Antibodies produced in response to a foreign antigen are characterized by polyclonality, not only in the diverse epitopes to which their variable domains bind but also in the various effector ...molecules to which their constant regions (Fc domains) engage. Thus, the antibody's Fc domain mediates diverse effector activities by engaging two distinct classes of Fc receptors (type I and type II) on the basis of the two dominant conformational states that the Fc domain may adopt. These conformational states are regulated by the differences among antibody subclasses in their amino acid sequence and by the complex, biantennary Fc-associated N-linked glycan. Here we discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in China at the end of 2019 has spread throughout the world and caused many thousands of deaths. The previous study ...reported a higher severe status rate and mortality rate in male patients in China. However, the reason underlying this difference has not been reported. The convalescent plasma containing a high level of SARS‐CoV‐2 immunoglobulin G (IgG) antibody has been used in clinical therapy and achieved good effects in China. In this study, to compare the differences of the SARS‐CoV‐2 IgG antibody between male and female patients, a total number of 331 patients confirmed SARS‐CoV‐2 infection were enrolled. The serum of these patients was collected during hospitalization and detected for the SARS‐CoV‐2 IgG antibody. Our data showed that the concentration of IgG antibody in mild, general, and recovering patients showed no difference between male and female patients. In severe status, compared with male patients, there were more female patients having a relatively high concentration of serum SARS‐CoV‐2 IgG antibody. In addition, the generation of IgG antibody in female patients was stronger than male patients in disease early phase. Our study identified a discrepancy in the SARS‐CoV‐2 IgG antibody level in male and female patients, which may be a potential cause leading to a different outcome of Coronavirus Disease 2019 between sex.
Antibodies are widely considered to be a frequent primary and often mechanistic correlate of protection of approved vaccines; thus evaluating the antibody response is of critical importance in ...attempting to understand and predict the efficacy of novel vaccine candidates. Historically, antibody responses have been analyzed by determining the titer of the humoral response using measurements such as an ELISA, neutralization, or agglutination assays. In the simplest case, sufficiently high titers of antibody against vaccine antigen(s) are sufficient to predict protection. However, antibody titer provides only a partial measure of antibody function, which is dependent on both the variable region (Fv) to bind the antigen target, and the constant region (Fc) to elicit an effector response from the innate arm of the immune system. In the case of some diseases, such as HIV, for which an effective vaccine has proven elusive, antibody effector function has been shown to be an important driver of monoclonal antibody therapy outcomes, of viral control in infected patients, and of vaccine-mediated protection in preclinical and clinical studies. We sought to establish a platform for the evaluation of the Fc domain characteristics of antigen-specific antibodies present in polyclonal samples in order to better develop insights into Fc receptor-mediated antibody effector activity, more fully understand how antibody responses may differ in association with disease progression and between subject groups, and differentiate protective from non-protective responses. To this end we have developed a high throughput biophysical platform capable of simultaneously evaluating many dimensions of the antibody effector response.
•High-throughput array-based characterization platform for polyclonal antibodies.•Development of a biophysical proxy for antibody effector function.•Antigen and Fc receptor recognition characteristics are captured.•Enables systematic serologic studies of NHP and human antibody samples.
In this study, the relationship between serum lgG levels and the prognosis for colorectal perforations was examined. The subjects of this study were patients with generalized peritonitis due to ...colorectal perforations who were treated at our hospital between September 1st, 2011 and June 30th, 2013. Comparisons on the systemic inflammatory response syndrome (SIRS) period after surgery, duration of respirator use, and ICU duration were made between two groups of patients with normal IgG levels of 800 mg/dL or more and with hypo-lgG levels of less than 800 mg/dL. There were 27 cases during the study period, out of which 18 had normal IgG levels and the remaining 9 had hypo-lgG levels. The SIRS period of the hypo-lgG group was longer compared to the normal IgG group (12.9±14.2 days vs. 6.4±9.1 days). In addition, the hypo-lgG group had a longer duration of respirator use (8.1±7.0 days vs. 2.0±2.8 days), which resulted in prolonged ICU duration compared to the normal IgG group (14.4±13.1 days vs. 5.7±4.5 days). Hypo-lgG levels prior to surgery for colorectal perforation were associated with severe conditions. Thus, our results suggest improvement of the prognosis can be achieved by compensating for the IgG levels.
Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral ...antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.
Mouse and human neutrophils induce anaphylaxis Jönsson, Friederike; Mancardi, David A; Kita, Yoshihiro ...
The Journal of clinical investigation,
04/2011, Volume:
121, Issue:
4
Journal Article
Peer reviewed
Open access
Anaphylaxis is a life-threatening hyperacute immediate hypersensitivity reaction. Classically, it depends on IgE, FcεRI, mast cells, and histamine. However, anaphylaxis can also be induced by IgG ...antibodies, and an IgG1-induced passive type of systemic anaphylaxis has been reported to depend on basophils. In addition, it was found that neither mast cells nor basophils were required in mouse models of active systemic anaphylaxis. Therefore, we investigated what antibodies, receptors, and cells are involved in active systemic anaphylaxis in mice. We found that IgG antibodies, FcγRIIIA and FcγRIV, platelet-activating factor, neutrophils, and, to a lesser extent, basophils were involved. Neutrophil activation could be monitored in vivo during anaphylaxis. Neutrophil depletion inhibited active, and also passive, systemic anaphylaxis. Importantly, mouse and human neutrophils each restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis in mice and suggesting that neutrophils can contribute to anaphylaxis in humans. Our results therefore reveal an unexpected role for IgG, IgG receptors, and neutrophils in anaphylaxis in mice. These molecules and cells could be potential new targets for the development of anaphylaxis therapeutics if the same mechanism is responsible for anaphylaxis in humans.
IgG antibodies (Abs) mediate their effector functions through the interaction with Fcγ receptors (FcγRs) and the complement factors. The main IgG-mediated complement activation pathway is induced ...through the binding of complement C1q to IgG Abs. This interaction is dependent on antigen-dependent hexamer formation of human IgG1 and IgG3 to increase the affinity for the six-headed C1q molecule. By contrast, human IgG4 fails to bind to C1q. Instead, it has been suggested that human IgG4 can block IgG1 and IgG3 hexamerization required for their binding to C1q and activating the complement. Here, we show that murine IgG1, which functionally resembles human IgG4 by not interacting with C1q, inhibits the binding of IgG2a, IgG2b, and IgG3 to C1q
, and suppresses IgG2a-mediated complement activation in a hemolytic assay in an antigen-dependent and IgG subclass-specific manner. From this perspective, we discuss the potential of murine IgG1 and human IgG4 to block the complement activation as well as suppressive effects of sialylated IgG subclass Abs on FcγR-mediated immune cell activation. Accumulating evidence suggests that both mechanisms seem to be responsible for preventing uncontrolled IgG (auto)Ab-induced inflammation in mice and humans. Distinct IgG subclass distributions and functionally opposite IgG Fc glycosylation patterns might explain different outcomes of IgG-mediated immune responses and provide new therapeutic options through the induction, enrichment, or application of antigen-specific sialylated human IgG4 to prevent complement and FcγR activation as well.
IgG subclasses determine pathways of anaphylaxis in mice Beutier, Héloïse, PharmD; Gillis, Caitlin M., BSci; Iannascoli, Bruno, BTS ...
Journal of allergy and clinical immunology,
01/2017, Volume:
139, Issue:
1
Journal Article
Peer reviewed
Open access
Background Animal models have demonstrated that allergen-specific IgG confers sensitivity to systemic anaphylaxis that relies on IgG Fc receptors (FcγRs). Mouse IgG2a and IgG2b bind activating FcγRI, ...FcγRIII, and FcγRIV and inhibitory FcγRIIB; mouse IgG1 binds only FcγRIII and FcγRIIB. Although these interactions are of strikingly different affinities, these 3 IgG subclasses have been shown to enable induction of systemic anaphylaxis. Objective We sought to determine which pathways control the induction of IgG1 -, IgG2a -, and IgG2b -dependent passive systemic anaphylaxis. Methods Mice were sensitized with IgG1 , IgG2a , or IgG2b anti-trinitrophenyl mAbs and challenged with trinitrophenyl-BSA intravenously to induce systemic anaphylaxis that was monitored by using rectal temperature. Anaphylaxis was evaluated in mice deficient for FcγRs injected with mediator antagonists or in which basophils, monocytes/macrophages, or neutrophils had been depleted. FcγR expression was evaluated on these cells before and after anaphylaxis. Results Activating FcγRIII is the receptor primarily responsible for all 3 models of anaphylaxis, and subsequent downregulation of this receptor was observed. These models differentially relied on histamine release and the contribution of mast cells, basophils, macrophages, and neutrophils. Strikingly, basophil contribution and histamine predominance in mice with IgG1 - and IgG2b -induced anaphylaxis correlated with the ability of inhibitory FcγRIIB to negatively regulate these models of anaphylaxis. Conclusion We propose that the differential expression of inhibitory FcγRIIB on myeloid cells and its differential binding of IgG subclasses controls the contributions of mast cells, basophils, neutrophils, and macrophages to IgG subclass–dependent anaphylaxis. Collectively, our results unravel novel complexities in the involvement and regulation of cell populations in IgG-dependent reactions in vivo.
Summary
Beyond their prominent role in hemostasis and thrombosis, platelets are increasingly recognized as having immunologic functions. Supporting this, human platelets express FcγRIIA (CD32a), a ...low‐affinity Fc receptor (FcR) for the constant region of IgG that recognizes immune complexes (ICs) and IgG‐opsonized cells with high avidity. In leukocytes, FcγRIIA engagement initiates strong effector functions that are key for immune and inflammatory responses, including cytokine release, antibody‐dependent cell‐mediated killing of pathogens, and internalization of ICs. However, the physiologic relevance of platelet‐expressed FcγRIIA has received little attention in previous reviews on FcRs. This article summarizes and discusses the available information on human platelet FcγRIIA. The importance of this receptor in heparin‐induced thrombocytopenia, a prothrombotic adverse drug effect, is well documented. However, studies demonstrating platelet activation by IgG‐opsonized bacteria point to the physiologic relevance of platelet FcγRIIA in immunity. In this context, platelet activation and secretion may facilitate both a direct antimicrobial function of platelets and crosstalk with other immune cells. Additionally, a role for platelet FcγRIIA in IgG‐independent hemostasis and physiologic thrombosis, by means of amplifying integrin αIIbβ3 outside‐in signaling, has also been proposed. Nonetheless, the thrombotic complications found in some infective and autoimmune diseases may result from unbalanced FcγRIIA‐mediated platelet aggregation. Moreover, FcγRIIA is not expressed in mice, and thrombocytopenia and/or thrombotic events found after drug administration can only be recapitulated by the use of human FcγRIIA‐transgenic mice. Altogether, the available data support a functional role for platelet FcγRIIA in health and disease, and emphasize the need for further investigation of this receptor.
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The adsorption of mouse monoclonal immunoglobulin G (IgG) on negatively charged polystyrene microparticles was studied by the laser Doppler velocimetry (LDV) electrophoretic mobility ...measurements. The dependence of the electrophoretic mobility of microparticles on the IgG concentration in the suspension was determined for different ionic strengths and pHs (3.5, 7.4). The increase in the electrophoretic mobility was quantitatively interpreted in terms of the 3D electrokinetic model. The maximum coverage of IgG on latex was determined by the depletion method aided by AFM imaging. It was shown by monitoring the electrophoretic mobility and hydrodynamic dimeter of IgG covered microparticles over prolonged time periods that IgG adsorption was irreversible. The acid-base properties of the IgG monolayers were also determined in pH cycling experiments. It was also confirmed that the adsorption of human serum albumin (HSA) on saturated IgG monolayers, often referred to as blocking, was negligible at pH 7.4.
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