The human low affinity immunoglobulin G Fc receptor IIC gene is a result of an unequal crossover event.

Warmerdam, Petra A. M.; Nabben, N. M. J. M.; Graaf, S. A. R. Van De; Winkel, Jan G. J. van de; Capel, P. J. A.

doi:10.1016/s0021-9258(18)53181-1

Cited by 83 publications

(5 citation statements)

References 19 publications

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“…The human FcgRII (CD32) family also contains two activating receptors: FcgRIIa and FcgRIIc. Highly homologous in the extracellular (EC) domains, FcgRII family receptors diverge in their cytoplasmic (CY) domains with an ITIM-bearing sequence in FcgRIIb and identical ITAM-bearing sequences in FcgRIIa and FcgRIIc (17)(18)(19). FCGR2C is often regarded as a pseudogene because of a translation termination codon at codon 13 in its first EC domain.…”

Section: Introductionmentioning

confidence: 99%

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Ptacek

et al. 2013

Sci. Transl. Med.

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B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.

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Section: Introductionmentioning

confidence: 99%

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Ptacek

et al. 2013

Sci. Transl. Med.

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“…40,41 We now know that in individuals with the variant FCGR2C*ORF, FcgRIIc is expressed by neutrophils, monocytes, and NK cells. 25,42 Macrophages and B cells may also express FcgRIIc. 11,13,43 Expression of FcgRIIc may result in enhanced phagocytic and antibody-dependent cellular cytotoxicity activity or impaired downregulation of B-cell responses, and thereby a predisposition to ITP.…”

Section: Discussionmentioning

confidence: 99%

Transient and chronic childhood immune thrombocytopenia are distinctly affected by Fc-γ receptor polymorphisms

et al. 2019

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In childhood immune thrombocytopenia (ITP), anti-platelet autoantibodies mediate platelet clearance through Fc-γ receptor (FcγR)–bearing phagocytes. In 75% to 90% of patients, the disease has a transient, self-limiting character. Here we characterized how polymorphisms of FcγR genes affect disease susceptibility, response to intravenous immunoglobulin (IVIg) treatment, and long-term recovery from childhood ITP. Genotyping of the FCGR2/3 locus was performed in 180 children with newly diagnosed ITP, 22 children with chronic ITP, and 180 healthy control children by multiplex ligation-dependent probe amplification. Children with newly diagnosed ITP were randomly assigned to a single administration of IVIg or observation, and followed for 1 year (Treatment With or Without IVIg for Kids With ITP [TIKI] trial). We defined transient ITP as a complete recovery (≥100 × 109/L) 3 months after diagnosis, including both self-limiting disease/IVIg responders and chronic ITP as absence of a complete recovery at 12 months. ITP susceptibility, as well as spontaneous recovery and response to IVIg, was associated with the genetic variants FCGR2C*ORF and FCGR2A*27W and the FCGR2B promoter variant 2B.4. These variants were overrepresented in patients with transient (N = 131), but not chronic (N = 43), disease. The presence of FCGR2C*ORF predisposed to transient ITP with an odds ratio of 4.7 (95% confidence interval, 1.9-14.3). Chronic ITP was associated with a deletion of FCGR2C/FCGR3B (copy number region 1) with an odds ratio of 6.2 (95% confidence interval, 1.8-24.7). Taken together, susceptibility to transient and chronic ITP is distinctly affected by polymorphic variants of FCGR2/3 genes. Our data suggest that genotyping of the FCGR2/3 locus may be useful for prognosis and guidance of treatment decisions in newly diagnosed childhood ITP.

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“…6,18,19 In particular, there is only one amino acid difference (encoded in exon 5) compared to FCGR2B and only one amino acid difference (encoded in exon 8) compared to FCGR2A. 10,20 Besides the 99% homology between FCGR2C and respective parts of FCGR2A and FCGR2B genes (Figure 1A), all three genes of the FCGR2 family share their highest homology within exons 3 -5 (> 96%, NCBI BLASTN 2.7.0+) (Supplementary Figure 1). This high degree of sequence homology in combination with the genomic variability of the FCGR2/3 gene cluster, reflected in the high degree of copy number variation.…”

Section: Molecular Approach For the Determination Of The Genetic Status Of The Fcgr2c Gene Locusmentioning

confidence: 99%

Comprehensive approach for identification of functional FCGR2C alleles resulting in protein expression as a determinant for predicting predisposition to autoimmunity

et al. 2021

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The balance of activating and inhibitory signals from the low affinity Fc gamma receptors modulates immune responses triggered by IgG antibody-immune complexes.In homeostasis, this leads to antigen clearance, while in autoimmune diseases to unwanted immune response. Besides the activating receptors FcɣRIIa, FcɣRIIIa, and the inhibitory FcɣRIIb receptor, a third activating receptor, FcɣRIIc, was shown to be expressed on several immune cell types, however, only in the presence of a functional FCGR2C-ORF allele. FcɣRIIc expression is associated with autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus or systemic sclerosis. Thus, the determination of the functional FCGR2C gene resulting in protein expression on immune cells becomes highly relevant, particularly in the context of unwanted immune responses through inadvertent FcɣRIIc activation by molecules targeting stimulation of the inhibitory receptor FcɣRIIb, currently pursued by several pharmaceutical companies. The high degree of homology within the FCGR2/3 gene cluster complicates development of an accurate method for identification of FcɣRIIc expression. Here we describe a comprehensive approach to characterize genetic status of the FCGR2C gene locus consisting of cDNA sequencing, SNaPshot genotyping and low-coverage next-generation sequencing. This might enable Mendelian randomization hypothesis testing across autoimmune diseases to personalize therapies and enhance treatment outcomes.

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The human low affinity immunoglobulin G Fc receptor IIC gene is a result of an unequal crossover event.

Cited by 83 publications

References 19 publications

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses

Transient and chronic childhood immune thrombocytopenia are distinctly affected by Fc-γ receptor polymorphisms

Comprehensive approach for identification of functional FCGR2C alleles resulting in protein expression as a determinant for predicting predisposition to autoimmunity

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