SNPs rs4656317 and rs12071048 located within an enhancer in FCGR3A are in strong linkage disequilibrium with rs396991 and influence NK cell-mediated ADCC by transcriptional regulation

Oboshi, Wataru; Watanabe, Tôru; Yukimasa, Nobuyasu; Ueno, Ichiro; Aki, Kensaku; Tada, Tomoki; Hosoi, Eiji

doi:10.1016/j.humimm.2016.06.012

Cited by 9 publications

(11 citation statements)

References 50 publications

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“…An F176V change, denoted rs396991, increases binding affinity for IgG and affects CD16 expression on NK cells . Alleles of two SNPs in FCRG3A (rs4656317 and rs12071048) in linkage disequilibrium with rs396991 also associated with levels of FCRG3A transcripts and CD16 expression on NK cells . When RTR and controls were analyzed together, rs396991 genotype frequencies were FF (38%), VF (44%), and VV (18%).…”

Section: Resultssupporting

confidence: 91%

“…15 Alleles of two SNPs in FCRG3A (rs4656317 and rs12071048) in linkage disequilibrium with rs396991 also associated with levels of FCRG3A transcripts and CD16 expression on NK cells. 16,17 When RTR and controls were analyzed together, rs396991 genotype frequencies were FF (38%), VF (44%), and VV (18%). CD16 expression (assessed as MFI) was lower in those with FF genotypes ( Figure 4A).…”

Section: A Genetic Determinant Of Cd16 Expression Affects Nk Cell Amentioning

confidence: 99%

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Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections

Lee

Doualeh

Affandi

et al. 2019

Journal of Medical Virology

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Cytomegalovirus (CMV) infections may affect natural killer (NK) cells and are implicated in age‐related disorders—notably poor vascular endothelial function. Changes may be greater in renal transplant recipients (RTR) as they have a high burden of CMV and may influence antibody‐dependent cellular cytotoxicity (ADCC) responses to viral antigen. We obtained blood mononuclear cells from RTR stable after transplantation (n = 27) and age‐ and sex‐matched controls (n = 28). Natural killer (NK) cells were assessed for expression of CD107a or TNF‐α, after stimulation with autologous antibodies bound to CMV glycoprotein B (measuring ADCC) or anti‐CD16 (measuring NK cell activation). Alleles of FCRG3A (encoding CD16; rs396991) were determined by the Taqman assay. The vascular endothelial function was assessed using flow‐mediated dilatation (FMD) of the brachial artery. Proportions of NK cells expressing CD16 ex vivo were lower in RTR. Frequencies of NK cells expressing NKG2C or LIR‐1 or lacking FcRγ were highest in CMV‐seropositive RTR. ADCC was affected by rs396991 genotype and CMV gB antibody levels, but not by RTR status or detection of CMV DNA in plasma. Responses of FcRγ‐NK cells to anti‐CD16 were lower compared to FcRγ+ NK cells. Increased percentages of LIR‐1 + and FcRγ− NK cells correlated with lower FMD. In summary, CMV evokes substantial and similar ADCC responses in CMV seropositive RTR and controls. The equivalence may reflect higher titers of CMV reactive antibody in RTR, as NK responses stimulated by ligation of CD16 were lower. NK cells that were LIR‐1 + and/or FcRγ− were induced by CMV and correlated inversely with vascular endothelial function.

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Section: Resultssupporting

confidence: 91%

Section: A Genetic Determinant Of Cd16 Expression Affects Nk Cell Amentioning

confidence: 99%

Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections

Lee

Doualeh

Affandi

et al. 2019

Journal of Medical Virology

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“…It is possible that there may be differences at the individual level as there are indices that the presence of certain CD16a polymorphisms may increase CD16a expression in NK cells. 29,30 Nevertheless, among the six patients and control subjects tested in the present study, we did not see any that would express CD16b as a dominant form of surface-bound CD16 (Table S4). We reproduced these unexpected findings at the mRNA level, where we confirmed by Sanger sequencing of nested RT-PCR products that CD16a is the dominant form of CD16 in basophils although we also detected low expression of CD16b ( Figure 5).…”

Section: Discussionmentioning

confidence: 62%

Updates on the surface antigens of basophils: CD16 on basophils of patients with respiratory or insect venom allergy and the rejection of CD203c and CD63 externalization decoupling by bisindolylmaleimides

Heneberg

Riegerová

Říhová

et al. 2018

Clin Experimental Allergy

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Summary Background CD16 was previously suggested to be a new marker of basophils that is subject to downregulation by FcεRI crosslinking. Certain compounds, including supraoptimal concentrations of the PKC inhibitors, bisindolylmaleimides, decouple the release of granules containing CD203c, CD63 and histamine, and may thus help to identify the mechanisms related to the CD16 externalization. Objective We hypothesized that CD16 is differentially expressed on the surface of basophils in patients with birch pollen or insect venom allergy and is subject to a regulation in response to allergens. We also employed CD203c and CD63 externalization decoupling by bisindolylmaleimides. Methods We performed a basophil activation test coupled with CD16 and histamine detection using cells isolated from patients with allergy to birch pollen or insect venom and negative controls. We employed two PKC inhibitors, bisindolylmaleimide II and Ro 31‐8220 at their supraoptimal concentrations and, after difficulties reproducing previously published data, we analyzed the fluorescence of these inhibitors alone. We identified the CD16 isoforms by sequencing nested RT‐PCR amplicons from flow cytometry sorted basophils and by cleaving the CD16b GPI anchor using a phospholipase C. Results We provide the first evidence that CD16a is expressed as a surface antigen on a small subpopulation of human basophils in patients with respiratory and insect venom allergy, and this antigen shows increased surface expression following allergen challenge or FcεRI crosslinking. We rejected the apparent decoupling of the surface expression of basophil activation markers following the administration of bisindolylmaleimides. Conclusions & Clinical Relevance The inclusion of αCD16 in negative selection cocktails selects against a subset of basophils that are CD16+ or CD16dim. Using CD16dim basophils and unstained leucocytes, we show that previous studies with supraoptimal concentrations of bisindolylmaleimides are likely flawed and are not associated with the differential expression of CD203c and CD63.

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“…Individuals with valine at position 158 show a higher affinity for rituximab, an augmented NK cell-mediated ADCC activity [82] and better clinical responses to rituximab in FL [83,84], Waldenström macroglobulinemia [85], and DLBCL patientstreated with rituximab plus CHOP (R-CHOP) [86]; although the presence of valine at position 158 does not predict clinical responses in CLL [87]. Furthermore, FCGR3A polymorphisms are involved in CD16 transcription and protein expression, hence influencing NK cell-mediated ADCC [82,88]. FCGR3A (V158F) polymorphism exerts similar effects on the effectiveness of trastuzumab-based therapies [89,90] and cetuximab-mediated ADCC, as well as other cetuximab-based therapies [91,92].…”

Section: The Genetic Backgroundmentioning

confidence: 99%

Mechanisms of Resistance to NK Cell Immunotherapy

Sordo‐Bahamonde

Vitale

Lorenzo‐Herrero

et al. 2020

Cancers

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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

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SNPs rs4656317 and rs12071048 located within an enhancer in FCGR3A are in strong linkage disequilibrium with rs396991 and influence NK cell-mediated ADCC by transcriptional regulation

Cited by 9 publications

References 50 publications

Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections

Functional and clinical consequences of changes to natural killer cell phenotypes driven by chronic cytomegalovirus infections

Updates on the surface antigens of basophils: CD16 on basophils of patients with respiratory or insect venom allergy and the rejection of CD203c and CD63 externalization decoupling by bisindolylmaleimides

Mechanisms of Resistance to NK Cell Immunotherapy

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