. Wines,
- P. Mark Hogarth,
- P. Mark Hogarth,
- P. Mark Hogarth
Affiliations
- Jessica C. Anania
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Jessica C. Anania
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Halina M. Trist
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Catherine S. Palmer
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Catherine S. Palmer
- Monash Micro Imaging, Monash University, Clayton, VIC, Australia
- Peck Szee Tan
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Betty P. Kouskousis
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Betty P. Kouskousis
- Monash Micro Imaging, Monash University, Clayton, VIC, Australia
- Alicia M. Chenoweth
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Alicia M. Chenoweth
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Stephen J. Kent
- Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
- Stephen J. Kent
- Melbourne Sexual Health Centre, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Stephen J. Kent
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, VIC, Australia
- Graham A. Mackay
- Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, VIC, Australia
- Alberta Hoi
- Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
- Rachel Koelmeyer
- Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
- Charlotte Slade
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Charlotte Slade
- 0Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Parkville, VIC, Australia
- Charlotte Slade
- 1Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC, Australia
- Charlotte Slade
- 2The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Vanessa L. Bryant
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Vanessa L. Bryant
- 0Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Parkville, VIC, Australia
- Vanessa L. Bryant
- 1Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC, Australia
- Vanessa L. Bryant
- 2The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Philip D. Hodgkin
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Philip D. Hodgkin
- 0Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Parkville, VIC, Australia
- Pei Mun Aui
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Pei Mun Aui
- 2The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Menno C. van Zelm
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Menno C. van Zelm
- 2The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia
- Bruce D. Wines
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- Bruce D. Wines
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Bruce D. Wines
- 3Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
- P. Mark Hogarth
- Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia
- P. Mark Hogarth
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- P. Mark Hogarth
- 3Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
- DOI
- https://doi.org/10.3389/fimmu.2018.01809
- Journal volume & issue
-
Vol. 9
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.
Keywords
- Fc receptors
- common variable immunodeficiency
- immunodeficiency
- systemic lupus erythematosus
- immune complex
- non-human primates
