Dynamics of the Interaction of Human IgG Subtype Immune Complexes with Cells Expressing R and H Allelic Forms of a Low-Affinity Fcγ Receptor CD32A

Shashidharamurthy, Rangaiah; Zhang, Fang; Amano, Aaron; Kamat, Aparna A.; Panchanathan, Ravichandran; Ezekwudo, Daniel; Zhu, Cheng; Selvaraj, Periasamy

doi:10.4049/jimmunol.0902550

Cited by 42 publications

(48 citation statements)

References 50 publications

(53 reference statements)

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“…It seems like the R/R131 allele increases the susceptibility to both bacterial infections and autoimmune diseases, whereas the H/H131 allele does not. The heterozygote R/H131 is phenotypically similar to H/H131 [29]. The R/R131 genotype binds CRP with high affinity, IgG with low affinity.…”

Section: Discussionmentioning

confidence: 99%

“…R/R131 homozygotes bind CRP with high affinity, H/H131 homozygotes with low affinity, and H/R131 heterozygotes with intermediate affinity [13]. Recently, it was shown that the H-allele outcompeted the R-allele when their protein products simultaneously competed for IgG as a ligand [29]. In contrast to CRP, IgG2-binding to FccRIIa is lower in the R131 than in the H131 allotype [30].…”

Section: Discussionmentioning

confidence: 99%

“…3). Previously, it has been shown that the H-allele coded receptor dominates over R in heterozygotes when they simultaneously compete for the same ligand; however, in these experiments, IgG was the ligand, not CRP [29]. CRP, C-reactive protein; fMLP, formyl-methionyl-leucyl-phenylalanine; RGD, Arginine-Glycine-Aspartic Acid.…”

Section: Characterization Of the Crp-responding Neutrophilsmentioning

confidence: 93%

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C‐Reactive Protein Triggers Calcium Signalling in Human Neutrophilic Granulocytes via FcγRIIa in an Allele‐Specific Way

et al. 2013

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C-reactive protein (CRP) binds to Fcc-receptors, FccRIIa (CD32) with high affinity and to FccRIa (CD64) with low affinity. The binding to CD32 has been shown to be allele specific, that is, it binds to R/R131 but not to H/H131. Little is known about the cooperation of CRP and neutrophilic granulocytes (PMNs) in inflammatory reactions. The purpose of the present study was to examine CRP signalling in human PMNs, and whether this signalling is also allele specific. Cytosolic calcium of PMN was measured in a single-cell digital imaging system. Receptor expression and polymorphism were studied by real-time RT-PCR, flow cytometry and standard PCR. C-reactive protein induced cytosolic calcium signals in PMNs from homozygote R/R131donors, but not in PMNs from heterozygote R/H131 donors. However, after the heterozygote PMNs had been incubated with IFN-c (100 U/ml) for 2 h, both the proportion of cells responding and the size of the CRP-induced calcium signals increased. IFN-c increased mRNA expression of CD64 about fivefold and surface protein expression of CD64 about fourfold. The calcium signal elicited by CRP was augmented by PMN adhesion to fibronectin, but almost totally abrogated by sphingosine kinase inhibitors. The signals were partly dependent on calcium influx. In conclusion, calcium signalling instigated by CRP in human PMN is FccRIIa allele specific, as R/R131 responded to CRP, whereas R/H131 did not. However, increased expression of FccRIa (CD64), stimulated by IFN-c, can augment calcium signalling by CRP in low-responders. This suggests that the state of the PMNs, as well as the genetic origin, affect sensitivity for CRP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Characterization Of the Crp-responding Neutrophilsmentioning

confidence: 93%

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C‐Reactive Protein Triggers Calcium Signalling in Human Neutrophilic Granulocytes via FcγRIIa in an Allele‐Specific Way

et al. 2013

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“…Phagocytes can express Fc␥R3a but typically do so at lower levels, relying primarily on Fc␥R2a, which may also bind to a broader array of subclasses, but is insensitive to Fc domain fucosylation, for activity (18,53). Thus, differences in IgG subclass distribution and glycosylation among or even within subclasses (particularly IgG1 and IgG3) within the broader pool of HIV-specific antibodies present in each patient population may lead to altered recruitment of innate immune cell subsets expressing different Fc␥Rs, resulting in the differential antiviral clearance observed in this study.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

Ackerman

Dugast

McAndrew

et al. 2013

J Virol

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While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their Fc␥R usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with Fc␥R2a and Fc␥R2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis-driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response.

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“…To determine whether this action plays a role in the generation of secondary Ab responses, we blocked ICs from binding to FcgRs by using CD32-Ig, a recombinant soluble FcgR dimer that binds the Fc regions of ICs with higher avidity than do cell-surface FcgRs (21,22). We immunized cohorts of B6 mice i.p.…”

Section: Ics Stimulate Secondary Responses Through Fcgr Binding Not mentioning

confidence: 99%

Immune Complex-Mediated Enhancement of Secondary Antibody Responses

Goins

Chappell

Shashidharamurthy

et al. 2010

The Journal of Immunology

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Immunologic memory is a hallmark of the vertebrate immune system. The first antigenic exposure leads to a slow and modest immune response, whereas repeated exposure, even many years later, leads to a rapid and exaggerated response that is two to three orders of magnitude greater than the primary. In the case of humoral immunity, the increased efficacy of recall responses is due to the production of amplified levels of Ag-specific Ab, as well as the accelerated kinetics of their production. Current thinking suggests that this is due to selective activation of long-lived, Ag-specific memory B cells. A downside of restricting secondary responses solely to memory cells is that the repertoire of the memory B cell pool remains static while pathogens continue to evolve. In this study, we propose that during secondary responses, naive Ag-specific B cells participate alongside memory cells. We show that immune complexes formed in vivo between the Ag and pre-existing Abs from the primary response activate these naive B cells, inducing them to respond with accelerated kinetics and increased magnitude. Thus, the continued recruitment of new B cell clones after each antigenic exposure enables the immune system to stay abreast of rapidly changing pathogens.

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Dynamics of the Interaction of Human IgG Subtype Immune Complexes with Cells Expressing R and H Allelic Forms of a Low-Affinity Fcγ Receptor CD32A

Cited by 42 publications

References 50 publications

C‐Reactive Protein Triggers Calcium Signalling in Human Neutrophilic Granulocytes via FcγRIIa in an Allele‐Specific Way

C‐Reactive Protein Triggers Calcium Signalling in Human Neutrophilic Granulocytes via FcγRIIa in an Allele‐Specific Way

Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

Immune Complex-Mediated Enhancement of Secondary Antibody Responses

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