The weaker-binding Fc γ receptor IIIa F158 allotype retains sensitivity to N-glycan composition and exhibits a destabilized antibody-binding interface

Kremer, Paul G.; Barb, Adam W.

doi:10.1016/j.jbc.2022.102329

Cited by 10 publications

(10 citation statements)

References 43 publications

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“…The FcgRIIIa-158V allotype has a higher binding affinity to IgG1 compared to the 158F allotype (62). This has recently been attributed to the formation of a less stable complex between the 158F allotype with IgG in comparison to the I58V allotype (63). This is also confirmed in our setup, where the FcgRIIIa-158V binding affinity is on average 4-6 times higher compared to FcgRIIIa-158F.…”

Section: Discussionsupporting

confidence: 88%

“…This is also confirmed in our setup, where the FcgRIIIa-158V binding affinity is on average 4-6 times higher compared to FcgRIIIa-158F. Besides the different allelic variants, the FcgRIIIa N-glycosylation of both the 158F and V allotype also influences IgG1 binding (29,30,63). The Asn162 N-glycan site, and to a lesser extent Asn45, have shown to affect antibody-binding affinity (29,30).…”

Section: Discussionsupporting

confidence: 77%

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Role of N-Glycosylation in FcγRIIIa interaction with IgG

Coillie

Schultz²,

Bentlage³

et al. 2022

Front. Immunol.

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Immunoglobulins G (IgG) and their Fc gamma receptors (FcγRs) play important roles in our immune system. The conserved N-glycan in the Fc region of IgG1 impacts interaction of IgG with FcγRs and the resulting effector functions, which has led to the design of antibody therapeutics with greatly improved antibody-dependent cell cytotoxicity (ADCC) activities. Studies have suggested that also N-glycosylation of the FcγRIII affects receptor interactions with IgG, but detailed studies of the interaction of IgG1 and FcγRIIIa with distinct N-glycans have been hindered by the natural heterogeneity in N-glycosylation. In this study, we employed comprehensive genetic engineering of the N-glycosylation capacities in mammalian cell lines to express IgG1 and FcγRIIIa with different N-glycan structures to more generally explore the role of N-glycosylation in IgG1:FcγRIIIa binding interactions. We included FcγRIIIa variants of both the 158F and 158V allotypes and investigated the key N-glycan features that affected binding affinity. Our study confirms that afucosylated IgG1 has the highest binding affinity to oligomannose FcγRIIIa, a glycan structure commonly found on Asn162 on FcγRIIIa expressed by NK cells but not monocytes or recombinantly expressed FcγRIIIa.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 77%

Role of N-Glycosylation in FcγRIIIa interaction with IgG

Coillie

Schultz²,

Bentlage³

et al. 2022

Front. Immunol.

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“…The degree of B cell depletion due to rituximab depends on the FCGR3A p158 polymorphism and NMOSD patients with the F allele have an increased risk of relapse due to insufficient memory B cell depletion. The suggested reason for this is that the FCGR3A p158 F/F genotype reduces the affinity of autoantibodies for NK cells and have the slower binding rate, resulting in reduced Antibody-dependent cellular cytotoxicity (ADCC) efficacy of NK cells [ 33 , 34 ]. Similar polymorphism changes have also been reported in anti-myelin-associated glycoprotein (MAG) neuropathy and rheumatoid arthritis [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder

Nishiyama

Wright

Lotan

et al. 2022

J Neuroinflammation

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Background and objectives Inhibition of terminal complement in neuromyelitis optica spectrum disorder (NMOSD) using eculizumab helps prevent relapses, but the exact mechanism of action of the drug remains unclear. Similarly, genetic variants in the Fc Gamma receptor 3A (FCGR3A), also known as CD16, are correlated with outcomes in NMOSD, but the immune cells expressing those CD16 are unknown. We compared CD16 expression on immune cells modulated by complement activity in natural killer (NK) cells and natural killer-T (NKT) cells in NMOSD to disease and normal-healthy controls. Methods Peripheral blood cell (PBMC) samples from 45 patients with NMOSD with aquaporin 4 (AQP4)-IgG, 18 disease controls, and 19 normal controls were analyzed for CD16 expression and complement receptors in vitro. Results At baseline, the number of NKT cells was increased in NMOSD (p < 0.001), but the proportion that was CD16 positive was lower compared to normal and disease controls (p = 0.0012). NK cell count was normal, but the ratio that was CD16 positive was also significantly lower (p < 0.001). In both NK cells and NKT cells from NMOSD, C5 complement receptor expression was much higher than normal and disease controls (p < 0.001 for both). We also evaluated activation markers CD69 and CD83, which were also significantly higher in NK and NKT cells from NMOSD patients. FCGR3A p158 V/V genotype group in NMOSD patients showed decreased NK cell proportion with activation, and fewer CD16-expressing NKT cells than the F/F genotype group. Discussion Our results support an immunopathogenesis model in which complement pathway activation in NK/NKT cells upregulates CD16 expression that binds to antibody/antigen complexes. In the context of NMOSD, these complement-sensitive cells may be responsible for the escalating autoimmune activity.

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“…The degree of B cell depletion due to rituximab depends on the FCGR3A p158 polymorphism and NMOSD patients with the F allele have an increased risk of relapse due to insu cient memory B cell depletion. The suggested reason for this is that the FCGR3A p158 F/F genotype reduces the a nity of autoantibodies for NK cells and have the slower binding rate, resulting in reduced ADCC e cacy of NK cells (32,33). Similar polymorphism changes have also been reported in anti-myelinassociated glycoprotein (MAG) neuropathy and rheumatoid arthritis (34,35).…”

Section: Discussionmentioning

confidence: 84%

Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder

Nishiyama

Wright

Lotan

et al. 2022

Preprint

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Background and objectives. Inhibition of terminal complement in neuromyelitis optica spectrum disorder (NMOSD) using eculizumab helps prevent relapses, but the exact mechanism of action of the drug remains unclear. Similarly, genetic variants in the Fc Gamma receptor 3A (FcGR3A), also known as CD16, are correlated with outcomes in NMOSD, but the immune cells expressing those CD16 are unknown. We compared CD16 expression on immune cells modulated by complement activity in Natural Killer (NK) cells and Natural Killer-T (NKT) cells in NMOSD to disease and normal-healthy controls. Methods. Peripheral blood cell (PBMC) samples from 45 patients with NMOSD with aquaporin 4 (AQP4)-IgG, 18 disease controls, and 19 normal controls were analyzed for FcGR3A expression and complement receptors in vitro. Results. At baseline, the number of NKT cells was increased in NMOSD (p < 0.001), but the proportion that was CD16 positive was lower compared to normal and disease controls (p=0.0012). NK cell count was normal, but the ratio that was CD16 positive was also significantly lower (p < 0.001). In both NK cells and NKT cells from NMOSD, C5 complement receptor expression was much higher than normal and disease controls (p < 0.001 for both). We also evaluated activation markers CD69 and CD83, which were also significantly higher in NK and NKT cells from NMOSD patients. FcGR3A p158 V/V genotype group in NMOSD patients showed decreased NK cell proportion with activation, and fewer CD16 expressed NKT cells than the F/F genotype group. Discussion. Our results support an immunopathogenesis model in which complement pathway activation in NK/NKT cells upregulates CD16 expression that binds to antibody/antigen complexes. In the context of NMOSD, these complement-sensitive cells may be responsible for the escalating autoimmune activity.

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The weaker-binding Fc γ receptor IIIa F158 allotype retains sensitivity to N-glycan composition and exhibits a destabilized antibody-binding interface

Cited by 10 publications

References 43 publications

Role of N-Glycosylation in FcγRIIIa interaction with IgG

Role of N-Glycosylation in FcγRIIIa interaction with IgG

Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder

Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder

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