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Summary Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti‐microbial antibody isotype due to their long half‐life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self‐reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self‐tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre‐clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc‐domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation. [ABSTRACT FROM AUTHOR]

Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures-either hybrid immunity or two doses of vaccine alone-represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus. IMPORTANCE Recent data indicates improved immunity to SARS-CoV-2 in individuals who experience a combination of two mRNA vaccine doses and infection, "hybrid immunity," compared to individuals who receive vaccination or experience infection alone. While previous infection accelerates the vaccine-induced immune response following the first dose of mRNA vaccination, subsequent doses demonstrate negligible increases in antibody titers or T cell immunity. Here, using systems serology, we observed a unique antibody profile induced by hybrid immunity, marked by the unique induction of robust Fc-recruiting antibodies directed at the conserved region of the viral Spike antigen, the S2-domain, induced at lower levels in individuals who only received mRNA vaccination. Thus, hybrid immunity clearly redirects vaccine-induced immunodominance, resulting in the induction of a robust functional humoral immune response to the most highly conserved region of the SARS-CoV-2 Spike antigen, which may be key to protection against existing and emerging variants of concern. Thus, next-generation vaccines able to mimic hybrid immunity and drive a balanced response to conserved regions of the Spike antigen may confer enhanced protection against disease.

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis. [Display omitted] • Antibodies are key drivers of thrombosis, irrespective of their antigen specificity • IgM binds endothelial FcμR and pIgR, starting platelet recruitment to the vessel wall • IgG locates to fibrin on activated platelets and activates classical complement • Therapeutic complement inhibition limits thrombosis without compromising hemostasis Conventional anticoagulant therapies to prevent thrombosis also carry inherent bleeding risks. Identifying that antibodies and complement are key drivers of venous thrombosis in mice, Stark et al. not only find hallmarks of the mechanism preserved in humans but also show that therapeutic complement inhibition prevents thrombosis without negatively impacting hemostasis. [ABSTRACT FROM AUTHOR]

Healthy immune responses require efficient protection without excessive inflammation. Recent discoveries on the degree of fucosylation of a human N-linked glycan at a conserved site in the immunoglobulin IgG-Fc domain might add an additional regulatory layer to adaptive humoral immunity. Specifically, afucosylation of IgG-Fc enhances the interaction of IgG with FcγRIII and thereby its activity. Although plasma IgG is generally fucosylated, afucosylated IgG is raised in responses to enveloped viruses and Plasmodium falciparum proteins expressed on infected erythrocytes, as well as during alloimmune responses. Moreover, while afucosylation can exacerbate some infectious diseases (e.g., COVID-19), it also correlates with traits of protective immunity against malaria and HIV-1. Herein we discuss the implications of IgG afucosylation for health and disease, as well as for vaccination. Afucosylation of the IgG-Fc acts as a binary switch for strong binding to Fc receptors (FcγRIII) expressed on myeloid and natural killer cells, thereby steering the cellular response elicited by the IgG. Although immune responses in humans generally produce fully fucosylated IgG, some antigen-specific IgG responses can be predominantly afucosylated. The consequences of afucosylated responses vary depending on the setting. Afucosylated antigen-specific IgG leads to immunopathology in SARS-CoV-2 and dengue virus infections, and enhanced severity in alloimmunity (pregnancy and transplantation), while correlating with control of HIV-1 infections and protective traits against malaria. Identifying how afucosylated responses are regulated is vital for understanding how these traits evolve in health and disease, as well as in preventing or promoting these responses after vaccination. IgG is normally fully fucosylated, and afucosylated IgG is only raised against antigens associated with human cells, thus introducing a mechanism for fine-tuning IgG potency through increased affinity for FcγRIII. Unveiling the molecular mechanisms underlying the formation of afucosylated IgG can enhance our understanding of infectious/non-infectious diseases and improved vaccine design. [ABSTRACT FROM AUTHOR]

Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity. [ABSTRACT FROM AUTHOR]

ABSTRACT Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures—either hybrid immunity or two doses of vaccine alone—represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus. IMPORTANCE Recent data indicates improved immunity to SARS-CoV-2 in individuals who experience a combination of two mRNA vaccine doses and infection, “hybrid immunity,” compared to individuals who receive vaccination or experience infection alone. While previous infection accelerates the vaccine-induced immune response following the first dose of mRNA vaccination, subsequent doses demonstrate negligible increases in antibody titers or T cell immunity. Here, using systems serology, we observed a unique antibody profile induced by hybrid immunity, marked by the unique induction of robust Fc-recruiting antibodies directed at the conserved region of the viral Spike antigen, the S2-domain, induced at lower levels in individuals who only received mRNA vaccination. Thus, hybrid immunity clearly redirects vaccine-induced immunodominance, resulting in the induction of a robust functional humoral immune response to the most highly conserved region of the SARS-CoV-2 Spike antigen, which may be key to protection against existing and emerging variants of concern. Thus, next-generation vaccines able to mimic hybrid immunity and drive a balanced response to conserved regions of the Spike antigen may confer enhanced protection against disease.

Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.

Summary: Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and “cytokine storm”. The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and "cytokine storm". The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response. [ABSTRACT FROM AUTHOR]

Receptors recognizing the Fc-part of immunoglobulins (FcR) are important in the engagement of phagocytes with opsonized micro-organisms, but they also play a major role in the pathogenesis of chronic inflammatory diseases. Different FcRs are specifically recognizing and binding the different classes of immunoglobulins, transmitting different signals into the cell. The function of IgG (FcγR's) and IgA (FcαR) recognizing receptors is controlled by cellular signals evoked by activation of heterologous receptors in a process generally referred to as inside-out control. This concept is clearly described for the regulation of integrin receptors. Inside-out control can be achieved at different levels by modulation of: (i) receptor affinity, (ii) receptor avidity/valency, (iii) interaction with signaling chains, (iv) interaction with other receptors and (v) localization in functionally different membrane domains. The inside-out control of FcRs is an interesting target for novel therapy by therapeutical antibodies as it can potentiate or decrease the functionality of the response to the antibodies depending on the mechanisms of the diseases they are applied for.

Receptors recognizing the Fc-part of immunoglobulins (FcR) are important in the engagement of phagocytes with opsonized micro-organisms, but they also play a major role in the pathogenesis of chronic inflammatory diseases. Different FcRs are specifically recognizing and binding the different classes of immunoglobulins, transmitting different signals into the cell. The function of IgG (FcγR's) and IgA (FcαR) recognizing receptors is controlled by cellular signals evoked by activation of heterologous receptors in a process generally referred to as inside-out control. This concept is clearly described for the regulation of integrin receptors. Inside-out control can be achieved at different levels by modulation of: (i) receptor affinity, (ii) receptor avidity/valency, (iii) interaction with signaling chains, (iv) interaction with other receptors and (v) localization in functionally different membrane domains. The inside-out control of FcRs is an interesting target for novel therapy by therapeutical antibodies as it can potentiate or decrease the functionality of the response to the antibodies depending on the mechanisms of the diseases they are applied for. [ABSTRACT FROM AUTHOR]

Therapeutic antibodies (IgG-type) contain several post-translational modifications (PTMs) whereby introducing a large heterogeneity, both structural and functional, into this class of therapeutics. Of these modifications, glycosylation in the fragment crystallizable (Fc) region is the most heterogeneous PTM, which can affect the stability of the molecule and interactions with Fc-receptors in vivo . Hence, the glycoform distribution can affect the mode of action and have implications for bioactivity, safety and efficacy of the drug. Main topics of the manuscript include: What factors influence the (Fc) glycan pattern in therapeutic antibodies and how can these glycans be characterized? How does structure of the Fc-glycan relate to function and what methods are available to characterize those functions? Although heterogeneous in their scope, the different sections are intended to combine current knowledge on structure-function correlations of IgG glycan structures with regard to Fc (effector) functions, as well as basic aspects and methodologies for their assessment. [ABSTRACT FROM AUTHOR]

Both lymphoid and myeloid cells express Fc-receptors (FcRs). Low affinity FcRs engage circulating immune complexes, which results in the cellular activation and proinflammatory cytokine production. FcRs participate in the internalization, transport and/or recycling of antibodies and antigens. Cytosolic FcRs also route these proteins to proteasomes and antigen presentation pathways. Non-activated CD4+ T-cells do not express FcRs. Once activated, naïve CD4+ T-cells express FcγRIIIa, which upon IC ligation, provide a co-stimulatory signal for the differentiation of these cells into effector cell population. FcγRIIIa present on CD4+ T-cell membrane could internalize nucleic acid containing ICs and elicit a cross-talk with toll-like receptors. FcγRIIIa common γ-chain forms a heterodimer with the ζ-chain of T-cell receptor complex, suggesting a synergistic role for these receptors. This review first summarizes our current understanding of FcRs on CD4+ T-cells. Thereafter, I will attempt to correlate the findings from the recent literature on FcRs and propose a role for these receptors in modulating adaptive immune responses via TLR signaling, nucleic acid sensing and epigenetic changes in CD4+ T-cells.

Abstract Since the first description in 1989 of CD4‐Fc‐fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc‐fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non‐clinical applications of Fc‐fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc‐fusion proteins for each application, with particular attention to the newer, less charted areas.

Despite global vaccination efforts, influenza virus continues to cause yearly epidemics and periodic pandemics throughout most of the world. Many of us consider the generation of broader, potent and long-lasting immunity against influenza viruses as critical in curtailing the global health and economic impact that influenza currently plays. To date, classical vaccinology has relied on the generation of neutralizing antibodies as the benchmark to measure vaccine effectiveness. However, recent developments in numerous related fields of biomedical research including, HIV, HSV and DENV have emphasized the importance of Fc-mediate effector functions in pathogenesis and immunity. The concept of Fc effector functions in contributing to protection from illness is not a new concept and has been investigated in the field for over four decades. However, in recent years the application and study of Fc effector functions has become revitalized with new knowledge and technologies to characterize their potential importance in immunity. In this perspective, we describe the current state of the field of Influenza Fc effector functions and discuss its potential utility in universal vaccine design in the future.

Neutrophils play a critical role in antimicrobial host defense, but their improper activation also contributes to inflammation-induced tissue damage. Therefore, understanding neutrophil biology is important for the understanding, diagnosis, and therapy of both infectious and inflammatory diseases. Neutrophils express a large number of cell-surface receptors that sense extracellular cues and trigger various functional responses through complex intracellular signaling pathways. During the last several years, we and others have shown that tyrosine kinases play a critical role in those processes. In particular, Src-family and Syk tyrosine kinases couple Fc-receptors and adhesion receptors (integrins and selectins) to various neutrophil effector functions. This pathway shows surprising similarity to lymphocyte antigen receptor signaling and involves various other enzymes (e.g. PLCγ2), exchange factors (e.g. Vav-family members) and adapter proteins (such as ITAM-containing adapters, SLP-76, and CARD9). Those mediators trigger various antimicrobial functions and play a critical role in coordinating the inflammatory response through the release of inflammatory mediators, such as chemokines and LTB4. Interestingly, however, tyrosine kinases have a limited direct role in the migration of neutrophils to the site of inflammation. Here, we review the role of tyrosine kinase signaling pathways in neutrophils and how those pathways contribute to neutrophil activation in health and disease. [ABSTRACT FROM AUTHOR]

Both lymphoid and myeloid cells express Fc receptors (FcRs). Low-affinity FcRs engage circulating immune complexes, which results in the cellular activation and p ro-inflammatory cytokine production. FcRs participate in the internalization, transport, and/or recycling of antibodies and antigens. Cytosolic FcRs also route these proteins to proteasomes and antigen-presentation pathways. Non-activated CD4+ T-cells do not express FcRs. Once activated, naive CD4+ T-cells express FcγRIIIa, which, upon IC ligation, provide a costimulatory signal for the differentiation of these cells into effector cell population. FcγRIIIa present on CD4+ T-cell membrane could internalize nucleic acid-containing ICs and elicit a cross-talk with toll-like receptors. FcγRIIIa common γ-chain forms a heterodimer with the ζ-chain of T-cell receptor complex, suggesting a synergistic role for these receptors. This review first summarizes our current understanding of FcRs on CD4+ T-cells. Thereafter, I will attempt to correlate the findings from the recent literature on FcRs and propose a role for these receptors in modulating adaptive immune responses via TLR signaling, nucleic acid sensing, and epigenetic changes in CD4+ T-cells. [ABSTRACT FROM AUTHOR]

The lack of vaccines against several important viral diseases necessitates the development of therapeutics to save lives and control epidemics. In recent years, therapeutic antibodies have received considerable attention due to their good safety profiles and clinical success when used against viruses such as respiratory syncytial virus, Ebola virus and Hendra virus. The binding affinity of these antibodies can directly impact their therapeutic efficacy. However, we and others have also demonstrated that the subtype of Fc-gamma receptors (FcγRs) engaged influences the stoichiometric requirement for virus neutralization. Hence, the development of therapeutic antibodies against infectious diseases should consider the FcγRs engaged and Fc-effector functions involved. This review highlights the current state of knowledge about FcγRs and FcγR effector functions involved in virus neutralization, with emphasis on factors that can affect FcγR engagement. A better understanding of Fc-FcγR interactions during virus neutralization will allow development of therapeutic antibodies that are efficacious and can be administered with minimal side effects. [ABSTRACT FROM PUBLISHER]

Helminths induce strong regulatory and T helper 2-type responses, whereby antibody-derived host protection and regulation are essential components. Lymphatic filariasis is an immune-mediated spectral disease that manifests as two main clinical outcomes: chronic pathology or asymptomatic infection. These outcomes depend on a multitude of factors, including parasite-induced immunoregulation and host genetic background; antibody responses contribute to this outcome. N-glycosylation of the Fc region of antibodies is a post-translational modification required for the structure and molecular function, influencing host inflammatory and regulatory responses. Altered IgG glycosylation correlates with disease, whereby decreased galactosylation is associated with inflammation while increased sialylation is associated with anti-inflammatory responses. We purified N-linked glycans from the Fc region of total IgG from Wuchereria bancrofti-infected patients characterizing the two clinical manifestations (chronic pathology and asymptomatic infection) and compared them to infection-free endemic normals. Using capillary electrophoresis, we found that there was no difference in galactosylation of total IgG between the three groups; however, asymptomatically infected patients had significantly lower levels of disialylated IgG compared to endemic normals and patients with pathology. These data suggest that while galactosylation does not contribute to disease outcome, sialylation may be involved in asymptomatic infection. [ABSTRACT FROM AUTHOR]

Monocytes are important in the defense against fungal infections due to their phagocytic and immunoregulatory functions. Platelets also contribute in such immune responses through their release of soluble mediators, including chemokines as well as several other soluble mediators. Both monocytes and platelets express several Toll-like receptors (TLRs) that can recognize fungal molecules and thus initiate intracellular signaling events. TLR ligation on monocytes and platelets may thereby be an early immunological event and function as an initiator of a local proinflammatory crosstalk between platelets and monocytes resulting in (i) monocyte-induced increase of platelet activation and (ii) platelet-associated enhancement of the monocyte activation/function. These effects may have clinical implications both for the efficiency of antifungal treatment and for the predisposition to fungal infections, for example, increased predisposition in patients with thrombocytopenia/monocytopenia due to chemotherapy- or disease-induced bone marrow failure. [ABSTRACT FROM AUTHOR]

Since the first description in 1989 of CD4-Fc-fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc-fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non-clinical applications of Fc-fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc-fusion proteins for each application, with particular attention to the newer, less charted areas. [ABSTRACT FROM AUTHOR]

This review combines the data obtained before the beginning of the 1990s with results published during the last two decades. The predominant form of the IgM molecule is a closed ring composed of five 7S subunits and a J chain. The new model of spatial structure of the pentamer postulates nonplanar mushroom-shaped form of the molecule with the plane formed by a radially-directed Fab regions and central protruding portion consisting of Cμ4 domains. Up to the year 2000 the only known Fc-receptor for IgM was pIgR. Interaction of IgM with pIgR results in secretory IgM formation, whose functions are poorly studied. The receptor designated as Fcα/μR is able to bind IgM and IgA. It is expressed on lymphocytes, follicular dendritic cells, and macrophages. A receptor binding IgM only named FcμR has also been described. It is expressed on T- and B-lymphocytes. The discovery of new Fc-receptors for IgM requires revision of notions that interactions between humoral reactions involving IgM and the cells of the immune system are mediated exclusively by complement receptors. In the whole organism, apart from IgM induced by immunization, natural antibodies (NA) are present and comprise in adults a considerable part of the circulating IgM. NA are polyreactive, germ-line-encoded, and emerge during embryogenesis without apparent antigenic stimuli. They demonstrate a broad spectrum of antibacterial activity and serve as first line of defense against microbial and viral infections. NA may be regarded as a transitional molecular form from invariable receptors of innate immunity to highly diverse receptors of adaptive immunity. By means of interaction with autoantigens, NA participate in maintenance of immunological tolerance and in clearance of dying cells. At the same time, NA may act as a pathogenic factor in atherosclerotic lesion formation and in development of tissue damage due to ischemia/reperfusion. [ABSTRACT FROM AUTHOR]

The complexity and number of antigens (Ags) seen during an immune response has hampered the development of malaria vaccines. Antibodies (Abs) play an important role in immunity to malaria and their passive administration is effective at controlling the disease. Abs represent approximately 25% of all proteins undergoing clinical trials, and these ‘smart biologicals’ have undergone a major revival with the realization that Abs lie at the interface between innate and adaptive immunity. At least 18 Abs have FDA approval for clinical use and approximately 150 are in clinical trials, the majority for the treatment of cancer, allograft rejection or autoimmune disease. Despite these triumphs none are in development for malaria, principally because they are perceived as being too expensive for a disease mainly afflicting poor and marginalized populations. Although unlikely, at least in the foreseeable future, that Ab-based prophylaxis will be made available to the millions of people at risk from malaria, they may be incorporated into current vaccine approaches, since Abs act as correlates of protection in studies aimed at defining the best Ags to include in vaccines. Abs may also form the basis for novel vaccination strategies by targeting Ags to appropriate antigen presenting cells. Therefore, to develop the most efficacious vaccines it will be necessary to fully understand which Abs and Fc-receptors (FcRs) are best engaged for a positive outcome. [ABSTRACT FROM AUTHOR]

The binding of antigens with antibodies forms immune complexes in the body. Usually these complexes are eliminated by the system of mononuclear phagocytes without development of pathological changes. This review highlights principal mechanisms responsible for safe removal of immune complexes in primates and humans. Special attention is given to diseases known as “immune complex diseases”, when antigen-antibody complexes induce inflammatory reactions. The review considers key experimental works that significantly contributed to current knowledge of etiology and pathogenesis of type III hypersensitivity. Some factors of the development of immune complex syndrome such as level of humoral immune response to antigen, isotype and affinity of forming antibodies, the amount of immune complexes, and the consequences of their interaction with the complement system and Fc-receptors are analyzed based on the molecular mechanisms involved. The review contains a retrospective analysis of the most significant scientific achievements in immune complex pathology investigation within the last 100 years. [ABSTRACT FROM AUTHOR]

Abstract: The binding of IgG to receptors for the Fc region of IgG (FcγR) is a critical step for the initiation and the control of effector immune functions. Activating FcγR induce antibody-dependent cell cytotoxicity (ADCC), endocytosis of immune complexes followed by antigen presentation, phagocytosis, and release of cytokines or pro-inflammatory mediators. By contrast, inhibitory FcγR regulate immune responses by inhibiting the activation of B lymphocytes, monocytes, mast cells and basophils, induced through activating receptors. Studies with FcγR-deficient mice support the critical role of the different FcγR in the in vivo functional effects of therapeutic monoclonal antibodies. Structural studies have provided detailed insights in the molecular mechanisms that govern IgG/FcγR interactions. The importance of the sugar components linked to asparagine 297 in the function of IgG has been also highlighted. These data have led to the engineering of a new generation of monoclonal antibodies for therapeutic use with optimized effector functions. [Copyright &y& Elsevier]

Intravascular Schistosoma mansoni worms seem to take up immunoglobulins from blood by surface Fc-receptors, but the process whereby bound immunoglobulins are processed by the parasite is poorly understood. We here present morphological data suggesting that two distinct main processes are involved: Host immunoglobulins were seen at two distinct locations in the parasite: in the frontal part of the enteric tube, the oesophagus, and as a fine granular staining at the surface and in the subtegumental region. The latter staining pattern corresponds to host immunoglobulin localization in discrete organelle-like aggregates tentatively identified as 'discoid or elongate bodies' at the ultrastructural level using immunogold staining. Immunoglobulin uptake by intravascular worms was also demonstrated in vivo after passive administration of 125I-labelled rabbit and mouse immunoglobulins. Radiolabelled immunoglobulins were taken up by the worms and shown to localize as fine strands running perpendicular to the parasite surface. Our results suggest that intravascular schistosomes take up host immunoglobulins both as part of their enteric digestion and by a surface Fc-receptor-mediated mechanism, involving transport and processing within organelles, 'elongate bodies;. Immunoglobulins taken up by intravascular schistosomes form a distinct organelle-like granules, which seem to be processed within the excretory system of the parasite. [ABSTRACT FROM AUTHOR]

Abstract: The binding of IgG antibodies to receptors for the Fc region of IgG (FcγR) is a critical step for the initiation and/or the control of effector immune functions once immune complexes have been formed. Site-directed and random mutagenesis as well as domain-swapping, NMR and X-ray cristallography have made it possible to get detailed insights in the molecular mechanisms that govern IgG/FcγR interactions and to define some of the structural determinants that impact IgG binding to the various FcγR. It has demonstrated the role of particular stretches and individual residues located in the lower hinge region of the CH2 domain and in the CH2 and CH3 domains of the Fc region. The importance of the sugar components linked to asparagine 297 in the binding properties of IgG1, the human IgG isotype the most widely used in antibody-based therapies, has been also highlighted. These data have led to the engineering of a new generation of monoclonal antibodies for therapeutic use with optimized effector functions. [Copyright &y& Elsevier]

Abstract: We investigated capture and activation of flowing human neutrophils through their Fc-receptors, FcRγIIIB (CD16) and FcRγIIA (CD32). Immobilised platelets bearing murine monoclonal antibody against glycoprotein IIbIIIA were able to capture and activate flowing neutrophils. The activation response was inhibited by antibody blockade of neutrophil CD32. However, capture only occurred efficiently at wall shear stress below 0.1Pa if platelet P-selectin was blocked. If neutrophils were perfused over immobilised human IgG, many adhered at 0.025 or 0.05Pa, but not at 0.1Pa. Adhesion was reduced by blockade of CD16 or CD32, but blockade of CD16 had the greater effect. When neutrophils were perfused over a combination of purified P-selectin and IgG, blockade of CD16 and CD32 inhibited activation of captured cells. Immunoglobulin deposited in tissue could capture and activate slow-flowing neutrophils. It might also potentiate inflammatory responses at higher stress if presented along with selectins. The dominant FcR for capture of neutrophils was CD16, but with murine antibody, CD32 played a greater role. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DCs) are professional antigen presenting cells, which take up pathogens/foreign structures in peripheral tissues, then migrate to secondary lymphoid organs where they initiate adaptive immune responses by activating naive T-cells. In the early phase of antigen uptake pattern recognition receptors (including mannose-, scavenger- and toll-like receptors) that recognize pathogen-associated molecular patterns play an important role. Later receptors binding opsonized antigen are also involved in phagocytosis. These cell membrane molecules include various Fc-receptors, recognizing different isotypes of antibodies and various complement-receptors, such as CR3, CR4 and the C1q-binding complex of calreticulin and CD91. Here we aim to summarize how these immunecomplex binding receptors are involved in the initiation of DC maturation, and how they influence antigen presentation as well as some additional functions of these cells. [Copyright &y& Elsevier]

Abstract: Antibodies can act like adjuvants. They can potently enhance the antibody response, and in the case of IgG and IgE also the T cell response, to the very antigen they are specific for. In this review we will discuss the recent advances made in our understanding of the underlying mechanisms of antibody-mediated feedback enhancement. The immuno-stimulatory properties of IgM, IgG1, IgG2a, IgG2b, IgG3 and IgE will be reviewed in relationship to the complement system and Fc receptors and the physiological relevance will be discussed. [Copyright &y& Elsevier]

Abstract: Membrane C1q (mC1q) of macrophages (MΦ) is a precursor of the IgG-binding serum protein C1q. Thus, mC1q potentially provides one of several Fcγ binding sites of mature MΦ and we analyzed whether simultaneous expression occurs of established receptors for IgG, FcγRI, II, and III, and mC1q during in vitro differentiation of MΦ. Using flow cytometry, immunoprecipitation combined with Western blotting and Northern blot analysis mC1q was hardly detected in freshly isolated blood monocytes, but increasingly in developing monocyte-derived MΦ. Laser scanning fluorescence microscopy confirmed the membrane localization of mC1q. Two-color-staining flow cytometry experiments indicated that mC1q and all three types of FcγRs are simultaneously expressed on mature monocyte-derived MΦ. A high correlation was found for the expression of mC1q and FcγRs, in particular FcγRII, but not mC1q and CD14, another marker of monocytes/MΦ. [Copyright &y& Elsevier]

Antibodies of all classes and subclasses except IgD have been shown to have the capacity to feedback regulate the production of themselves . This phenomenon has been known for over a century and was originally described by the first Nobel laureate in physiology, Emil von Behring . When an animal is immunized with antibodies together with an antigen they recognize, the antibody response to this very antigen is often dramatically modulated. Sometimes feedback regulation results in complete suppression and sometimes in several 100-fold enhancement of the specific response. An immune complex contains the antigen, the specific antibodies bound to it and, when the antibodies can activate complement, complement factors, and can, therefore, bind to antigen-specific receptors on B cells (BCR), various Fc-receptors (FcRs) as well as to complement receptors. This gives the immune complex many possibilities to regulate the immune response via e.g. receptor cocrosslinking, leading to changes in signal transduction, or by increased antigen uptake and processing by antigen-presenting cells. This review will focus on the role of IgG as a feedback regulator. Three different pathways will be discussed: (i) the ability of IgG to induce complete suppression of erythrocyte responses, which takes place equally efficiently in the absence as in the presence of FcγRs, (ii) the ability of IgG to enhance responses to soluble protein antigens, a phenomenon severely impaired in FcRγ-chain-deficient mice (with non-functional FcγRI and FcγRIII), and (iii) the ability of IgG to, via FcγRIIB, downregulate the response to IgG-complexed soluble antigens. [Copyright &y& Elsevier]

Deficiency in the number and function of phagocytes is associated with gingival inflammation and periodontitis. A hereditary deficiency in membrane glycoproteins involved in granulocyte adherence causes impaired chemotaxis, reduced phagocytosis and periodontal problems. Virus infections of antigen- presenting cells interfere with immune responses and lead to seriously increased susceptibility to infections with bacteria which cause no problems in normal patients. Increased levels of IgG antibodies may limit penetration of antigens in the tissues, but at the cost of local inflammation and tissue injury. Mucosal inflammatory disease with increased local formation of IgG is more frequent in IgA deficient patients. The immunological homeostasis depends on a balance between the respective classes and subclasses of antibodies. Deficiencies in the IgA system may contribute to a disturbed balance of the humoral immune response to critical antigens from oral bacteria. A disproportional increase in IgG1 and IgG3 antibodies may persistently activate complement, stimulate the inflammatory activity and cause tissue injury. [ABSTRACT FROM AUTHOR]

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Histiocytic (HRC) and interdigitating (IDC) reticulum cells were obtained from human lymphoid tissue (lymph nodes, tonsils), suspended in cell culture medium and cultured. The suspended cells, which were identified by morphological and enzyme histochemical criteria, were studied for surface binding properties for Fc-receptors using erythrocytes coated with IgG. HRC show strong surface binding, IDC, somewhat weaker, but definitely positive surface binding. Both types of reticulum cells possess Fc-receptors; on IDC, however, they are fewer in number and less dense. In connection with recently discovered Fc-receptors on Langerhans cells of the epidermis, functional relationships between blood monocytes, Langerhans cells in skin and IDC in lymphoid tissue are discussed. [ABSTRACT FROM AUTHOR]

Copyright of Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We investigated the effect of chrysotherapy on the Fc and complement receptor binding activity of peripheral blood (PB) monocytes and peritoneal (PE) macrophages isolated from normal rats and rats with adjuvant induced arthritis. The adjuvant induced severe disease in Dark Agouti (DA) rats and less marked disease in J. C. Lewis (JC) rats. Gold treatment reduced the disease in DA rats but exacerbated the disease in JC rats. PB monocytes generally exhibited increased receptor activity after adjuvant injection. Gold treatment resulted in a simultaneous reduction of the PB monocyte receptor activity and increased the PE macrophage receptor activity. This was considered to be due to a direct effect of gold, since the Fc receptor activity of PE macrophages increased after in vitro gold treatment. [ABSTRACT FROM AUTHOR]

Polymorphonuclear leukocytes (PMNLs) are the most numberous cell population among the cellular infiltrates in gingival crevicular fluid (GCF) and play important roles in the host-defensive system in the gingival crevices. We determined the percentage of neutrophils, eosinophils and basophils in total PMNLs by light microscopic observation using Randolph-methylene blue staining, then assessed flow cytometric differences in the expression of CR3, FcγRIII, Fc∊RII, LFA-1α, and LFA-1β on PMNL in GCF and peripheral blood (PB) from 21patients with adult periodontitis (AP ) and 13 healthy donors. Percentages of basophils and eosinophils were higher in GCF than in PB. In both AP patients and healthy subjects, expression of CR3 and Fc∊RII was higher while FcγRIII was lower in GCF than in PB. The statistical analysis showed that the expressions of FcγRIII and Fc∊RII on GCF PMNLs were lower in AP patients than in healthy subjects. Expressions of LFA-1α and β on GCF were similar to those on PB PMNLs. PB PMNLs stimulated in vitro with Porphyromonas gingivalis culture supernatant and fMLP displayed an expression pattern of CR3, FcγRIII and Fc∊RII on GCF PMNLs. However, C5a and IL-1 failed to induce changes in FcγRIII and Fc∊RII> The results indicate that GCF neutrophils are activated, present enhanced adhesion and a decreased IgG-binding ability which would reflect that they are at the terminal stage of activation, and that GCF contains a larger eosinophil fraction than in PB. Moreover, these GCF eosinophils appear to be activated. [ABSTRACT FROM AUTHOR]